AU2017100960A4

AU2017100960A4 - Method of identifying a gene associated with a disease or pathological condition of the disease

Info

Publication number: AU2017100960A4
Application number: AU2017100960A
Authority: AU
Inventors: Lai Han Leung; Ying Li; Liang Liu; Hu Dan PAN; Xiao Jun Yao
Original assignee: Macau University of Science and Technology
Current assignee: Macau University of Science and Technology
Priority date: 2017-07-13
Filing date: 2017-07-13
Publication date: 2017-08-10
Anticipated expiration: 2025-07-13

Abstract

A method of identifying a gene associated with a disease or pathological condition of the disease, comprising the steps of: a) obtaining a first group of exome 5 sequences from a first population of individuals and a second group of exome sequences from a second population of individuals, wherein the first population of individuals suffer from the disease or pathological condition of the disease, and the second population of individuals do not have the disease or pathological condition of the disease; b) identifying one or more variants in the first group of exome sequences 10 by comparing the first group of exome sequences with the second group of exome sequences, and optionally with a public database, to generate a first set of variant data; c) applying a variant quality score calibration tool with a truth sensitivity threshold to remove false-positive variants having a sensitivity lower than the threshold and background variants from the first set of variant data so as to obtain a second set of 15 variant data; d) removing synonymous variants from the second set of variant data to obtain a third set of variant data; and e) identifying one or more deleterious variants from the third set of variant data using a gene burden analysis, optionally generating a fourth set of variant data. Ancestry composition (SNP used = 126,235) Ancestry cEu Fig. 1A MDS (SNP used = 126,235) 0.005 T; AA A *CEU E+ Patint a normals -0.05 -0.10 0.0 0.05 0.10 Dimension 1 Fig. 1B

Description

METHOD OF IDENTIFYING A GENE ASSOCIATED WITH A DISEASE OR PATHOLOGICAL CONDITION OF THE DISEASE 2017100960 13 Μ 2017

TECHNICAL FIELD 5 10

The present application relates to a method of identifying a gene associated with a disease or its pathological condition. In particular, but not exclusively, the method makes use of exome sequences for the identification.

BACKGROUND OF THE INVENTION

To date, there are various methods of determining the pathogenic gene form the human genome, for example, by whole-genome sequencing. Whole-exome sequencing (WES) has become a popular means for studying the genetic information, 15 in particular for investigating the disease related genes. However, WES studies are generally susceptible to genotyping errors which may significantly affect the results.

Rheumatoid arthritis (RA) is the most common form of systemic autoimmune arthritis with unknown etiology, characterized by systemic inflammation and persistent 20 poly-joint synovitis, principally leading to injury of the flexible joints, often with symptoms of joint pain and swelling, stiffness, bone destruction and fatigue, as well as implications of extra articular organs. The prevalence of RA varies largely in different populations, from 0.25% in Eastern Asians to 0.75% in European ancestry, and to as high as 6% in American Indians. It remains largely unknown whether genetics, cultural, 25 or environmental factors contribute to these differences. During the past years, an increasing list of genetic associations with RA has emerged from genome wide association studies (GWAS), which attributes great relevance to immune system contributed by profound sources of genetic variation with a panel of surface and intracellular signaling molecules as well as cytokines. GWAS has also revealed a 30 complex picture of both shared and population-specific genetic susceptibility loci to this autoimmune disease in comparison of Asian and European populations. Generally, GWASs are designed to capture common genetic variation, and to date, a large portion of the heritability of complex traits has not been explained, which has prompted us to explore other potential sources of genetic susceptibility to RA, such as rare variants. 35

Accordingly, there remains a strong need for an improved method for identifying deleterious and/or pathogenic gene which may be involved in the 1 progression, severity or reoccurrence of a disease, in particular an autoimmune disease highly related to genetic mutations. 2017100960 13 Μ 2017 SUMMARY OF THE INVENTION 5

The present invention provides a method of identifying a gene associated with a disease or pathological condition of the disease, comprising the steps of: a) obtaining a first group of exome sequences from a first population of individuals and a second group of exome sequences from a second population of 10 individuals, wherein the first population of individuals suffer from the disease or pathological condition of the disease, and the second population of individuals do not have the disease or pathological condition of the disease; b) identifying one or more variants in the first group of exome sequences by comparing the first group of exome sequences with the second group of exome 15 sequences, and optionally with a public database, to generate a first set of variant data; c) applying a variant quality score calibration tool with a truth sensitivity threshold to remove false-positive variants having a sensitivity lower than the threshold and background variants from the first set of variant data so as to obtain a second set of variant data; 20 d) removing synonymous variants from the second set of variant data to obtain a third set of variant data; and e) identifying one or more deleterious variants from the third set of variant data using a gene burden analysis, optionally generating a fourth set of variant data. 25 The method of the present invention is exceptionally useful for the determination of deleterious and/or pathogenic gene and for further developments in diagnostic method and treatment methods of the diseases and alleviation of the pathological conditions of the disease. In particular, the method at least improves the genotype accuracy of the results, removes substantial errors resulting from the whole- 30 exome sequencing, and differentiates the rare variants from the common variant efficiently.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The 35 invention includes all such variations and modifications. The invention also includes all steps and features referred to or indicated in the specification, individually or collectively, and any and all combinations of the steps or features. 2

Other features and aspects of the invention will become apparent by consideration of the following detailed description and accompanying drawings. 2017100960 13 Μ 2017

5 BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the ancestral composition of RA group, i.e. patients suffering from RA, and control group, i.e. people who do not have RA, with Hapmap reference populations. Ten HapMap samples were randomly chosen from each of the three 10 reference populations: CEU, Utah Residents with Northern and Western European Ancestry; CHS, Southern Han Chinese; and YRI, Yoruba in Ibadan, Nigeria. Fig. 1A shows the results obtained from Admixture analysis. All of the people in RA group and control group were found to be Chinese ancestry, i.e. having at least 80% (indicated by white horizontal line) Chinese ancestry. Fig. 1B shows Dimension 1 and 2 obtained 15 from multidimensional scaling analysis for the RA and control groups.

Fig. 2 shows the coverage distribution for all exons targeted by enrichment evaluated by inter-quartile range calculation using SPSS 22.0 software. Fig. 2A shows that the median coverage for all RA samples was 76-fold, with on average 96% of all 20 targets covered at least 20-fold. Fig. 2B shows that the median coverage for all healthy control samples was 68-fold, with on average 94% of all targets covered at least 20-fold.

Fig. 3 is a flow chart of whole-exome sequencing for detecting and prioritizing 25 variants conferring susceptibility to rheumatoid arthritis (RA) using variant filtration and gene burden analysis. The variant list for all groups can be found in Table 5. MAF = minor allele frequency in the 1000 Genomes Southern Han Chinese (phase III) population. Pathway analysis in candidate genes identified from 58 RA patients was performed using DAVID 6.8 (https://david.ncifcrf.gov/summarv.isp)· 30

Fig. 4 shows the sequence alignment of target proteins. Fig. 4A refers to the SAA1 (Protein RefSeq: NP_000322.2; Fig. 4B refers to SCOT1 (Protein RefSeq: NP_000427.1), each with its template structures used in homolog modeling. Red line represents alpha helix, yellow arrow represents beta sheet, and blue line represents 35 loop region. 3

Fig. 5 shows Ramachandran plots for evaluation of protein model. Fig. 5A refers to the plot for SAA1, 99.03% of the residues are in the favored region and 0.97% are in the allowed region. Fig. 5B refers to the plot for SCOT1,95.81% of the residues are in the favored region, 3.77% are in the allowed region and only 0.42% are in the 5 disfavored region. Green represents favored region and light-brown represents allowed region. 2017100960 13 Μ 2017

Fig. 6 shows the modeled 3D structure comparison of human wild type SAA1 (Fig. 6A) and its mutant G90D (Fig. 6B), as well as wild type SCOT1 (Fig. 6C) and its 10 mutant T58M (Fig. 6D). Left panel: the ribbon secondary structure diagram with a helices in red and β sheets in yellow; middle panel: the proposed interactions between mutated residue and its surrounding residues, distances are not represented to scale; right panel: the lipophilic surface representation by showing hydrophilic (magenta), neutral (green) and lipophilic (white). 15

Fig. 7 shows the comparison of X chromosome associated variants distribution between female and male in RA patients.

20 DETAILED DESCRIPTION OF THE EMBODIMENTS

Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one skilled in the art to which the invention belongs. 25

As used herein, “comprising” means including the following elements but not excluding others. “Essentially consisting of means that the material consists of the respective element along with usually and unavoidable impurities such as side products and components usually resulting from the respective preparation or method 30 for obtaining the material such as traces of further components or solvents. “Consisting of means that the material solely consists of, i.e. is formed by the respective element. As used herein, the forms “a,” “an,” and “the,” are intended to include the singular and plural forms unless the context clearly indicates otherwise. 35 The present invention pertains to a method of identifying a gene associated with a disease or pathological condition of the disease. In particular, the disease is an autoimmune disease, a neurodegenerative disease, a cardiovascular disease, a 4 cancer, a gastrointestinal disease, an inflammatory disease, or an endocrine disease. Preferably, the disease is an autoimmune disease. In an embodiment, the disease is rheumatoid arthritis. The expression “pathological condition of the disease” as used herein may refer to any symptoms closely related to the systemic effects of the disease 5 which may be acute or chronic. 2017100960 13 Μ 2017

According to the present invention, the method comprises the steps of: a) obtaining a first group of exome sequences from a first population of individuals and a second group of exome sequences from a second population of 10 individuals, wherein the first population of individuals suffer from the disease or pathological condition of the disease, and the second population of individuals do not have the disease or pathological condition of the disease; b) identifying one or more variants in the first group of exome sequences by comparing the first group of exome sequences with the second group of exome 15 sequences, and optionally with a public database, to generate a first set of variant data; c) applying a variant quality score calibration tool with a truth sensitivity threshold to remove false-positive variants having a sensitivity lower than the threshold and background variants from the first set of variant data so as to obtain a second set of variant data; 20 d) removing synonymous variants from the second set of variant data to obtain a third set of variant data; and e) identifying one or more deleterious variants from the third set of variant data using a gene burden analysis, optionally generating a fourth set of variant data. 25 The term “exome sequence” as used herein refers to a sequence consisting of all expressed genes in a genome, i.e. formed by exons that encode a part of the final mature RNA produced by the gene after introns have been removed by RNA splicing. In the present invention, the exome sequence of the individuals is preferably obtained through whole-exome sequencing. 30

An individual in the present invention is preferably a human or an animal, preferably the individual is a mammal. In an embodiment, the first population of individuals are preferably humans suffering from an autoimmune disease in particular rheumatoid arthritis and are diagnosed according to standard medical criteria. The 35 second population of individuals are humans who do not have the disease, in particular the autoimmune disease, and do not have the associated pathological conditions of the disease. In an embodiment, each of the first and second population of individual 5 has at least 10, 20, 30, 40, or 50 individuals, preferably at least 50 individuals. The first and second population may or may not have the same number of individuals. 2017100960 13 Μ 2017

The step a) of the method may comprise steps of collecting plasma samples 5 from the first and second population of individuals, extracting the DNAs from the plasma samples and performing whole-exome sequencing (WES) to obtain the exome sequence of each of the individuals. Preferably, the first and second exome data are obtained by whole-exome sequencing. It is advantageous to use the WES in the present invention so as to focus on the mutation of gene and/or variant which 10 contributes or likely contributes to the pathogenesis and/or progression of the disease.

In particular, it saves lots of efforts and costs in preparing a whole genome and conducting the analysis of the lengthy genome. The person having ordinary skills in the art is aware of suitable methods for performing whole-exome sequencing. 15 In step b) of the method, one or more variants in the first group of exome sequences are identified. The term “variant” as used herein refers to a polynucleotide having a nucleotide sequence different from the reference polynucleotide, i.e. there is a change in the nucleotide sequence compared to the reference one. In this method, the second group of exome sequences act as the reference polynucleotide, optionally 20 normal exome sequences annotated by public accessible database can also provide the reference polynucleotide for the comparison so as to locate and identify the one or more variants present in the first group of exome sequences, i.e. present in the individuals suffering from the disease or the pathological condition of the disease. After the identification, a first set of variant data is obtained and said set of variant data is 25 presented in a computer-readable format. In an embodiment, the first set of variant data is further subject to electronic conversion of format, for instance for subsequent sequence alignment and/or for storage.

After obtaining the first set of variant data which shows the differences between 30 the first group of exome sequences with the second group of exome sequences, a variant quality score calibration tool is applied, i.e. step c) of the method. In an embodiment, the step (c) comprises a step (i) of applying the variant quality score calibration tool with the truth sensitivity threshold of about 90% to remove the falsepositive variants, and removing the background variants having a read depth of less 35 than 5 and a genotype quality of less than 10 from the first set of variant data. “Variant quality score recalibration tool” (VQSC tool) is preferably applied to improve concordance of sequenced genotype, i.e. remove errors resultant from the whole- 6 exome sequencing. In general, VQSC too! filters variants by using a recalibrated quality score and a sensitivity threshold. In an embodiment herein, the VQSC tool is applied with a truth sensitivity threshold of about 90%, preferably about 95%, more preferably about 99%, to remove the false-positive variants. 2017100960 13 Μ 2017 5

Also, the background variants having a read depth of less than 5, preferably less than 7.5, more preferably less than 10 and a genotype quality of less than 10, less than 15 or less than 20 are also removed from the first set of variant data. In an embodiment, the background variant having a read depth of less than 10 and a 10 genotype quality of less than 20 are moved. These background variants refer to the variants which may significantly affect the detection of deleterious variants in the later steps and are likely generated by errors or not relevant to the disease. The term “depth of data” (DP) refers to the number of reads passing quality control used to calculate the genotype at a specific site in the sample. A higher value of DP generally denotes 15 a more accurate genotype call. The term “genotype quality” (GQ) refers to a Phred-scaled value representing the confidence that the called genotype is the true genotype. A higher GQ generally denotes a more accurate genotype call. Therefore, by using the variant filtering process of step c), a more accurate set of variant data may be obtained. 20 In an advanced embodiment, the step c) of the method further comprises a step (ii) of screening the resultant variants from step c) (i) based on the dataset provided by UCSC genome browser, in particular based on UCSC genome browser build 37 human reference sequence gene annotation, to keep exonic or slicing variants in the second set of variant data. Alternatively, other accessible dataset showing the already 25 identified variants in human genome may also be applied in combination to better analyze the variants.

Next, the second set of variant data is subject to a further variant filter to remove synonymous variants so as to obtain a third set of variant data. Synonymous 30 variants are commonly regarded as benign in their effects towards diseases, in particular less likely to have any effect, and are generally not overexpressed in an individual suffering from a disease or pathological condition. This removal step may be conducted by computer-implemented program and/or in combination with database having annotation of the synonymous variants. 35

In the method of the present invention, a gene burden analysis is conducted to identify one or more deleterious variants from the third set of variant data obtained 7 after step d). The term “deleterious variant” used herein refers to a variant which is consistently appear to cause all reasonable individuals to cause premature death or health problem, i.e. disease, that significantly com promise the capacity of the individual to carry out normal activities. In other words, the deleterious variant is highly related to 5 the disease or pathological condition of the disease. 2017100960 13 Μ 2017

Preferably, the step e) comprises a step (i) of identifying one or more deleterious variants having a gene burden ratio of larger than 1, preferably larger than 1.2 or more preferably larger than 1.5, or being present in the first group of exome 10 sequences in an amount of at least three but absent in the second group of exome sequences. The gene burden ratio is calculated by dividing the allele frequency in the first group of exome sequences by the allele frequency in the reference group, i.e. the second group of exome sequences and optionally an additional control group. 15 In a further embodiment, the step e) further comprises a step (ii) of grouping the identified one or more deleterious variants having a minor allele frequency less than or equal to about 0.02, preferably less than or equal to 0.015, less than or equal to 0.01, most preferably less than 0.01, into a rare variant group, and grouping the rest of the identified one or more deleterious variants into a common variant group. Minor 20 allele frequency (MAF) generally refers to the frequency at which the second most common allele occurs in a given population. The identification of rare and common variants helps to investigate the genetic susceptibility of the individual to the disease.

The method may further comprises a step f), after step e), of determining a 25 pathogenic gene associated with the disease or pathological condition of the disease from the fourth set of variant data by using a logistic regression model and public accessible database. The term “pathogenic gene” refers to a gene that contributes or likely contributes to the pathogenesis and progression of the disease. 30 In a further embodiment, the method further comprises a biological pathway analysis to determine the functional role of the identified one or more deleterious variants in the onset, progression, severity or recurrence of the disease. In particular, a structural analysis may be performed by using a homology model for 3D determination of the associated protein. 35 8

In order to improve the accuracy of the identification, the method further comprises a step of confirming the ethnicity of the first and second population of individuals via ancestry composition analysis. 2017100960 13M2017 5 Accordingly, the present invention provides an improved approach for the identification of deleterious and/or pathogenic variants involved in the disease onset, progression, severity or recurrence of a disease. The comprehensive method as disclosed herein at least improves the genotype accuracy of the results, removes substantial errors resulting from the whole-exome sequencing, and differentiates the 10 rare variants from the common variant efficiently. The application of whole-exome sequencing also saves lots of efforts in preparing whole-genome which may contain substantial irrelevant genetic information of the disease, and of course less labor intensive. 15 The method of the present invention is exceptionally useful for the determination of deleterious and/or pathogenic gene for further developments in diagnostic method and treatment methods of the diseases and alleviation of the pathological conditions of the disease.

20 EXAMPLES EXAMPLE 1 Sample collections 1. Patients 25 58 patients diagnosed as having RA were unrelated individuals of Han Chinese descent recruited from hospitals in Southern and Eastern China (Guangzhou and Changzhou) using 2010 Rheumatoid Arthritis Classification Criteria established by American College of Rheumatology and European League Against Rheumatism Collaborative Initiative (2010 ACR/EULAR). 30

In addition, 66 healthy and unrelated blood donors of Han Chinese ancestry from Medical Center for Physical Examination and Health Assessment, were included as controls. 35 Detailed descriptions of sequenced individuals and clinical characteristics of the enrolled patients are provided in Table 1 and 2. Written informed consent was obtained from all of the participants, and the study was registered in Chinese Clinical 9 2017100960 13 Μ 2017

Trial Registry (ChiCTR-ROC-17010351) and approved by the local ethics committees of Macau University of Science and Technology (Macau, China).

Table 1: Basic information of the 124 sequenced individuals Parameter Cases Controls n 58 66 Sex 43 female, 15 male 41 female, 25 male Age 48.48±14.08 35.23±10.73 Table 2: Demographic and clinical characteristics of the 58 patients with RA

Women/men, no. (%) Age at diagnosis, mean + SD years 43 (74.1%)/ 15(25.9%) All 45.17+14.13 Women 43.67+12.67 Men 49.47 + 17.46 Disease duration (years), mean± SD 3.31+4.29 <1 Year 26 >3 Year 23 Rheumatoid factor +/-, no.(%) 49 (87.5%) / 7 (12.5%); 2 Not Test No. of tender joints, mean + SD 7.00 + 7.36 No. of swollen joints, mean + SD 3.43+4.53 CRP(mg/l) 19.46 + 22.62 ESR(mm/h) 40.38 + 30.48 CRP: C-reactive protein; ESR: Erythrocyte Sedimentation Rate. 10 2. Confirmation of the ethnicity of the RA and control groups

The ethnicity of the patients suffering from RA, i.e. RA group, and the healthy control group was verified by conducting ancestry composition analysis using admixture v1.3.0 (https://www.genetics.ucla.edu/software/admixture) and 15 multidimensional scaling in PUNK v1.07 (http://zzz.bwh.harvard.edU//plink/). The results are shown in Fig. 1. Three ethnic populations were used as reference samples from 1000 Genome Project Phase III data (http://ftp.1000qenomes.ebi.ac.uk/vol1/ftp/release/20130502/ALL.chr9.phase3 shape it2 mvncall integrated v5a.20130502.qenotypes.vcf.qz), including Utah Residents 20 with Northern and Western European Ancestry (EUR-CEU), Yoruba in Ibadan, Nigeria (AFR-YRI) and Southern Han Chinese (EAS-CHS). 10 3. Preparation of the samples for gene sequencing 2017100960 13 Μ 2017

Blood samples were collected from the patients of the RA group and the healthy people from the control group, according to protocols approved by local institutional 5 review boards. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) using PureLink® Genomic DNA Mini Kit (Invitrogen, USA) according to the manufacturer’s protocol. 500 ng of double-stranded DNA was determined by Qubit (Invitrogen, USA) and randomly fragmented to 150-200bp with Covaris cracker (Covaris, USA). Fragments with specific indexes were hybridized with probes. After 10 PCR amplification and quality control, libraries were sequenced by next-generation sequencing. Agilent liquid phase hybridization was applied to efficiently enrich whole exons which would be sequenced on lllumina platform. Agilent SureSelect Human All ExonV5A/6 (Agilent Technologies, USA) with reagents were used for sequencing libraries and capture, which was recommended by the instruction manual and followed 15 by optimized experimental procedures.

Sequencing was performed on an lllumina HiSeq X sequencer with a paired-end read length of 150bp in the Genomics Core Facility at Novogene (Genome Sequencing Company, Beijing, China). Data generated in this study will be submitted 20 to the National Center for Biotechnology Information (NCBI) BioProject. EXAMPLE 2

Preparation of a list of candidate genes associated with rheumatoid arthritis 25 A list of 159 candidate RA-associated genetic variants reported by previous genome wide association studies (GWAS) with the P value threshold of P < 1 x 10 5, as shown in Table 3, was prepared based on Rheumatoid Arthritis associated genes in the NHGRI GWAS Catalog (Welter D et al., Nucleic acids research 2014; 42:D1001-D1006) and literatures (Freudenberg J etal., Arthritis Rheumatol 2014;66:1121-1132; 30 Manolio TA et al., Nature 2009;461:747-753; Okada Y et al., Nature 2014;506:376-381; and Diogo D et al., The American Journal of Human Genetics 2013;92:15-27).

Table 3: A list of candidate genes having high priority in RA

Gene SNP p-Value Odd ratio References ABHD6 ACOXL AFF3 AHNAK2 rs73081554 rs6732565 rs9653442|rs116 76922|rs108650 35 rs2582532 5.00E-08 3.00E-08 1.00E-14|1.00E- 14|2.00E- 08|2.00E-06 3.00E-07 1.18 1.07 1.12|1.12|1.12 1.17 Okada Y,PMID: 24390342 Okada Y.PMID: 24390342 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Jiang L.PMID: 24782177|Stahl EA.PMID: 20453842 Okada Y.PMID: 24390342 11 2017100960 13 Μ 2017 AIRE rs2075876]rs760 426 4.00E-09|4.40E- 08 1.18|1.16 ANAPC4 rs3816587 9.00E-06 1.09 ANKRD55 rs77331626|rs77 31626jrs685921 9 7.00E-24|8.00E-23j 1.00E-11 1.21 j 1.2111.28 ANXA3 rs2867461 1.00E-12 1.13 APOM rs805297 3.00E-10 1.56 ARAP1 rs3781913 6.00E-10 1.12 ARHGEF3 rs2062583 rs71508903|rs71 2.16E-06 1.00E-08]1.00E-08J6.00E-18 0.63 ARID5B 508903|rs10821 944 1.18|1.18|1.16 ARL15 rs255758 7.00E-06 1.42 ATG5 rs9372120 4.00E-08 1.10 ATM chr11:10796735 0 1 00E-08 1.21 B3GNT2 rs13385025|rs11 9.00E-07|1.00E- 1.11(1.11 900673 08 BATF rs7155603 1.00E-07 1.16 BLK rs2736337]rs160 0249|rs2736340 2.00E-07|5.00E- 06|1.22E- 05|6.00E-09 1.15j0.77|1.29|1 19 BTNL2 rs3763309 2.00E-124 2.30 C1QBP rs72634030 2.00E-09 1.12 C4orf52 rs11933540 1.00E-16 1.15 C5 rs10985070|rs37 4.00E-09I2.00E- 1.09|1.13|NR 61847| rs881375 07|4.00E-Q8 C5orf30 rs2561477|rs262 32 1.00E-10j4.00E- 08 1.09(1.14 C6orf10 rs9275406 3.00E-12 2.10 CASP8 rs6715284 2.00E-09 1.15 CCL19 rs11574914 2.00E-15 1.13 CCL21 rs951005|rs281 4.00E-10|3.00E- 1.19(1.1211.13 2378|rs1157491 4 08|2.00E-15 CCR6 rs1571878|rs30 1,00E-22|2.00E- 1.28|1.13|NR|N 93023|rs185485 11 J4.00E- R 3|rs3093024 09|2.00E- 10|8.00E-19 CD2 rs624988 8.00E-10 1.09 CD226 rs2469434 1.00E-08 NR CD244 rs11265493|rs3 4.10E-07]8.00E- 1.28(1.3)1.31 (1. 753389|rs37663 08|3.00E- 28|1.31 79|rs1319651 |rs 08|6.40E- 6682654 07|7.00E-08 CD247 rs84Q016 2.00E-06 1.11 CD28 rs 1980422 2.00E-13 1.13 CD40 rs4239702|rs48 1.00E-16|3.00E- 1 14|0.85|1.15 10485 09|8.00E-09 CD5 rs508970 3.00E-06 1.07

Terao C,PMID: 21505073|Terao C.PMID:21505073 WTCCC.PMID: 17554300 Okada Y.PMID: 24390342|Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 Okada Y.PMID: 22446963 Hu HJ.PMID: 21844665 Okada Y,PM!D: 22446963 Freudenberg J.PMID: 21452313 Okada Y.PMID: 24390342|Okada Y.PMID: 24390342|Okada Y.PMID:22446963 Negi S.PMID: 23918589 Okada Y.PMID: 24390342

Okada Y.PMID: 24390342

Okada Y.PMID: 24390342|Okada Y.PMID:22446963 Stahl EA.PMID: 20453842 Okada Y.PMID: 24390342|Freudenberg J.PMID: 21452313|Freudenberg J.PMID: 21452313|Gregersen PK.PMID: 19503088

Orozco G.PMID: 24449572 Okada Y.PMID: 24390342

Okada Y.PMID: 24390342

Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Gregersen PK.PMID: 19503088 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 Negi S.PMID: 23918589 Okada Y.PMID: 24390342 Okada Y.PMID: 24390342 Stahl EA.PMID: 20453842|Raychaudhuri S.PMID: 18794853|Okada Y.PMID:24390342 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842]Jiang L.PMID: 24782177|Jiang L.PMID: 24782177|Kochi Y.PMID:20453841 Okada Y.PMID: 24390342 Okada Y.PMID: 24390342 Suzuki A.PMID: 18794858|Suzuki A.PMID: 18794858|Suzuki A.PMID: 18794858|Suzuki A.PMID: 18794858|Suzuki A.PMID: 18794858

Stahl EA.PMID: 20453842 Okada Y.PMID: 24390342 Okada Y.PMID: 24390342|Stah! EA.PMID: 20453842|Raychaudhuri S.PMID:18794853 Okada Y.PMID: 24390342 12 2017100960 13M2017 CD83 chr6:14103212|r S12529514 3.00E-06|2.00E- 08 1.16|1.14 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 CDK2 rs773125 1.00E-10 1.09 Okada Y,PMID: 24390342 CDK4 rs1633360 1.00E-07 1.07 Okada Y.PMID: 24390342 CDK5RAP2 rs12379034 1.00E-12 1.34 Jiang L.PMID: 24782177 CDK6 rs4272|rs42041 1.00E-08|4.00E-06 1.10|1.11 Okada Y.PMID: 24390342|Raychaudhuri S.PMID:18794853 CEP57 rs4409785 1.00E-11 1.12 Okada Y.PMID: 24390342 CFLAR rs6715284 2.00E-09 1.15 Okada Y.PMID: 24390342 CLNK rs13142500 2.00E-06 1.10 Okada Y.PMID: 24390342 CLYBL rs9557321 6.00E-08 1.73 Bossini-Castillo L.PMID: 24532677 COG6 rs9603616 2.00E-12 1.10 Okada Y.PMID: 24390342 CSF2 rs657075|rs657 075 6.00E-06|3.00E- 10 1.12J1.12 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 CSF3 chr17:38031857 2.00E-12 1.09 Okada Y.PMID: 24390342 Gene SNP p-Va!ue Odd ratio References CTLA4 rs3087243|rs30 87243|rs231775 |rs231735 3.00E-25I1.00E- 08|6.30E- 07|6.00E-09 1.14|1.15|1.09|N R Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Doroth??e Diogo,PMID:23261300|Gregerse n PK.PMID: 19503088 CXCR5 rs10790268 1.00E-15 1.14 Okada Y.PMID: 24390342 DNASE1L3 rs73081554 5.00E-08 1.18 Okada Y.PMID: 24390342 DPP4 rs12617656 1.00E-08 1.24 Jiang L.PMID: 24782177 EOMES rs3806624 3.00E-08 1.08 Okada Y.PMID: 24390342 ETS1 rs73013527jrs4 937362 1.00E~06|8.00E- 07 1.08)1.09 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 ETV7 rs2234067 1.60E-09 1.15 Okada Y.PMID: 24390342 FADS1 rs968567 2.00E-08 1.12 Okada Y.PMID: 24390342 FADS2 rs968567 2.00E-08 1.12 Okada Y.PMID: 24390342 FADS3 rs968567 2.00E-08 1.12 Okada Y.PMID: 24390342 FAM124A rs3790022 1.00E-06 1.49 Bossini-Castillo L.PMID: 24532677 FCGR2A rs72717009jrs1 801274|rs11810 143 1.00E-07|2.40E-07|1.80E-07 1.13|1.10|1.14 Okada Y.PMID: 24390342|Doroth??e Diogo,PMID:23261300|Doroth?? e Diogo,PMID:23261300 FCRL3 rs2317230 2.00E-07 1.07 Okada Y.PMID: 24390342 FLI1 rs4937362 8.00E-07 1.09 Okada Y.PMID: 22446963 GATA3 rs3824660 2.00E-08 1.08 Okada Y.PMID: 24390342 GATSL3 rs1043099 7.00E-09 1.19 Orozco G.PMID: 24449572 13 GCH1 rs3783637 GMCL1L rs2961663 GPR125 rs6448119 GRHL2 rs678347 GRM5 rs518167 HLA rs12194148|rs2 157337 HLA-B rs2596565 HLA-DQA1 rs9271348|rs64 57617|rs927540 6 HLA-DQA2 rs12525220|rs6 457617|rs92754 06 HLA-DQB1 rs12525220|rs9 275406 Gene SNP HLA-DRB1 rs9268839|rs92 68839jrs691007 1|rs7765379|rs1 3192471 Irs6608 95|rs6457620|rs 615672|rs92713 48 IFNGR2 rs73194058 IGFBP1 rs6956740 IKZF3 chr17:38031857 |rs2872507 IL2 rs45475795|rs1 3119723 IL20RB rs9826828 IL21 rs45475795|rs1 3119723 IL2RA rs706778|rs706 778|rs2228150|r s2104286 IL2RB rs3218251 IL3 rs657075 IL6R rs2228145 IL6ST rs6859219 INPP5B rs28411352 intergenic rs12413578

2.00E-06 1.10 4.00E-06 NR 7.00E-06 NR 2.00E-08 1.08 2.00E-06 2.24 5.00E-58|9.00E- 52 NR|NR 9.00E-09 1.40 5.00E-07|1.00E- 09|3.00E-12 1.28|NR|2.10 2.0QE-13j1,00E- 09|3.00E-12 2.87|NR|2.10 2.00E-13|3.00E- 12 2.8712.10 p-Value Odd ratio 1.00E-250|1.00E- 2.47|2.47|2.88|2 250|1.00E- ,51|NR|3.62|2.5 299|5.00E- 23|2.00E- 58|1.00E- 108|4.00E- 186|8.00E- 27|5.00E-07 5|NR|1.28 1.00E-06 1.08 5.00E-07 NR 2.00E-12|9.00E- 07 1.09|1.10 4.00E-06]7.00E- 07 1.14|1.12 9.00E-10 1.44 4.00E-06|7.00E- 07 1.14)1.12 5.00E-14|1.00E- 1.1011.14)1.25)1 11|6.60E- 06|1.00E-06 .19 6.00E-06 1.08 6.00E-06 1.12 4.00E-09 1.08 1.00E-11 1.28 3.00E-12 1.11 5.00E-08 NR 2017100960 13 Μ 2017

Okada Y.PMID: 22446963

Padyukov L.PMID: 21156761

Okada Y.PMID: 24390342

Bossini-Castillo L.PMID: 24532677 Padyukov L.PMID: 21156761 (Padyukov L.PMID: 21156761

Bossini-Castillo L.PMID: 24532677

Bossini-Castillo L.PMID: 24532677|Julia A.PMID: 18668548|Negi S.PMID: 23918589

Jiang L.PMID: 24782177|Julia A.PMID: 18668548|Negi S.PMID:23918589 Jiang L.PMID: 24782177|Negi S.PMID:23918589 References

Padyukov L.PMID: 21156761

Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 Okada Y.PMID: 24390342

Okada Y.PMID: 24390342|Stah! EA.PMID: 20453842 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Doroth??e Diogo,PMID:23261300|Orozco G.PMID: 24449572 Okada Y.PMID: 24390342

Okada Y.PMID: 24390342

Stahl EA.PMID: 20453842

Okada Y.PMID: 24390342

Okada Y.PMID: 24390342 14 IRAKI rs5987194 IRF4 rs9378815 IRF5 chr7:128580042 |rs104886311 rs3 807306 IRF8 rs13330176|rs2 280381 JAZF1 rs67250450 KCNIP4 rs6448119 KIF3 rs17374222 KIF5A rs1678542|rs16 78542 LBH rs10175798 Gene SNP LOC100506 023 rs2105325 LOC100506 403 rs8133843 LOC145837 rs8026898 LOC339442 rs12140275 MED1 rs1877030 MHC rs7748270|rs64 57617|rs125252 20 MICA rs2596565 MMEL1 chr1:2523811 |rs 3890745 MTF1 rs28411352 NFKBIE rs2233424|rs22 33434 OLIG3 rs2230926|rs69 20220|rs104991 94 P2RY10 chrX:78464616 PADI4 rs2301888|rs22 40335 PDE2A rs3781913 PIP4K2C rs 1678542 PLCL2 rs4452313 PLD4 rs2582532|rs28 41277 3.00E-12 1.16 1.00E-07 1.09 1.00E-14I4.00E-1113.00E-07 1.12| 1.19|1.44 1,00E-12|2.00E-06 1,12| 1.12 3.00E-09 1.11 7.00E-06 NR 2.00E-06 1.13 1.00E-07|9.00E- 08 1.20|1.12 1.00E-09 1.08 p-Value Odd ratio 3.00E-11 1.12 2.00E-08 1.09 4.00E-19 1.15 2.00E-09 1.11 2.00E-08 1.09 1.00E-16]5.00E-75 |2.00E-13 2.0112.36|2.87 9.00E-09 1.40 5.00E-09|1.00E- 07 1.10|1.12 3.00E-12 1.11 1.00E-19|6.00E-19 11.00E-15 1.26|1.19 2.00E-06|1.00E-07 11 ,ΟΟΕ-09 1.3111.22|1.33 4.00E-08 1.11 1.00E-18|2.00E- 08 1.13|1.50 6.00E-10 1.12 9.00E-08 1.12 2.00E-10 NR 3.00E-07|2.00E- 14 1.17| 1.15 2017100960 13 Μ 2017

Okada Y.PMID: 24390342

Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Padyukov L,PMID: 21156761 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963

Okada Y.PMID: 24390342

Padyukov L.PMID: 21156761

Stahl EA.PMID: 20453842

Orozco G.PMID: 24449572|Raychaudhuri S.PMID:18794853 Okada Y.PMID: 24390342

References

Okada Y.PMID: 24390342

Jiang L.PMID: 24782177|WTCCC,PMID: 17554300|Jiang L.PMID: 24782177

Bossini-Castillo L.PMID: 24532677 Okada Y.PMID: 24390342|Raychaudhuri S.PMID:18794853 Okada Y.PMID: 24390342

Okada Y.PMID: 24390342]Okada Y.PMID: 22446963|Myouzen K.PMID: 23028356

Kochi Y.PMID: 20453841 |Plenge RM.PMID: 17982456|Plenge RM.PMID: 17982456 Okada Y.PMID: 24390342

Okada Y.PMID: 24390342|Freudenberg J.PMID: 21452313

Okada Y.PMID: 22446963

Raychaudhuri S.PMID: 18794853

Okada Y.PMID: 24390342

Okada Y.PMID: 24390342]Okada Y.PMID: 22446963 15 2017100960 13 Μ 2017 POU3F1 rs12131057 4.00E-07 1.16 Stahl EA.PMID: 20453842 PPIL4 rs9373594 3.00E-09 1.09 Okada Y.PMID: 24390342 PRKCB1 rs7404928 4.00E-06 1.08 Okada Y.PMID: 22446963 PRKCH rs3783782|rs19 57895 2.00E-09|4.00E- 07 1.14| 1.09 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 PRKCQ rs947474|rs475 0316 3,00E-10|2.00E- 06|4.00E-06 1.12|1.15|1.14 Okada Y.PMID: 24390342|Stahi EA.PMID: 20453842|Raychaudhuri S.PMID:18794853 PTPN11 rs10774624 7.00E-09 1.09 Okada Y.PMID: 24390342 PTPN2 rs8083786|rs28 47297 2.0QE-11 |2,00E-08 1.18| 1.10 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 PTPN22 rs2476601 |rs24 76601 ]rs667967 7 9.00E-170|9,00E- 74|0|1.00E- 08|6.00E- 42|6.00E-25 1.80|1.94|1.82|1 .7911.98 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Doroth??e Diogo,PMID:23261300|Padyuko vL.PMID: 21156761 jRaychaudhuri S.PMID: 18794853|WTCCC,PMID: 17554300 Gene SNP p-Value Odd ratio References PVT1 rs1516971 1.00E-10 1.15 Okada Y.PMID: 24390342 PXK rs73081554|rs1 3315591 5.00E-08|5.00E- 08 1.18|1.29 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 RAD51B rs1950897 5.00E-08 1.09 Okada Y.PMID: 24390342 RAG1 rs331463 1.00E-07 1.12 Okada Y.PMID: 24390342 RAG2 rs331463 1.00E-07 1.12 Okada Y.PMID: 24390342 RASGRP1 rs8032939 2.00E-18 1.13 Okada Y.PMID: 24390342 RBPJ rs874040|rs644 8432 1.00E-16|4.00E- 07 1.14|1.19 Stahl EA.PMID: 20453842|Orozco G.PMID: 24449572 RCAN1 chr21:35928240 3.00E-07 1.11 Okada Y.PMID: 24390342 REL rs34695944|rs1 3031237]rs1301 7599 2.00E-15|8.00E- 07|2.00E-12 1.12|1.13|NR Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Gregersen PK.PMID: 19503088 RNASEH2B rs3790022 1.00E-06 1.4925 Bossini-Castillo L.PMID: 24532677 RPS12P4 rs4305317 2.00E-06 1.45 Padyukov L.PMID: 21156761 RTKN2 rs6479800|rs31 25734 4.00E-06|5.00E- 09 1.19|NR Okada Y.PMID: 24390342|Myouzen K.PMID: 23028356 RUNX1 rs8133843 2.00E-08 1.09 Okada Y.PMID: 24390342 SALL3 rs2002842 6.00E-06 1.61 Julia A.PMID: 18668548 SFTPD rs726288 9.00E-09 1.22 Okada Y.PMID: 24390342 SH2B3 rs10774624|rs3 184504 7.00E-09|6.00E- 06 1-09)1.08 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 SMIM21 rs1943199 2.00E-08 1.94 Bossini-Castillo L.PMID: 24532677 16 2017100960 13M2017 SPRED2 rs1858037|rs93 4734 1 00E-08|5.00E-10|2.00E-08 1.19|1.13 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Jiang L,PMiD: 24782177 STAT4 rs11889341 |rs7 574865 1.00E-12|3.00E-07|2.00E-06 1.12|1.16 Okada Y,PMID: 24390342|Stahl EA.PMID: 20453842|Kochi Y.PMID:20453841 SYNGR1 rs909685 1.00E-16 1.13 Okada Y.PMID: 24390342 TAGAP rs2451258 2.00E-10 1.10 Okada Y.PMID: 24390342 TEC rs2664035 1.00E-07 1.07 Okada Y.PMID: 24390342 TNFAIP3 rs7752903|rs69 20220|rs223092 6|rs10499194 2.00E-20|9.00E- 13|1.00E- 07|6.80E- 14|2.00E- 06|1.00E-09 1.41|1.22|1.38|1 .33 Okada Y.PMID: 24390342]Stahl EA.PMID: 20453842|Plenge RM.PMID: 17982456IDoroth??e Diogo,PMID:23261300|Kochi Y.PMID: 20453841 |Plenge RM.PMID: 17982456 TNFRSF14 chr1:2523811|rs 3890745 5.00E-09|4.00E-06|1.00E-06|1.00E-07 1.10|1.12|NR| 1.12 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Orozco G.PMID: 24449572|Raychaudhuri S.PMID:18794853 TNFRSF9 rs227163 3.00E-09 1.11 Okada Y.PMID: 24390342 Gene SNP p-Value Odd ratio References TPD52 rs998731 2.00E-08 1.08 Okada Y.PMID: 24390342 TRAF1 rs10985070|rs3 761847|rs22396 57|rs881375|rs2 072438 4.00E-09|2.00E- 07|5.40E- 08|4.00E- 08|3.00E-09 1.09|1.13| 1.10|N RjNR Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Doroth??e Diogo,PMID:23261300jGregerse n PK.PMID: 19503088|Jiang L.PMID: 24782177 TRAF1-C5 rs3761847 4.00E-14 1.32 Plenge RM.PMID: 17804836 TRAF6 rs331463 1.00E-07 1.12 Okada Y.PMID: 24390342 TRHDE rs12831974 6.00E-06 1.27 Freudenberg J.PMID: 21452313 TXNDC11 rs4780401 4.00E-08 1.07 Okada Y.PMID: 24390342 TYK2 rs34536443 5.00E-16 1.46 Okada Y.PMID: 24390342 UBASH3A rs1893592|rs11 203203 7.00E-12|4.00E- 06 1.11(1.11 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 UBE2L3 rs11089637 2.00E-07 1.10 Okada Y.PMID: 24390342 WDFY4 rs2671692 3.00E-09 1.07 Okada Y.PMID: 24390342 YDJC rs11089637 2.00E-07 1.10 Okada Y.PMID: 24390342 ZNF438 rs793108 1.00E-09 1.08 Okada Y.PMID: 24390342 ZNF774 rs6496667 1.00E-06 1.09 Okada Y.PMID: 22446963

Example 3

Analysis of the whole-exome sequencing (WES) 5 To analyze the entire cohort of samples for genotype calls, variant analysis and joint genotyping were performed according to the pipeline recommended by the 17

Genome Analysis Toolkit software and the GATK Best Practices procedures on RA patients and healthy controls (San Lucas FA et al., Bioinformatics 2012;28:421-422; and Dong C et al., Human molecular genetics 2015;24:2125-2137). Briefly, Burrows-Wheeler Aligner (BWA) software was utilized to align the raw sequencing reads in 5 FASTQ formats to the 1000 Genomes (GRCh37 + decoy) human genome reference. The BWA alignment files were converted to BAM files with SAMtoois v1.1, which was used for sorting the BAM files. Duplicate reads were marked for BAM files with Picard MarkDuplicates (https://sourceforqe.net/proiects/picard/). The coverage and depth were computed based on the final BAM file. Local realignment, base quality 10 recalibration, variant calling, joint genotyping, and variant quality score recalibration and filtration were applied using with GATK v3.7 (https://software.broadinstitute.org/qatk/). Default settings were used for BWA, SAMtoois, Picard and GATK tools. 2017100960 13 Μ 2017 15 Further filtration for the joint genotyped variants was performed using Variant

Tools (San Lucas FA et al., Bioinformatics 2012;28:421-422). The inventors applied the following filters to generate a list of preliminary variants by removing false-positive variants through Variant Quality Score Recalibration with tranche truth sensitivity threshold <99.00, as well as variants with low read depth (DP) <10 and poor 20 genotyping quality (GQ) <20, keeping exonic or splicing variants based on University of California, Santa Cruz (UCSC) genome browser build 37 human Reference Sequence Gene annotation, and removing synonymous variants.

From the preliminary variant list, variants annotated as “pathogenic” in ClinVar 25 and deleterious variants were identified, respectively, including those candidate genes that overlapped with previous studies or passed the case-control gene burden test threshold. Deleterious variants were predicted to be damaging (disease-related, D) or benign/neutral (tolerated, T) based on LR score determined by logistic regression (LR) model (Dong C et al., Human molecular genetics 2015;24:2125-2137). The novel 30 deleterious variants were divided into the rare and common variant groups, which were distinguished by minor allele frequency (MAF) in Chinese Southern population from the 1000 Genomes Project phase III study.

Example 4 35

Analysis of burden association signal. 18

Case-control gene burden analysis was assessed on both rare and common deleterious variants to investigate causal genes using RA patients with > 80% Chinese ancestry as cases and two types of controls: 105 southern Chinese samples from the 1000 Genomes Project phase III study and 66 healthy controls with >80% Chinese 5 ancestry. Regardless of DP or GQ, all available genotype calls contributed to the number of allele count across the retained deleterious variants in each individual gene. The gene burden ratio was calculated by dividing the allele frequency in cases by the allele frequency in controls. We identified an enrichment of deleterious variants in a gene according to the gene burden ratio >1.5-fold with both types of controls, or the 10 deleterious alleles in the gene with at least 3 RA cases if zero allele frequency in the controls. The inventors further identified genes with rare variants that were homozygous in RA cases but not present in controls, which were considered greater contribution to functional impact. 2017100960 13 Μ 2017 15 Example 5

Pathway analysis

To discover enriched functional-related gene groups, pathway analysis was performed using DAVID Bioinformatics Resource 6.8 program (DAVID 6.8) 20 (https://david.ncifcrf.gov/summary.isp) with a Modified Fisher Exact P value less than 0.05 as the significance threshold and strong enrichment in the annotation categories.

Homology modeling is one of the best and reliable ways to construct the three dimensional (3D) structure of protein (Yamaguchi H et al., European journal of 25 medicinal chemistry 2011;46:1325-1330). Firstly, protein sequence was imported into the Molecular Operating Environment (MOE) 2015.09 software (Chemical Computing Group Inc., Montreal, Canada) to search an optimal template. The top ranked structure based on the Z score towards the target sequence was selected as the template. Target protein sequence and its corresponding crystal structure coordinates of 30 template were separately loaded and aligned. A series of protein models were independently constructed by using a Boltzmann-weighted randomized procedure (Levitt M., Journal of molecular biology 1992;226:507-533). Amber force field was applied in the process of construction and energy minimization (Case D et al., Amber 12 reference manual). Finally, the model with the best packing quality function was 35 selected for further full energy minimization, and the stereochemical qualities of protein model was assessed by means of Ramachandran plots. 19

To analyze the effect on the point mutation in the 3D structure of the protein, the mutant protein were carried out in Residue Scan module of MOE 2015.09 software based on the 3D structure of homology modeling. In addition, we further analyze the hydrogen bonds, solvent interactions, metal ligation and non-bonded interaction 5 between the target mutant residue and its surrounding key amino acid residues. 2017100960 13 Μ 2017

Example 6 Results 10 1. Deleterious variants in novel RA candidate genes WES data were generated from 58 RA patients with a median coverage of 76-fold on targeted exome regions (Fig. 2A). An average of 96% of all targeted regions was covered by at least 20-fold. The healthy control group had a median coverage of 68-fold on targeted exome regions, and an average of 94% of those regions was 15 covered by at least 20-fold (Fig. 2B).

As shown in the flow chart of Fig. 3, a total of 3,537,952 variants were identified from 58 RA samples. After applying the quality filters and removing synonymous variants, we found 72,024 exonic and splicing variants, including nonsynonymous 20 substitutions and a small number of stop-gain, stop-loss, frameshift and non-frameshift indels (Table 4). Of these, 135 variants were identified as deleterious based on the “pathogenic” annotation in ClinVar, and an additional 21,755 variants predicted to be deleterious were identified using an ensemble logistic regression score. 25 Table 4: Types of exonic, splicing and nonsynonymous variants (total =72,024).

Mutation type No. of variants Nonsynonymous SNV 56,466 Stop-gain 828 Stop-loss 49 Frameshift Deletion 408 Insertion 215 Nonframeshift Deletion 705 Insertion 466 Splicing 11,377 Unknown 1510 20

It was surprising that the identified genes were not found in previously reported candidate risk variants GWAS data (group 1 and group 3 in Fig. 3; Table 5 and 6), such as HLA-associated genes. After reviewing the location of the reported RA-associated variants, the inventors found that only 9 of over 200 variants are located in 5 the exome area, including CTLA4 (rs231775), FCGR2A (rs1801274), IL6R (rs2228145), OLIG3 (rs2230926), PTPN22 (rs2476601), RTKN2 (rs3125734), SH2B3 (rs3184504), TNFAIP3 (rs223092) and TYK2 (rs34536443). Since the inventors applied WES technique to focus on exome regions, the results are different from the previously reported studies. It is advantageous that the presently disclosed method of 10 identification of RA associated genes is capable of providing more comprehensive information of RA associated genes. According to the results, a number of new RA associated genes have now been identified and may be be useful in developing advanced methods for diagnosis and treatment of RA. 2017100960 13 Μ 2017 15 Interestingly, two novel risk variant loci were identified associated with TGFfil (transforming growth factor β1) and FOXP3 (forkhead box P3) genes (group 4 and group 6 in Fig. 3; Table 5) whereas other known variations of these two genes were previously found to be involved in the risk to RA (Zhou TB et al., J Recept Signal Transduct Res 2014;34:469-475; and Paradowska-Gorycka A et al., J Rheumatol 20 2015;42:170-180).

In order to identify novel genes and pathways that could enhance understanding of RA pathogenesis, the inventors performed a gene burden analysis to identify genes for which deleterious variants were enriched in the Han Chinese RA 25 samples compared to healthy control and public control samples. Six such genes were identified (group 2 in Fig. 3; Table 5 and 7). Of these, a missense variant of SAA1 (Serum Amyloid A1) was found in 3 RA patients but not present in healthy controls. SAA1 is highly expressed in response to inflammation and tissue injury, and strongly associated with activity of the disease and risk of cardiovascular and renal involvement 30 in RA patients, suggesting that this novel deleterious variant may potentially contribute to RA disease risk through its interference with pro-inflammatory effectors. Additional pathogenic variant of OXCT1 (3-Oxoacid CoA-Transferase 1) was predicted to be damaging (disease-related, D) in the RA patients, encoding Succinyl-CoA:3-ketoacid coenzyme A transferase 1 (SCOT1), which is a key enzyme for synthesis and 35 degradation of ketone bodies involved in cardiovascular disease. 21

Rare variants are more likely to predict a significant impact on protein function and result in clinically relevant consequences than common ones. Thus, the inventors grouped variants that were indicated to be deleterious into rare (minor allele frequency <1%) and common variants, which did not overlap with previously reported candidates 5 (Table 5). Performing a gene burden analysis for variants within each of these groups, we identified 241 genes (group 4 in Fig. 3; Table 5) with rare, deleterious variants specifically enriched in our Chinese RA samples compared to healthy control and public control samples. Notably, since the functional impact of rare and deleterious variants is likely to be greater when present as homozygote, 5 rare and deleterious 10 homozygous variants (NCR3LG1, RAP1GAP, CHCHD5, HIPK2 and DIAPH2) were identified in the Chinese RA samples and absent in the controls (group 5 in Fig. 3; Table 3). Finally, we also identified 144 genes with common and deleterious variants in RA patients (group 6 in Fig. 3; Table 5). 2017100960 13M2017 15 2. Pathway analysis

Using the method as disclosed herein, the inventors identified a total of 381 genes as candidates for increased risk of RA (Table 5). In order to further identify the associated biologic pathways, the inventors performed the functional enrichment analysis using DAVID 6.8 and identified the pathways of the extracellular matrix 20 (ECM)-receptor interaction, protein digestion and absorption, focal adhesion and glycerophospholipid metabolism as significantly overrepresented (Table 8), which were reported to be relevant in pathogenesis of arthritis (Lv W et al., Mol Biosyst 2015;11:2986-2997; and Choe JY et al., Rheumatology (Oxford) 2016;55:928-938). 25 In order to identify variants that might predispose RA patients to disease duration, the inventors repeated the variant filtration and gene burden analysis on Chinese RA samples with the disease duration £3-year compared to the disease duration <1-year. A total of 277 genes were identified (Table 9) compared to the 381 genes identified in the case-control comparison (Table 5). Of these, 87 genes were 30 unique to disease duration with exonic variants (Table 10). Pathway analysis performed on the 87 genes identified olfactory transduction pathway as significantly overrepresented (Table 8), including OR14C36, OR4A15, OR52N4, OR6C74, OR6C75, OR7G3 and OR9K2. 35 3. Structural analysis and function change prediction of potential biomarkers

In order to gain structure insights of the potential biomarkers with pathogenic variants into the clinical conditions of RA patients, the inventors derived a three- 22 dimensionally structure model of SAA1 Gly90Asp (rs79681911) and SCOT 1 Thr58Met (rs75134564) by combining homology modeling with point mutation in MOE 2015.09 package. The crystal structures of human SAA1 protein (PDB code: 4IP8.A) and SCOT1 protein (PDB code: 3K6M.C) were selected to be used as templates due to 5 their optimal identity with the target sequences of SAA1 (Protein RefSeq: NP_000322.2) and SCOT1 (Protein RefSeq: NP_000427.1), 83.6% and 83.5%, respectively (Fig 4). The SAA1 and SCOT1 models with the best packing quality function and full energy minimization were assessed by Ramachandran plots, indicating that the phi and psi backbone dihedral angles in the models were reasonable 10 (Fig. 5). 2017100960 13 Μ 2017

Structural analysis of SAA1 Gly90Asp (Figs. 6A and 6B) revealed that the substitution of glycine with aspartic acid induced the formation of two pairs of hydrogen bonds with two threonine residues (Ala91 and Asp93), exhibiting more stable structure 15 of loop region and promoting the polar interaction. Moreover, this mutation shortened the length of a helix 4, which may affect the stability of SAA1. Structural changes in SAA1 protein caused the surface of Asp90 to be exposed in solvent environment, leading to the increased hydrophilic region. In addition, the construction of 3D models in SCOT1 and its mutant Thr58Met revealed that this substitution resulted in the 20 disappearance of the hydrogen bond between Thr58 and Asp206, the reduction of intramolecular polar interactions and the expansion of hydrophobic region (Figs. 6C and 6D), suggesting its potential function alteration in RA pathogenesis. 4. Discussion 25 The inventors performed perspective WES aiming to identify potentially causal biomarkers in a cohort of Chinese RA patients. The inventors used the method as disclosed herein to focus on investigating the occurrence frequency of variants in genes previously associated with RA as well as novel genes. Despite known variants of TGF/37 and FOXP3 genes associated with increased RA risk, two novel risk variant 30 loci in these two genes were for the first time identified to be implicated in the RA risk (group 4 and group 6 in Table 5). A novel splicing variant (rs199982059) of 7GF/37 was found to be significantly enriched in 4 RA patients, but absent in healthy controls. TGFpi is a pivotal protein in the pathogenesis of a number of autoimmune disorders and its dysregulation is also increasingly implicated in the risk of developing RA. RNA 35 splicing is a focal point on connection between genetic variations and complex disorders, and this novel splicing variant of TGFfil might provide new insights into the genetic determinants of RA disease. In addition, a novel missense variant 23 (chrX:49114808) of FOXP3 was observed in 8 RA patients. FOXP3 is a unique regulatory T cell (Treg)-specific marker and important in the development of RA-derived Treg cells as a transcriptional factor. In spite of the other known variants in 7"GF/37 and FOXP3 genes associated with RA, these two newly-identified variants in our Chinese 5 RA patients may offer the novel genetic contributions to the RA risk. 2017100960 13 Μ 2017

The inventors have also identified six novel and deleterious genes that are classified as pathogenic in ClinVar database (Table 7). Of these, a missense variant (rs79681911) of SAA1, initially characterized by serum amyloid a variant (OMIM 10 104750) and required for the amyloidosis disease process, was identified in the RA patients. SAA1 has been reported to play a pathogenic role in the pro-inflammatory cascades in RA, therefore, this novel deleterious variant may be implicated in RA risk as a sensitive indicator of inflammatory activity. Additional pathogenic variant (rs75134564) of OXCT1 was predicted to be disease-related in 4 RA patients based 15 on LR score, which previously implicated in succinyl-CoA acetoacetate transferase deficiency (OMIM 601424) in clinic. OXCT1 encoding enzyme SCOT1 is essential for ketone body metabolism and involved in cardiovascular disease, which are shown to be strongly associated with the course of RA, suggesting this enzyme may potentially contribute to RA prognosis. Importantly, the 3D structural analysis of these two 20 potential biomarkers revealed that the substitution of mutation points may be involved in the functional alteration of the proteins and further impact on RA disease progression (Fig. 6).

The inventors sought to identify novel genes or biological candidate 25 pathways fundamental to the risk of RA disease, including both rare and common variants. To elucidate additive effects of polygenic variants that affect the same gene or pathway, the inventors performed gene burden test and pathway analysis. Notably, the biological impact of rare and deleterious variants is likely to be greater when present as two copies. In the study, 5 homozygous variants (group 5 in Fig. 3; Table 30 5) were detected in the RA patients but not in healthy controls. Intriguingly, a non- frameshift indel variant (rs61406813) of NCR3LG1 (natural cytotoxicity triggering receptor 3 ligand 1) was identified in the RA patients as homozygote. NCR3LG1 could be detected on monocytes and neutrophils after application of inflammatory stimuli, and itwas initially described as a tumor cell-expressed ligand of NKp30, which is found 35 to be implicated in RA-associated inflammation. Additionally, a missense variant (rs61014678) of FIAP1GAP (RAP1 GTPase Activating Protein) was identified as damaging (disease-related, D) by determinant of LR model in the RA patients. 24 RAP1GAP regulates the activity of the ras-related RAP1 protein, which involves in induction of apoptotic pathway in synovial fibroblasts and plays a critical role in oxidative stress and T cell behavior in RA synovial tissues. Thus, these two homozygous variants may perform stronger functions in RA pathogenic mechanisms. 2017100960 13 Μ 2017 5

The WES analysis totally identified 381 genes that may partially contribute to RA pathogenesis and disease progression, including 3 genes (TGFfil, FOXP3 and SAA1) previously implicated in RA and 378 novel candidate genes. Biologic pathway analysis might help us to deeply understand RA pathogenesis, and previously biological 10 pathways have been identified from genes in large-scale association analysis of GWAS data (Table 6), such as autoimmune thyroid disease, natural killer cell mediated cytotoxicity and T cell receptor signaling pathways. The inventors deciphered enrichment of the identified deleterious genes within additional pathways of ECM-receptor interaction, protein digestion and absorption, focal adhesion and 15 glycerophospholipid metabolism based on our WES data (Table 8), which have been implicated in the autoimmune conditions or pathogenesis of RA. The inventors also sought to identify potential deleterious variants associated with disease duration among RA patients. The pathway analysis focusing on variants enriched among RA patients with disease duration >3-year highlighted seven novel genes in olfactory 20 transduction pathway (Table 8), which has been previously reported to be implicated in regulating inflammatory responses.

Pathogenesis of RA is complicated and includes both environmental and genetic factors. Recently, gut microbiota has been evident of being implicated in RA 25 pathogenesis and treatment responses as a critical environmental factor that influences metabolic and immune homeostasis, involvement of protein digestion and absorption, glycerophospholipid metabolism and olfactory transduction pathway, which were also enriched by novel candidate genes identified in the Chinese RA patients (Table 5). In addition, the homozygous variant NCR3LG1 (group 5 in Table 5) 30 may mediate autoimmune and microbial infection-induced inflammation by associating with the ligand of NKp30. Therefore, these involved novel deleterious genes might be convincingly considered genetic contributions to microbial alteration in relation to the pathogenesis and development of RA. 35 Genetic factors on the X chromosome always contribute to the increased risk of developing autoimmune disorders in females compared with males, such as RA. According to the method as described herein, four novel and deleterious variants were 25 investigated to be associated with sex bias in the Chinese RA patients, including OTC (Ornithine Transcarbamylase) (rs72554348), DIAPH2 (Diaphanous Related Formin 2) (rs363755), ARSE (Arylsulfatase E) (rs56393981) and FOXP3 (chrX:49114808) (Fig. 7). Notably, OTC, ARSE and FOXP3 were previously reported to be implicated in x-5 linked diseases (Bennett CL et al., Nature genetics 2001 ;27:20; Luksan O et al., Hum Mutat 2010;31 :E1294-1303; and Jeon GW et al., Ann Clin Lab 2013;43:70-75), in which these three novel variants identified in the present study are also associated with female, supporting that the association of variants on X chromosome and RA may further provide molecular evidence as a risk factor contributing to increased 10 susceptibility in Chinese female RA patients. 2017100960 13 Μ 2017

In summary, the inventors have performed WES to present support and improve our understanding of associations with genetic biomarkers that may be involved in the development of RA in the Chinese population. The biomarkers 15 highlighted include previously implicated genes as well as novel genes and pathways, involved in regulation of adaptive immune response, transmission of nerve impulse and chromosome organization. This study significantly extends the work of GWAS and provides new insight into fundamental etiologic mechanisms in this common autoimmune disease. Taken together, these novel biomarkers can be served as novel 20 biomarkers for valid diagnosis tools for identification of RA patients from normal people specifically for Chinese Han population. 26

Table 5. Candidate variant list from RA versus control comparison. group chr pos id ref alt gene

LR

Gene burden ratio 2017100960 13M2017

Total No. of alleles in gene

No. alt alleles in genes

No. of cases with alt alleles 2 10 101829514 rs61751507 C T CPN1 2 11 18291302 rs79681911 G A SAA1 2 3 133476698 rs41295774 A G TF 2 5 41862758 rs75134564 G A OXCT1 2 7 44104839 rs77938727 C T PGAM2 2 X 38229135 rs72554348 G c OTC 4 10 102027318 rs200164003 G c CWF19L1 4 10 114917776 rs191206106 C G TCF7L2 4 10 114925441 rs138649767 G A TCF7L2 4 10 135086331 rs536126291 C T ADAM 8 4 10 135087305 rs3810960 G A ADAM8 4 10 25144247 rs 199794379 A G PRTFDC1 4 10 25147326 rs199983667 C A PRTFDC1 4 10 35894560 rs142589386 G A GJD4 4 10 35897091 rs547212582 T C GJD4 4 10 35897205 rs 192362407 G A GJD4 4 10 50854641 rs539884711 C A CHAT 4 10 50857631 rs201293521 G T CHAT 4 10 50870806 rs116628504 G A CHAT 4 1 100174455 rs192583899 T C FRRS1 4 1 100177969 rs187278122 A G FRRS1 KG East Asia healthy healthy Ctrl Ctrl RA health y Ctrl RA T 1.81 1.52 132 116 3 4 4 T 1.81 132 116 0 3 3 T 1.81 3.41 132 116 2 6 6 D 3.62 4.55 132 116 1 4 4 D 1.81 2.28 132 116 1 2 2 2.79 2.32 132 114 3 6 5 7.24 132 116 0 4 4 12.67 7.97 264 232 1 7 7 D 12.67 7.97 264 232 1 7 7 5,43 3.41 264 232 1 3 3 5.43 3.41 264 232 1 3 3 D 5.43 264 232 0 3 3 D 5.43 264 232 0 3 3 5.43 3.41 396 348 1 3 3 D 5.43 3.41 396 348 1 3 3 D 5.43 3.41 396 348 1 3 3 D 1.81 2.28 396 348 1 2 2 D 1.81 2.28 396 348 1 2 2 D 1.81 2.28 396 348 1 2 2 1.81 264 232 0 3 3 1.81 264 232 0 3 3

Variant alieie frequency KG East Asia 0.0248 0.0198 0.0238 0.0069 0.0129 0.0144 0.001 0.001 0.0089 0.002 0.003 0.004 0.001 0.003 0.002 0.004 0.001 0.001 0.006 0.003 0.006 27 2017100960 13 Μ 2017 4 1 103444283 rs 192842970 G A COL11A1 4 1 103468295 rs2622875 C T COL11A1 4 1 103544434 rs12136865 A G COL11A1 4 11 111857624 T C DIXDC1 4 11 111889694 T C DIXDC1 4 11 121426036 rs 140499624 A G SORL1 4 11 124006828 rs2276055 C T VWA5A 4 11 124742777 rs117828759 C T R0B03 4 11 2432720 rs548094761 C T TRPM5 4 11 2434772 rs74570003 G T TRPM5 4 11 2441443 rs201184691 G A TRPM5 4 1 1267086 rs201655269 C T TAS1R3 4 1 1268119 rs548456115 C T TAS1R3 4 1 1269146 rs576045705 G A TAS1R3 4 11 2909699 rs80153297 C T SLC22A18AS 4 11 2920835 rs 189560463 G C SLC22A18AS 4 1 146759364 C T CHD1L 4 11 479160 rs2301168 G T PTDSS2 4 11 490416 rs200466000 C T PTDSS2 4 1 151958735 rs190916122 A G S100A10 4 11 56756398 rs13343184 G T OR5AK2 4 11 56756578 rs189588796 C T OR5AK2 4 1 160121885 rs146860131 C T ATP1A4 4 1 160143514 rs45441496 T G ATP1A4 4 1 160143945 rs199962758 T C ATP1A4 4 1 160144538 rs185461260 G T ATP1A4 4 1 161090011 rs201971149 G c NIT1 4 11 63400493 rs17656941 C T ATL3 4 11 63403670 rs3781606 C T ATL3 28 D 10.86 3.4 394 348 2 6 6 0.004 10.86 3.4 394 348 2 6 6 0.001 10.86 3.4 394 348 2 6 6 0.001 5.43 1.71 264 232 2 3 3 0.002 5.43 1.71 264 232 2 3 3 0.001 7.24 2.28 132 116 1 2 2 0.004 7.24 132 116 0 4 4 0.0079 4.95 2.01 128 106 3 5 5 0.0079 D 3.62 6,83 396 348 1 6 6 0.003 D 3.62 6.83 396 348 1 6 6 0.003 3.62 6.83 396 348 1 6 6 0.004 D 7.24 4.55 396 348 1 4 4 0.001 D 7.24 4.55 396 348 1 4 4 0.001 D 7.24 4.55 396 348 1 4 4 0.001 2.41 264 232 0 4 4 0.005 2.41 264 232 0 4 4 0.002 5.62 3.54 132 112 1 3 3 0.001 3.62 4.55 264 232 1 4 4 0.003 3.62 4.55 264 232 1 4 4 0.004 5.43 1.68 130 116 2 3 3 0.005 2.72 3.41 264 232 1 3 3 0.002 2.72 3.41 264 232 1 3 3 0.002 10.86 3.41 528 464 2 6 6 0.003 10.86 3.41 528 464 2 6 6 0.0089 D 10.86 3.41 528 464 2 6 6 0.003 10.86 3.41 528 464 2 6 6 0.004 D 3.62 2.28 132 116 1 2 2 0.001 3.62 2.28 264 232 1 2 2 0.003 3.62 2.28 264 232 1 2 2 0.0079

4 11 6585361 rs 113574909 A G DNHD1 4 11 67786664 rs535638253 G A ALDH3B1 4 11 67789111 rs371833737 C T ALDH3B1 4 11 67789277 rs370461081 G A ALDH3B1 4 11 67795344 rs374814356 G A ALDH3B1 4 11 74716666 rs202090872 G C NEU3 4 11 74716935 rs200629627 G A NEU3 4 11 74717001 rs539514716 C T NEU3 4 1 176853472 rs79630456 C T ASTN1 4 11 76873966 C T MY07A 4 11 76900487 G c MY07A 4 1 17949680 rs75914589 C T ARHGEF10L 4 11 82536079 rs202237309 C T PRCP 4 11 82549453 rs536616254 C T PROP 4 11 82644887 rs553247583 G GC DDIAS 4 1 183084778 rs200671087 A G LAMC1 4 1 183086586 rs544527088 G A LAMC1 4 11 8959479 rs 147479456 G A ASCL3 4 11 8959607 rs201803232 C T ASCL3 4 11 93754643 rs192979315 T A HEPHL1 4 11 93754667 rs564600266 A G HEPHL1 4 11 93779075 rs151306000 A T HEPHL1 4 11 93797581 rs146491431 G C HEPHL1 4 1 19566783 rs201918168 C T EMC1 4 1 197070906 rs118010078 C T ASPM 4 1 197072871 rs 144969324 C T ASPM 4 1 203195004 rs190551025 C T CHIT1 4 1 203198732 rs16851144 C T CHIU 4 12 122247945 rs375525174 G T SETD1B 29 3.62 2.28 132 116 1 2 2 0.0099 1.81 2.84 528 464 2 5 5 0.001 1.81 2.84 528 464 2 5 5 0.003 1.81 2.84 528 464 2 5 5 0.002 1.81 2.84 528 464 2 5 5 0.005 D 5.43 3.41 396 348 1 3 3 0.003 D 5.43 3.41 396 348 1 3 3 0.003 D 5.43 3.41 396 348 1 3 3 0.002 2.72 1.71 132 116 2 3 3 0.0089 D 3.62 2.28 264 232 1 2 2 0.001 D 3.62 2.28 264 232 1 2 2 0.004 3.62 2.28 132 116 1 2 2 0.0089 D 3.62 2.28 264 232 1 2 2 0.004 D 3.62 2.28 264 232 1 2 2 0.001 1.81 2.28 132 116 1 2 2 0.006 3.62 2.28 264 232 1 2 2 0.002 3.62 2.28 264 232 1 2 2 0.001 D 3.62 264 232 0 4 4 0.001 D 3.62 264 232 0 4 4 0.003 D 5.43 6.83 528 464 1 6 6 0.002 D 5.43 6.83 528 464 1 6 6 0.005 D 5.43 6.83 528 464 1 6 6 0.0069 D 5.43 6.83 528 464 1 6 6 0.002 1.81 3.41 132 116 1 3 3 0.0079 D 3.62 2.28 264 232 2 4 4 0.0069 D 3.62 2.28 264 232 2 4 4 0.005 3.62 4.55 264 232 1 4 4 0.006 3.62 4.55 264 232 1 4 4 0.001 D 7.24 1.52 264 232 3 4 4 0.002 2017100960 13 Μ 2017

4 12 122261544 rs553963413 G A SETD1B 4 12 12672941 rs187382315 T G DUSP16 4 1 21926031 rs138045307 C T RAP1GAP 4 1 22149838 rs554059442 C T HSPG2 4 1 22157470 rs77527456 C T HSPG2 4 1 22157544 rs368497178 C T HSPG2 4 1 225599137 rs192884088 C T LBR 4 1 225600276 rs145104817 C T LBR 4 1 225607507 rs144956313 T A LBR 4 1 225611800 rs375540112 T C LBR 4 1 228109706 rs 1462 33417 C A WNT9A 4 1 23281822 rs543523784 C T LACTBL1 4 1 23285238 rs374793392 C T LACTBL1 4 1 23285418 rs 186492394 A G LACTBL1 4 1 23289623 rs557724162 C T LACTBL1 4 1 241850753 rs146579868 T C WDR64 4 1 241929510 rs576824811 C T WDR64 4 12 52822463 rs192170292 A T KRT75 4 12 52825806 rs548132126 A G KRT75 4 12 52908938 rs375140289 C T KRT5 4 12 52913517 rs638907 G A KRT5 4 1 27875517 rs111827498 AAGG A AHDC1 4 12 94613786 rs 117324576 G A PLXNC1 4 12 99478699 rs370166322 T C ANKS1B 4 12 99640652 rs74712860 G A ANKS1B 4 13 103392313 rs372526941 C G CCDC168 4 13 103396838 rs183822515 A G CCDC168 4 13 103397088 rs192109030 C T CCDC168 4 13 106142185 rs113341591 C T DAOA 30 D 7.24 1.52 264 232 3 4 4 0.002 7.24 2.24 130 116 2 4 4 0.005 D 7.24 4.55 264 232 2 8 7 0.001 D 2.72 396 348 0 3 3 0.002 2.72 396 348 0 3 3 0.0079 D 2.72 396 348 0 3 3 0.001 D 3.64 4.55 526 462 1 4 4 0.001 D 3.64 4.55 526 462 1 4 4 0.002 3.64 4,55 526 462 1 4 4 0.001 3.64 4.55 526 462 1 4 4 0.002 5.43 3.41 132 116 1 3 3 0.005 3.62 2.28 528 464 2 4 4 0.001 3.62 2.28 528 464 2 4 4 0.004 3.62 2.28 528 464 2 4 4 0.003 3.62 2.28 528 464 2 4 4 0.001 7.24 2.28 264 232 2 4 4 0.002 7.24 2.28 264 232 2 4 4 0.001 D 1.81 2.28 264 232 1 2 2 0.002 D 1.81 2.28 264 232 1 2 2 0.001 D 5.43 1.71 264 232 2 3 3 0.002 5.43 1.71 264 232 2 3 3 0.0079 7.24 132 116 0 4 4 0.004 9.05 1.9 132 116 3 5 5 0.0099 3.85 2.22 242 218 1 2 2 0.004 3.85 2.22 242 218 1 2 2 0.0079 2.72 1.71 396 348 2 3 3 0.003 2.72 1.71 396 348 2 3 3 0.006 2.72 1.71 396 348 2 3 3 0.001 6.34 2.66 264 232 3 7 7 0.0069 2017100960 13 Μ 2017 4 13 106142236 rs111916808 G A DAOA 4 1 35226964 rs146378222 G A GJB4 4 1 35227225 rs373126632 C T GJB4 4 1 35227231 rs146979528 G A GJB4 4 1 35227585 rs201000959 C T GJB4 4 1 35350573 rs34565935 CT c DLGAP3 4 1 36056256 rs 114404250 G A TFAP2E 4 13 76378421 rs190172966 A T LM07 4 13 76395306 rs181473989 C T LM07 4 13 76419523 rs566129586 C T LM07 4 1 38025103 rs41267309 T c DNALI1 4 13 95117993 rs144365832 C T DCT 4 13 95121301 rs202004134 T c DCT 4 14 21793077 rs543867152 c T RPGRIP1 4 14 21793236 rs7157052 G A RPGRIP1 4 1 43664319 rs10711519 TA T CFAP57 4 1 43688508 rs549638533 T TCAC CFAP57 4 1 43689879 rs 138114943 c A CFAP57 4 14 59954385 rs76472382 A G JKAMP 4 14 77735581 rs 117207261 C G NGB 4 14 77735593 rs77722833 G C NGB 4 14 88406259 rs 138577661 A G GALC 4 14 88411994 rs 146286491 C T GALC 4 14 88450836 rs534598133 C T GALC 4 15 39876498 rs200938835 T C THBS1 4 15 39881204 rs200366954 A G THBS1 4 15 39886402 rs 185847032 G A THBS1 4 15 45388079 rs147945181 G A DU 0X2 4 15 45388106 rs200541410 G A DU 0X2 31 6.34 2.66 264 232 3 7 7 0.0099 D 3.02 1.9 528 464 3 5 5 0.006 D 3.02 1.9 528 464 3 5 5 0.001 D 3.02 1.9 528 464 3 5 5 0.002 D 3.02 1.9 528 464 3 5 5 0.003 1.81 2.28 132 116 1 2 2 0.006 D 2.72 3.41 132 116 1 3 3 0.0069 3.62 396 348 0 4 4 0.003 3.62 396 348 0 4 4 0.005 3.62 396 348 0 4 4 0.001 3.62 2.28 132 116 1 2 2 0.0089 D 1.81 2.28 264 232 1 2 2 0.004 1.81 2.28 264 232 1 2 2 0.001 D 7.24 264 232 0 4 4 0.001 7.24 264 232 0 4 4 0.002 7.54 2.3 384 334 2 4 4 0.003 7.54 2.3 384 334 2 4 4 0.005 7.54 2.3 384 334 2 4 4 0.003 2.72 130 116 0 3 3 0.0069 D 2.72 264 232 0 3 3 0.004 D 2.72 264 232 0 3 3 0.001 D 7.24 2.28 396 348 2 4 4 0.0079 D 7.24 2.28 396 348 2 4 4 0.006 D 7.24 2.28 396 348 2 4 4 0.002 3.62 4.55 396 348 1 4 4 0.002 D 3.62 4.55 396 348 1 4 4 0.001 3.62 4.55 396 348 1 4 4 0.002 D 4.07 1.71 660 580 6 9 9 0.005 D 4.07 1.71 660 580 6 9 9 0.004 2017100960 13 Μ 2017 4 15 45391946 rs368488511 C T DU 0X2 4 15 45399533 rs76411432 c T DU 0X2 4 15 45399648 rs180671269 T A DU 0X2 4 1 54694412 rs75191666 G A SSBP3 4 1 54707891 rs 199692606 A G SSBP3 4 15 48512855 rs 116848967 G A SLC12A1 4 15 48566800 rs201516084 T C SLC12A1 4 15 65766537 rs192889990 A G DPP8 4 15 65790192 rs564795298 T C DPP8 4 15 79298783 rs 182075492 G C RASGRF1 4 15 89869833 rs55962804 C T POLG 4 15 99670848 G A SYNM 4 15 99673059 C T SYNM 4 1 6184131 rs200938629 T A CHD5 4 1 6188678 rs193121978 c G CHD5 4 1 6228290 rs571052710 c G CHD5 4 16 19883621 rs200345676 G T GPRC5B 4 16 27492392 rs200888316 C T GTF3C1 4 16 27494449 rs536534746 G A GTF3C1 4 16 424403 rs11641325 C T TMEM8A 4 16 426536 rs 143874266 C T TMEM8A 4 16 4624799 rs574569398 C G C16orf96 4 16 4644389 rs139232890 CAGG C C16orf96 4 16 57935248 rs374813501 C G CNGB1 4 16 57984441 rs146170855 C T CNGB1 4 16 57993840 rs201703193 C T CNGB1 4 16 57996967 rs570828500 G A CNGB1 4 1 6638781 rs201116489 C T TAS1R1 4 1 6638995 rs150612979 C T TAS1R1 32 D 4.07 1.71 660 580 6 9 9 0.002 4.07 1.71 660 580 6 9 9 0.005 4.07 1.71 660 580 6 9 9 0.003 2.84 3.35 248 222 1 3 3 0.0099 2.84 3.35 248 222 1 3 3 0.001 D 10.86 4.55 264 232 1 4 4 0.003 D 10.86 4.55 264 232 1 4 4 0.005 5.43 264 232 0 3 3 0.002 5.43 264 232 0 3 3 0.001 1.81 132 116 0 3 3 0.005 2.72 1.71 132 116 2 3 3 0.0089 3.62 2.28 264 232 1 2 2 0.001 3.62 2.28 264 232 1 2 2 0.002 D 1.81 2.28 396 348 1 2 2 0.004 1.81 2.28 396 348 1 2 2 0.001 D 1.81 2.28 396 348 1 2 2 0.002 D 1.81 2.28 132 116 1 2 2 0.0079 5.43 1.71 264 232 2 3 3 0.001 5.43 1.71 264 232 2 3 3 0.003 5.48 3.42 262 230 1 3 3 0.004 5.48 3.42 262 230 1 3 3 0.004 3.62 2.28 264 232 1 2 2 0.001 3.62 2.28 264 232 1 2 2 0.003 3.62 4.55 528 464 1 4 4 0.0069 D 3.62 4.55 528 464 1 4 4 0.002 D 3.62 4.55 528 464 1 4 4 0.001 D 3.62 4.55 528 464 1 4 4 0.003 D 2.72 1.71 264 232 2 3 3 0.003 D 2.72 1.71 264 232 2 3 3 0.006 2017100960 13 Μ 2017 4 16 75642789 rs191524413 G C ADAT1 4 16 75646659 rs536106427 A T ADAT1 4 16 84476135 rs 189678245 A G ATP2C2 4 16 84482136 rs138818397 A G ATP2C2 4 16 84485620 rs544756548 C T ATP2C2 4 17 10429123 rs187438258 G A MYH2 4 17 10432499 rs150830535 T C MYH2 4 17 10541353 rs201166774 G A MYH3 4 17 10558169 rs374786690 G C MYH3 4 17 15554781 rs 140413277 G T TRIM16 4 17 19246867 rs7221577 T C B9D1 4 17 19246919 rs556859873 G T B9D1 4 17 19247075 rs4924987 G A B9D1 4 17 26856125 rs 188424977 G A FOXN1 4 17 26861343 rs200401045 C T FOXN1 4 17 26864171 rs187814037 C T FOXN1 4 17 27233472 rs200441251 T c PHF12 4 17 27234599 rs368783828 G A PHF12 4 17 27240924 rs189300962 G C PHF12 4 17 29226507 rs201170896 C T TEFM 4 17 3417212 rs547743528 T C TRPV3 4 17 3417877 rs112791047 G A TRPV3 4 17 38792637 rs 199790447 C G SMARCE1 4 17 38975376 rs565976410 C G KRT10 4 17 38977344 rs200239146 G A KRT10 4 17 39884092 G A HAP1 4 17 39890576 C T HAP1 4 17 46878711 rs 184362955 G A TTLL6 4 17 5347841 rs 192062270 G A DHX33 33 D 2.72 264 232 0 3 3 0.003 D 2.72 264 232 0 3 3 0.001 D 3.62 2.28 396 348 1 2 2 0.001 3.62 2.28 396 348 1 2 2 0.0089 D 3.62 2.28 396 348 1 2 2 0.001 D 3.62 4.55 264 232 1 4 4 0.002 D 3.62 4.55 264 232 1 4 4 0.002 1.81 264 232 0 4 4 0.006 1.81 264 232 0 4 4 0.002 1.81 2.28 132 116 1 2 2 0.0089 6.34 1.99 396 348 4 7 7 0.0079 6.34 1.99 396 348 4 7 7 0.005 6.34 1.99 396 348 4 7 7 0.004 D 1.81 3.41 396 348 1 3 3 0.002 1.81 3.41 396 348 1 3 3 0.001 D 1.81 3.41 396 348 1 3 3 0.005 D 1.81 2.28 396 348 1 2 2 0.001 1.81 2.28 396 348 1 2 2 0.001 D 1.81 2.28 396 348 1 2 2 0.002 D 7.24 1.52 132 116 3 4 4 0.004 2.72 3.41 264 232 1 3 3 0.001 2.72 3.41 264 232 1 3 3 0.004 1.81 132 116 0 3 3 0.004 D 1.81 2.28 264 232 1 2 2 0.002 D 1.81 2.28 264 232 1 2 2 0.001 5.43 1.71 264 232 2 3 3 0.003 5.43 1.71 264 232 2 3 3 0.006 D 5.43 1.71 132 116 2 3 3 0.001 1.81 3.98 396 348 2 7 7 0.004 2017100960 13 Μ 2017 4 17 5364438 rs192014491 G A DHX33 4 17 5371883 rs16954727 C G DHX33 4 17 64216866 rs181936071 A C APOH 4 17 64219860 rs373658444 CA C APOH 4 17 6546267 rs145492116 A G TXNDC17 4 17 67079395 rs 117323775 G T ABCA6 4 17 67121109 rs200376492 A G ABCA6 4 17 67246623 rs559974558 G A ABCA5 4 17 67247973 rs201343208 G A ABCA5 4 17 67250466 rs199641093 C T ABCA5 4 17 67299017 rs201944918 A G ABCA5 4 17 67305519 rs 199888749 G A ABCA5 4 17 73827216 rs 140184929 C T UNC13D 4 17 73839609 rs527842266 C G UNC13D 4 17 7701543 rs141742705 G A DNAH2 4 17 7705344 rs8073196 G C DNAH2 4 17 7736250 rs201527036 G A DNAH2 4 17 79684531 rs201577202 C T SLC25A10 4 17 79684871 rs77609145 A T SLC25A10 4 18 2707800 rs 184984483 C T SMCHD1 4 18 2777922 rs527648000 C T SMCHD1 4 18 28911778 rs147775289 T c DSG1 4 18 28934293 rs149191001 C T DSG1 4 18 28934674 rs 181411154 G A DSG1 4 18 28934927 rs148488583 C G DSG1 4 18 580853 rs114933134 G A CETN1 4 18 61160178 rs370525785 T C SERPINB5 4 18 61170818 rs185364126 G A SERPINB5 4 18 61305002 rs201297323 T C SERPINB4 34 1.81 3.98 396 348 2 7 7 0.003 1.81 3.98 396 348 2 7 7 0.0099 3.62 2.28 264 232 1 2 2 0.0069 3.62 2.28 264 232 1 2 2 0.0069 5.43 1.71 132 116 2 3 3 0.0069 D 1.63 1.64 254 232 2 3 3 0.001 D 1.63 1.64 254 232 2 3 3 0.0079 D 2.9 1.5 652 580 6 8 8 0.001 D 2.9 1.5 652 580 6 8 8 0.001 D 2.9 1.5 652 580 6 8 8 0.004 D 2.9 1.5 652 580 6 8 8 0.0079 D 2.9 1.5 652 580 6 8 8 0.0079 D 5.43 264 232 0 3 3 0.006 5.43 264 232 0 3 3 0.002 D 1.81 2.28 396 348 1 2 2 0.001 1.81 2.28 396 348 1 2 2 0.001 1.81 2.28 396 348 1 2 2 0.001 3.62 1.52 264 232 3 4 4 0.001 D 3.62 1.52 264 232 3 4 4 0.006 5.48 3.37 258 230 1 3 3 0.001 5.48 3.37 258 230 1 3 3 0.005 D 5.43 1.71 528 464 2 3 3 0.003 D 5.43 1.71 528 464 2 3 3 0.001 D 5.43 1.71 528 464 2 3 3 0.001 D 5.43 1.71 528 464 2 3 3 0.004 D 3.62 132 116 0 4 4 0.005 3.62 2.28 264 232 1 2 2 0.001 D 3.62 2.28 264 232 1 2 2 0.002 D 1.81 3.41 264 232 1 3 3 0.0069 2017100960 13 Μ 2017 4 18 61305289 rs 188021365 A T SERPINB4 4 1 87380851 rs546745 A G HS2ST1 4 1 87563514 rs143260332 G A HS2ST1 4 18 76886315 rs200431802 C T ATP9B 4 18 77096664 rs201172611 G A ATP9B 4 18 9549345 rs 199964908 G A PPP4R1 4 19 14071095 rs140301367 G A DCAF15 4 19 15285063 rs141320511 G T NOTCH3 4 19 15298126 rs201118034 G A NOTCH3 4 19 15302951 rs202157633 G A NOTCH3 4 19 39367429 rs58188607 G A RINL 4 19 44662139 rs201230189 G A ZNF234 4 19 41837123 rs199982059 C T TGFβ1 4 19 46184983 rs 186639840 A T GIPR 4 19 46242968 rs183304235 G c BHMG1 4 19 51470542 rs201586262 G T KLK6 4 1 95303290 rs140889980 G A SLC44A3 4 1 95322899 rs 184943086 C T SLC44A3 4 19 8140232 rs145316149 G A FBN3 4 19 8150331 rs142940013 G A FBN3 4 19 8155130 rs 183278638 G A FBN3 4 19 8188820 rs 145435433 C T FBN3 4 19 8979212 rs149481309 C T MUC16 4 19 9002496 rs553074376 C T MUC16 4 19 9043416 rs17417801 G A MUC16 4 19 9056878 rs200934751 GAGA G MUC16 4 20 23433244 rs146114915 G A CST11 4 20 34117097 rs141795719 G A C20orf173 4 20 37394884 rs141204447 G A ACTR5 35 1.81 3.41 264 232 1 3 3 0.005 3.62 2.28 264 232 1 2 2 0.006 3.62 2.28 264 232 1 2 2 0.004 D 3.62 2.28 264 232 1 2 2 0.004 D 3.62 2.28 264 232 1 2 2 0.001 2.72 1.71 132 116 2 3 3 0.0079 5.43 3.41 132 116 1 3 3 0.0079 D 4.53 5.69 396 348 1 5 5 0.0099 D 4.53 5,69 396 348 1 5 5 0.001 D 4.53 5.69 396 348 1 5 5 0.005 3.62 2.28 132 116 1 2 2 0.006 D 1.81 2.28 132 116 1 2 2 0.004 1.81 132 116 0 4 4 0.006 1.81 2.28 132 116 1 2 2 0.0069 D 2.72 132 116 0 3 3 0.0069 D 5.43 132 116 0 3 3 0.001 D 1.81 264 232 0 3 3 0.004 1.81 264 232 0 3 3 0.002 D 1.81 3.41 528 464 1 3 3 0.004 D 1.81 3.41 528 464 1 3 3 0.004 D 1.81 3.41 528 464 1 3 3 0.002 D 1.81 3.41 528 464 1 3 3 0.006 3.62 1.82 528 464 5 8 8 0.0089 3.62 1.82 528 464 5 8 8 0.006 3.62 1.82 528 464 5 8 8 0.0079 3.62 1.82 528 464 5 8 8 0.0069 5.43 3.41 132 116 1 3 3 0.0079 3.62 2.28 132 116 1 2 2 0.006 D 6.34 7.97 264 232 1 7 7 0.0069 2017100960 13 Μ 2017

4 20 37400374 rs3752289 C T ACTR5 4 20 39788407 rs201733074 T c PLCG1 4 20 39797820 rs547025579 GACCAGAA G PLCG1 CC (SEQ ID NO:1) 4 20 39798092 rs183538599 C T PLCG1 4 20 39974514 rs201526389 C T LPIN3 4 20 39981270 rs200870645 C G LPIN3 4 20 39987396 rs202035187 T C LPIN3 4 20 40052247 rs569454917 C G CHD6 4 20 40161851 rs75576471 C G CHD6 4 20 45839488 rs144592314 G A ZMYND8 4 2 101093702 rs 149056157 C T NMS 4 2 11295694 rs372049512 C A PQLC3 4 2 118577378 rs145263993 A C DDX18 4 21 34018908 rs115353088 A T SYNJ1 4 21 34045841 rs115989459 G A SYNJ1 4 21 34048669 rs533995497 T C SYNJ1 4 21 38072227 rs200569203 G A SIM2 4 21 38098456 rs201356831 T C SIM2 4 2 141115543 rs77178150 C T LRP1B 4 2 141253160 rs572325724 T A LRP1B 4 2 141458125 rs369842040 G A LRP1B 4 21 47571485 rs199508525 C T FTCD 4 2 178534249 rs142433460 T A PDE11A 4 2 178562138 rs201572288 A T PDE11A 4 2 179404792 rs556524594 C T TTN 4 2 179425208 rs 142478636 G T TTN 4 2 179430305 rs185887755 G A TTN 6.34 7.97 264 1.81 6.83 396 1.81 6.83 396 1 7 7 0.0089 1 6 6 0.0079 1 6 6 0.0069 1.81 6.83 396 D 3.62 2.28 396 D 3.62 2.28 396 D 3.62 2.28 396 D 3.62 2.28 264 D 3.62 2.28 264 D 3.62 2.28 132 1.81 132 D 1.81 2.28 132 5.43 1.71 132 D 2.41 2.26 394 D 2.41 2.26 394 2.41 2.26 394 1.81 2.28 264 D 1.81 2.28 264 2.72 3.41 396 D 2.72 3.41 396 D 2.72 3.41 396 D 1.81 3.41 132 D 7.24 4.55 264 D 7.24 4.55 264 3.02 1.9 1056 D 3.02 1.9 1056 D 3.02 1.9 1056 1 6 6 0.0079 1 2 2 0.0079 1 2 2 0.002 1 2 2 0.003 1 2 2 0.001 1 2 2 0.0069 1 2 2 0.003 0 5 5 0.0079 1 2 2 0.004 2 3 3 0.004 2 4 4 0.001 2 4 4 0.003 2 4 4 0.001 1 2 2 0.001 1 2 2 0.001 1 3 3 0.0089 1 3 3 0.002 1 3 3 0.001 1 3 3 0.0069 1 4 4 0.004 1 4 4 0.002 3 5 5 0.001 3 5 5 0.004 3 5 5 0.003 36

LlOZMil 096001Z, 103 4 2 179437342 rs567446185 C T TTN D 3.02 1.9 1056 928 3 5 5 0.001 4 2 179481839 rs 144688960 C A TTN 3.02 1.9 1056 928 3 5 5 0.001 4 2 179504772 rs551963261 C T TTN 3.02 1.9 1056 928 3 5 5 0.001 4 2 179577222 rs 186857044 C A TTN D 3.02 1.9 1056 928 3 5 5 0.001 4 2 179585717 rs367826445 C T TTN D 3.02 1.9 1056 928 3 5 5 0.002 4 2 196718225 rs139835496 G A DNAH7 2.72 132 116 0 3 3 0.005 4 2 202356803 rs557048083 G A ALS2CR11 2.72 264 232 0 3 3 0.001 4 2 202467972 rs148342903 C G ALS2CR11 D 2.72 264 232 0 3 3 0.0069 4 2 203058233 rs13024221 T C KIAA2012 7.3 4.59 264 230 1 4 4 0.003 4 2 203059076 rs141298049 G A KIAA2012 7.3 4.59 264 230 1 4 4 0.006 4 2 208477907 rs192886645 G A METTL21A 3.62 2.28 132 116 1 2 2 0.002 4 2 213921827 rs150075012 T C IKZF2 2.72 1.71 132 116 2 3 3 0.0089 4 2 219029361 rs201920477 c T CXCR1 D 3.62 2.28 132 116 1 2 2 0.004 4 22 19864729 rs146133764 G A TXNRD2 D 2.72 3.41 396 348 1 3 3 0.004 4 22 19868190 rs184640901 C G TXNRD2 2.72 3.41 396 348 1 3 3 0.002 4 22 19870857 rs147383232 G A TXNRD2 2.72 3.41 396 348 1 3 3 0.0089 4 22 26159232 rs79294358 C T MY018B D 2.41 4.55 396 348 1 4 4 0.0079 4 22 26166958 rs117430010 C T MY018B 2.41 4.55 396 348 1 4 4 0.006 4 22 26264278 rs137859315 T c MY018B 2.41 4.55 396 348 1 4 4 0.0079 4 2 227872169 rs 192411379 T c COL4A4 D 2.72 3.4 526 464 1 3 3 0.001 4 2 227920837 rs199710625 A G COL4A4 2.72 3.4 526 464 1 3 3 0.004 4 2 227967506 rs373741172 C T COL4A4 D 2.72 3.4 526 464 1 3 3 0.001 4 2 227985873 rs 190570269 G C COL4A4 2.72 3.4 526 464 1 3 3 0.006 4 22 29881766 rs201416955 G A NEFH D 1.81 2.28 264 232 1 2 2 0.003 4 22 29881844 rs117036372 G A NEFH 1.81 2.28 264 232 1 2 2 0.006 4 22 31522450 rs150976596 G A INPP5J D 3.62 1.9 264 232 3 5 5 0.0099 4 22 31522715 rs370874308 A T INPP5J 3.62 1.9 264 232 3 5 5 0.003 4 22 32614713 rs78144589 C T SLC5A4 5.43 6.83 264 232 1 6 6 0.0099 4 22 32631002 rs554791323 T c SLC5A4 D 5.43 6.83 264 232 1 6 6 0.001 37

LlOZMil 096001Z, 103 4 2 234835171 rs188545335 G A TRPM8 1.81 2.28 264 232 1 2 2 0.002 4 2 234890409 rs202160114 T C TRPM8 1.81 2.28 264 232 1 2 2 0.001 4 2 242046783 rs199503351 G A PASK 5.43 3.41 396 348 1 3 3 0.002 4 2 242047581 rs563432464 C A PASK 5.43 3.41 396 348 1 3 3 0.001 4 2 242089016 rs187718988 G C PASK 5.43 3.41 396 348 1 3 3 0.001 4 2 242695306 rs 149628174 C T D2HGDH D 4.53 2.84 132 116 2 5 5 0.0099 4 22 43926729 rs201816198 C A EFCAB6 D 1.63 3.41 264 232 1 3 3 0.0079 4 22 44030977 rs181939688 G C EFCAB6 1.63 3.41 264 232 1 3 3 0.001 4 22 46664409 rs144175578 A G TTC38 3.62 264 232 0 4 4 0.0099 4 22 46684376 rs202139216 C T TTC38 3.62 264 232 0 4 4 0.001 4 22 51041663 rs41282359 C A MAPK8IP2 4.53 2.84 924 812 2 5 5 0.002 4 22 51042484 rs56314791 C T MAPK8IP2 4.53 2.84 924 812 2 5 5 0.002 4 22 51042861 rs9616795 C G MAPK8IP2 4.53 2.84 924 812 2 5 5 0.004 4 22 51042864 rs571810591 G C MAPK8IP2 4.53 2.84 924 812 2 5 5 0.001 4 22 51043374 rs550444582 G A MAPK8IP2 4.53 2.84 924 812 2 5 5 0.002 4 22 51044243 rs916005 C T MAPK8IP2 4.53 2.84 924 812 2 5 5 0.004 4 22 51045178 rs200208943 C T MAPK8IP2 4.53 2.84 924 812 2 5 5 0.001 4 2 27721143 rs 146175795 G A GCKR D 5.43 3.41 264 232 1 3 3 0.0069 4 2 27730834 rs200225266 C T GCKR 5.43 3.41 264 232 1 3 3 0.004 4 2 31751329 rs9332966 G c SRD5A2 1.81 2.28 264 232 1 2 2 0.005 4 2 31805775 rs550866120 C T SRD5A2 1.81 2.28 264 232 1 2 2 0.003 4 2 46588019 rs150877473 C G EPAS1 2.72 3.41 264 232 1 3 3 0.0099 4 2 46603672 rs187543960 C G EPAS1 2.72 3.41 264 232 1 3 3 0.004 4 2 65571844 rs182442107 T C SPRED2 3.62 2.28 132 116 1 2 2 0.002 4 2 98165911 rs1839230 T C ANKRD36B 3.62 132 116 0 4 4 0.0069 4 3 108147410 rs552849827 T C MYH15 D 3.02 1.86 518 464 3 5 5 0.001 4 3 108178230 rs560378764 G A MYH15 D 3.02 1.86 518 464 3 5 5 0.001 4 3 108219046 rs182324086 C A MYH15 D 3.02 1.86 518 464 3 5 5 0.001 4 3 108220556 rs368131843 C T MYH15 3.02 1.86 518 464 3 5 5 0.006 38

LlOZMil 096001Z, 103

4 3 121713035 rs 142746163 G A ILDR1 4 3 121724081 rs200883040 C G ILDR1 4 3 124485068 rs200221434 C T ITGB5 4 3 124492606 rs140023830 G A ITGB5 4 3 124567399 rs28372859 T A ITGB5 4 3 124716667 rs181022733 G T HEG1 4 3 124731800 rs183321802 T A HEG1 4 3 124738285 rs200164121 G C HEG1 4 3 130120633 rs370632529 T G COL6A5 4 3 130124457 rs537224684 A G COL6A5 4 3 130145236 rs202221090 G A COL6A5 4 3 130150614 rs79358579 C T COL6A5 4 3 13420488 rs200748145 T C NUP210 4 3 154861227 rs2304504 C T MME 4 3 154861228 rs 182602615 G A MME 4 3 154886310 rs200308077 G A MME 4 3 183906578 rs531703061 C T ABCF3 4 3 183911416 rs76223160 G A ABCF3 4 3 183952934 rs374722127 C T VWA5B2 4 3 183957472 rs565285822 C T VWA5B2 4 3 186937924 rs3774266 C T MASP1 4 3 186953975 rs72549155 G C MASP1 4 3 2928719 rs184171731 A C CNTN4 4 3 3080611 rs10510251 G C CNTN4 4 3 3081959 rs339284 T C CNTN4 4 3 44762826 rs181738022 c T ZNF502 4 3 44762827 rs185260708 A T ZNF502 4 3 49850176 rs192575536 G A UBA7 4 3 58107069 rs76471260 G A FLNB 1.81 264 1.81 264 2.72 396 D 2.72 396 D 2.72 396 D 7.24 2.28 396 D 7.24 2.28 396 D 7.24 2.28 396 D 3.62 1.52 528 D 3.62 1.52 528 D 3.62 1.52 528 D 3.62 1.52 528 5.43 132 5.43 1.71 396 5.43 1.71 396 D 5.43 1.71 396 D 5.43 4.55 264 D 5.43 4.55 264 2.41 1.52 264 2.41 1.52 264 D 3.62 2.28 264 D 3.62 2.28 264 4.53 5.69 396 4.53 5.69 396 4.53 5.69 396 D 2.72 3.41 264 D 2.72 3.41 264 3.62 2.28 132 D 2.41 4.55 396 0 3 3 0.0099 0 3 3 0.003 0 3 3 0.002 0 3 3 0.0079 0 3 3 0.002 2 4 4 0.003 2 4 4 0.004 2 4 4 0.0079 3 4 4 0.002 3 4 4 0.001 3 4 4 0.003 3 4 4 0.003 0 3 3 0.001 2 3 3 0.003 2 3 3 0.003 2 3 3 0.002 1 4 4 0.003 1 4 4 0.006 3 4 4 0.001 3 4 4 0.0089 1 2 2 0.004 1 2 2 0.003 1 5 5 0.003 1 5 5 0.003 1 5 5 0.002 2 6 6 0.0079 2 6 6 0.0079 1 2 2 0.002 1 4 4 0.002 39

LlOZMil 096001Z, 103

4 3 58109123 rs199959926 G C FLNB 4 3 58134099 rs143066905 A G FLNB 4 3 62309627 rs1881268 G C C3orf14 4 3 62317022 rs186089632 C A C3orf14 4 4 15599021 rs 117667651 C A CC2D2A 4 4 16168246 rs2271748 C T TAPT1 4 4 17842302 rs527561771 TAA T NCAPG 4 4 26322320 rs200707132 A c RBPJ 4 4 6596385 rs3216941 AC A MAN2B2 4 4 674349 rs376244258 AC A MYL5 4 4 84378118 rs199634680 A AT MRPS18C 4 4 96762012 rs144813590 C G PDHA2 4 4 983115 rs143381873 G A SLC26A1 4 4 983342 rs201608921 C T SLC26A1 4 4 983810 rs563866785 G A SLC26A1 4 4 984938 rs139024319 G A SLC26A1 4 5 106716975 rs201008479 G A EFNA5 4 5 118862922 rs190659146 T C HSD17B4 4 5 130815199 rs 187240567 T C RAPGEF6 4 5 130841167 rs201819833 G A RAPGEF6 4 5 134102599 rs200408238 C G DDX46 4 5 134143635 rs20Q296518 A G DDX46 4 5 137506607 rs191895585 G A BRD8 4 5 1495038 rs201521332 G A LPCAT1 4 5 156675967 rs34482255 C T ITK 4 5 180477285 rs200884524 C T BTNL9 4 5 180483533 rs373494500 T c BTNL9 4 5 38337618 rs376475358 G A EGFLAM 4 5 38425202 rs201409353 A G EGFLAM D 2.41 4.55 396 2.41 4.55 396 1.81 264 1.81 264 2.72 132 2.9 4.55 132 2.76 1.66 126 3.62 2.28 132 5.43 3.41 132 3.62 2.28 132 1.84 2.32 132 D 5.43 132 D 3.62 1.52 528 D 3.62 1.52 528 D 3.62 1.52 528 D 3.62 1.52 528 D 2.41 132 3.62 132 3.62 2.28 264 D 3.62 2.28 264 2,41 2.28 264 2.41 2.28 264 3.62 2.28 132 5.53 126 D 1.81 2.28 132 1.81 1.71 264 1.81 1.71 264 3.62 2.28 264 3.62 2.28 264 1 4 4 0.006 1 4 4 0.0099 0 3 3 0.001 0 3 3 0.003 0 3 3 0.0079 1 4 4 0.0099 2 3 3 0.0079 1 2 2 0.0079 1 3 3 0.006 1 2 2 0.006 1 2 2 0.0079 0 3 3 0.003 3 4 4 0.005 3 4 4 0.002 3 4 4 0.001 3 4 4 0.002 0 4 4 0.006 0 4 4 0.005 1 2 2 0.001 1 2 2 0.002 2 4 4 0.001 2 4 4 0.0069 1 2 2 0.005 0 3 3 0.0069 1 2 2 0.005 2 3 3 0.001 2 3 3 0.0069 1 2 2 0.003 1 2 2 0.001 40

LlOZMil 096001Z, 103 4 5 43675682 rs80011859 C A NNT 4 5 43677914 rs144007922 C T NNT 4 5 94245090 rs543643285 G GA MCTP1 4 5 94259730 rs555638017 GAAAC G MCTP1 4 5 95226800 rs560418641 C T ELL2 4 5 95278698 rs74836108 G A ELL2 4 6 106960382 rs201789082 G C AIM1 4 6 106968092 rs371163103 TC T AIM1 4 6 106991468 rs147230945 G A AIM1 4 6 110636694 rs141656597 T C METTL24 4 6 127899925 rs141247870 C T C6orf58 4 6 147014059 rs 192310446 T c ADGB 4 6 149959701 rs375809770 AAAG A KATNA1 4 6 158454680 rs 147847428 G A SYNJ2 4 6 158516905 rs202164985 C G SYNJ2 4 6 20113198 rs199830796 G A MBOAT1 4 6 20118693 rs553353326 G A MBOAT1 4 6 33134570 G A COL11A2 4 6 33138929 G A COL11A2 4 6 33146518 A C COL11A2 4 6 33147564 C A COL11A2 4 6 33154514 C A COL11A2 4 6 35438350 rs187631484 C T MIR7111 4 6 35438350 rs187631484 C T RPL10A 4 6 39883802 rs34757428 A T MOCS1 4 6 42933047 rs187435179 A G PEX6 4 6 43160731 rs568565110 C G CUL9 4 6 43170522 rs200509434 G T CUL9 4 6 43172581 rs80345623 G A CUL9 D 3.62 2.28 264 3.62 2.28 264 11.05 2.28 260 11.05 2.28 260 1.81 2.28 264 1.81 2.28 264 D 3.62 2.28 396 3.62 2.28 396 D 3.62 2,28 396 1.81 2.28 132 5.43 3.41 132 1.81 132 5.43 132 D 2.41 4.55 264 D 2.41 4.55 264 D 5.43 264 D 5.43 264 D 1.81 3.79 660 D 1.81 3.79 660 1.81 3.79 660 D 1.81 3.79 660 D 1.81 3.79 660 2.72 1.71 132 2.72 1.71 132 5.73 3.6 132 D 3.62 2.28 132 5.43 396 D 5.43 396 D 5.43 396 232 1 2 2 232 1 2 2 228 6 12 12 228 6 12 12 232 1 2 2 232 1 2 2 348 1 2 2 348 1 2 2 348 1 2 2 116 1 2 2 116 1 3 3 116 0 3 3 116 0 3 3 232 1 4 4 232 1 4 4 232 0 3 3 232 0 3 3 580 3 10 10 580 3 10 10 580 3 10 10 580 3 10 10 580 3 10 10 116 2 3 3 116 2 3 3 110 1 3 3 116 1 2 2 348 0 3 3 348 0 3 3 348 0 3 3 2017100960 13 Μ 2017 0,002 0.004 0.001 0.006 0.001 0.0069 0.005 0.003 0.001 0.0099 0.0079 0.006 0.005 0.0079 0.001 0.004 0.001 0.006 0.0099 0.004 0.001 0.0089 0.0069 0.0069 0.0069 0.0089 0.001 0.0069 0.0099 41 2017100960 13 Μ 2017 4 6 49416648 rs199555550 G A MUT 4 6 49425591 rs200908035 T C MUT 4 6 49425720 rs528689712 T C MUT 4 6 72678681 rs532652925 C G RIMS1 4 6 72974764 rs564292772 C A RIMS1 4 6 76540124 rs187811833 C T MY06 4 6 89977391 rs 146618576 T c GABRR2 4 6 89977789 rs141423190 A c GABRR2 4 6 89978946 rs 188424932 G A GABRR2 4 7 100357429 rs374243234 C T ZAN 4 7 100363045 rs184742914 A T ZAN 4 7 100389715 rs369936309 C T ZAN 4 7 100656178 rs74570695 G A MUC12 4 7 117144344 rs1800073 C T CFTR 4 7 117171053 rs141723617 T c CFTR 4 7 117199578 rs138427145 A T CFTR 4 7 117235045 rs397508395 G A CFTR 4 7 117307076 rs4148725 C T CFTR 4 7 131888058 rs143605398 TGCTAGGC T PLXNA4 CCCAGCC (SEQ ID NO:2) 4 7 131888117 rs181597184 C T PLXNA4 4 7 139260038 rs56338252 T c HIPK2 4 7 143017768 rs201509501 c T CLCN1 4 7 143029550 rs202119213 c T CLCN1 4 7 26678881 rs78525926 G A C7orf71 4 7 26678910 rs111516571 C T C7orf71 4 7 29535662 rs3815512 G C CHN2 4 7 47342658 rs 192974657 G A TNS3 9.05 5.32 370 348 1 5 5 0.0079 D 9.05 5.32 370 348 1 5 5 0.0079 D 9.05 5.32 370 348 1 5 5 0.001 1.81 2.28 264 232 1 2 2 0.001 1.81 2.28 264 232 1 2 2 0.003 1.81 130 116 0 3 3 0.0089 7.24 3.03 396 348 3 8 8 0.002 D 7.24 3.03 396 348 3 8 8 0.0079 D 7.24 3,03 396 348 3 8 8 0.003 1.81 3.41 396 348 1 3 3 0.001 1.81 3.41 396 348 1 3 3 0.003 D 1.81 3.41 396 348 1 3 3 0.003 2.72 3.41 132 116 1 3 3 0.003 D 3.62 2.26 654 580 2 4 4 0.002 D 3.62 2.26 654 580 2 4 4 0.0079 D 3.62 2.26 654 580 2 4 4 0.001 D 3.62 2.26 654 580 2 4 4 0.001 D 3.62 2.26 654 580 2 4 4 0.006 1.81 2.28 264 232 1 2 2 0.0099 D 1.81 2.28 264 232 1 2 2 0.003 2.41 2.28 264 232 2 4 3 0.003 D 5.43 3.41 264 232 1 3 3 0.002 D 5.43 3.41 264 232 1 3 3 0.003 3.62 264 232 0 4 4 0.004 3.62 264 232 0 4 4 0.004 3.62 2.28 132 116 1 2 2 0.003 D 3.62 2.28 264 232 1 2 2 0.002 42 2017100960 13 Μ 2017

4 7 47454718 rs 187456873 C T TNS3 4 7 75192236 C A HIP1 4 7 75210547 A T HIP1 4 8 116426988 rs181035264 T A TRPS1 4 8 116631783 rs202001185 T C TRPS1 4 8 133900823 rs368037086 C T TG 4 8 133981695 rs189500765 C T TG 4 8 144895478 C A SCRIB 4 8 145694225 rs193131687 C T KIFC2 4 8 145736896 rs557256260 C T RECQL4 4 8 145738985 rs536831548 G C RECQL4 4 8 145741388 rs200097701 C G RECQL4 4 8 145741602 rs34633809 C T RECQL4 4 8 145742799 rs34642881 T C RECQL4 4 8 17400906 rs12680645 G A SLC7A2 4 8 17407821 rs188973136 C G SLC7A2 4 8 17417839 rs201373242 A G SLC7A2 4 8 24771326 rs182011677 C G NEFM 4 8 24775743 rs557507354 C T NEFM 4 8 25293853 rs2271114 A G KCTD9 4 8 41470357 rs372694683 C T GPAT4 4 8 43155706 rs 182905752 C T POTEA 4 8 43211970 rs534445172 A c POTEA 4 8 89086826 rs200104505 T A MMP16 4 9 136917570 rs200913664 G A BRD3 4 9 138235867 rs531171616 G A C9orf62 4 9 138236230 rs560393458 T G C9orf62 4 9 139008659 rs373479265 C T C9orf69 4 9 139360706 rs189523223 C T SEC16A 43 D 3.62 2.28 264 232 1 2 2 0.002 3.62 4.55 264 232 1 4 4 0.0089 3.62 4.55 264 232 1 4 4 0.001 D 5.43 1.71 264 232 2 3 3 0.003 D 5.43 1.71 264 232 2 3 3 0.004 1.84 260 228 0 3 3 0.002 1.84 260 228 0 3 3 0.004 1.81 4.55 132 116 1 4 4 0.006 5.43 132 116 0 3 3 0.003 1.81 1.71 660 580 4 6 6 0.001 1.81 1.71 660 580 4 6 6 0.001 1.81 1.71 660 580 4 6 6 0.005 1.81 1.71 660 580 4 6 6 0.0089 1.81 1.71 660 580 4 6 6 0.0079 D 2.26 2.84 396 348 2 5 5 0.0079 D 2.26 2.84 396 348 2 5 5 0.006 D 2.26 2.84 396 348 2 5 5 0.001 D 2.72 264 232 0 3 3 0.004 D 2.72 264 232 0 3 3 0.001 3.68 2.25 128 114 1 2 2 0.005 3.62 2.28 132 116 1 2 2 0.003 3.68 2.23 254 228 1 2 2 0.001 3.68 2.23 254 228 1 2 2 0.001 3.62 2.28 132 116 1 2 2 0.0099 3.62 2.28 132 116 1 2 2 0.0069 3.62 2.28 264 232 1 2 2 0.001 3.62 2.28 264 232 1 2 2 0.004 3.62 2.28 132 116 1 2 2 0.003 7.24 264 232 0 4 4 0.004 2017100960 13 Μ 2017 4 9 139372145 rs192612248 G T SEC16A 4 9 15571614 rs 182199324 T C CCDC171 4 9 15745503 rs530529615 A T CCDC171 4 9 15777828 rs202139088 T G CCDC171 4 9 439392 rs117109271 A G DOCK8 4 9 441423 rs188141951 C T DOCK8 4 9 5968714 rs 183413824 C T KIAA2026 4 9 72517162 rs12344550 T c C9orf135 4 9 72517293 rs11140833 G T C9orf135 4 X 8759354 rs768509456 A T FAM9A 4 X 8763309 rs774169916 GCTGCTG G FAM9A CTG CTGCGGC TT (SEQ ID NO:3) 4 X 96136645 rs778550013 C T DIAPH2 5 11 17394037 rs61406813 CTT c NCR3LG1 5 1 21926063 rs61014678 c T RAP1GAP 5 2 113342071 rs528909726 G A CHCHD5 5 7 139285351 rs3735196 C G HIPK2 5 X 96396659 rs363755 C T DIAPH2 6 10 126714641 rs12571821 G C CTBP2 6 10 28970433 rs79472556 G C BAMBI 6 10 28970914 rs750723477 C T BAMBI 6 10 61956386 rs34796699 GA G ANK3 6 10 61956386 rs772920191 G GAAA ANK3 6 10 61956386 rs772920191 G GA ANK3 6 10 62023781 rs144841334 G A ANK3 6 10 81901943 rs7080405 G C PLAC9 7.24 264 3.62 2.28 396 3.62 2.28 396 3.62 2.28 396 1.81 1.52 264 1.81 1.52 264 3.62 2.28 132 3.62 264 3.62 264 3.69 4.56 262 3.69 4.56 262 0 4 4 0.005 1 2 2 0.002 1 2 2 0.003 1 2 2 0.002 3 4 4 0.0099 3 4 4 0.003 1 2 2 0.005 0 4 4 0.005 0 4 4 0.005 1 4 4 0.0013 1 4 4 0.0026 3.66 2.24 260 5.43 3.41 132 7.24 4.55 264 124 2.41 2.28 264 3.66 2.24 260 1.81 1.52 132 1.81 2.28 264 1.81 2.28 264 2.45 1.6 240 2.45 1.6 240 2.45 1.6 240 2.45 1.6 240 3.62 2.28 132 2 4 3 0.0013 2 6 5 0.0089 2 8 7 0.0069 0 2 1 0.002 2 4 3 0.0089 2 4 3 0.0052 3 4 4 0.0446 1 2 2 0.0159 1 2 2 14 22 19 14 22 19 14 22 19 14 22 19 0.0268 1 2 2 0.0188 44

6 10 81926637 rs777020491 G A ANXA11 6 10 81926750 rs34332933 G C ANXA11 6 10 94822756 rs58993699 C T CYP26C1 6 10 94834060 rs 185421897 C T CYP26A1 6 10 94835071 rs80188100 A G CYP26A1 6 10 94835072 rs75053982 G A CYP26A1 6 1 10042683 rs138626416 G A NMNAT1 6 11 121323228 G A SORL1 6 11 121430331 T C SORL1 6 11 121440905 rs753319585 G A SORL1 6 11 121457048 rs146197030 T G SORL1 6 11 121460027 rs752525626 G C SORL1 6 11 121489543 rs751110498 A C SORL1 6 1 116933040 rs28622933 C G ATP1A1 6 11 22232870 rs78987921 G A AN05 6 11 22239801 C T AN05 6 1 145414790 G c HFE2 6 11 487419 G A PTDSS2 6 11 489522 rs375041205 C T PTDSS2 6 11 490077 rs374769797 G A PTDSS2 6 1 15834360 rs2020902 A G CASP9 6 1 15860803 rs11583306 C T DNAJC16 6 1 159410340 rs12409540 T A OR10J1 6 1 160011511 rs3795339 c T KCNJ10 6 11 613605 G C IRF7 6 11 615010 rs12290989 G T IRF7 6 11 615011 rs12272434 A T IRF7 6 11 615087 rs761513714 G T IRF7 6 1 16382911 rs72474563 A G CLCNKB 2017100960 13 Μ 2017 2.72 1.71 264 2.72 1.71 264 2.41 1.52 132 1.96 2.11 396 1.96 2.11 396 1.96 2.11 396 D 1.81 132 D 7.24 2.28 792 D 7.24 2,28 792 D 7.24 2.28 792 7.24 2.28 792 D 7.24 2.28 792 D 7.24 2.28 792 2.41 2.28 132 3.62 4.55 264 3.62 4.55 264 2.72 132 3.62 4.55 396 3.62 4.55 396 3.62 4.55 396 1.81 1.71 132 2.17 3.41 132 1.51 5.69 132 D 2.72 1.71 132 1.58 2.65 526 1.58 2.65 526 1.58 2.65 526 1.58 2.65 526 5.43 1.71 132 2 3 3 2 3 3 0.0188 3 4 4 0.0119 7 13 11 0.0139 7 13 11 0.0119 7 13 11 0.0119 0 3 3 0.0159 2 4 4 2 4 4 2 4 4 2 4 4 2 4 4 2 4 4 4 8 8 0.0268 1 4 4 0.0109 1 4 4 0 3 3 0.0129 1 4 4 1 4 4 1 4 4 2 3 3 0.0317 2 6 6 0.0466 1 5 5 0.0278 2 3 3 0.0129 3 7 7 3 7 7 0.0208 3 7 7 0.0208 3 7 7 4 6 6 0.0357 45 6 11 7060977 rs76274604 A T NLRP14 6 11 74082748 rs117508615 C T PGM2L1 6 1 177247693 rs 138799872 C T BRINP2 6 1 182821420 rs573535598 AAGG A DHX9 6 12 1023218 rs4987207 G T RAD52 6 12 1036304 rs2286030 C T RAD52 6 12 1038978 rs35278212 C CT RAD52 6 12 109719311 rs146550988 C T FOXN4 6 12 11001963 AT A PRR4 6 12 113592306 rs200344876 G GC CFAP73 6 12 16377347 rs 117974895 C T SLC15A5 6 1 227968222 rs12568707 C T SNAP47 6 1 22924364 rs72651347 G A EPHA8 6 1 22927298 rs569320402 C T EPHA8 6 12 404774 rs 140234136 G T KDM5A 6 12 417081 rs373321785 G A KDM5A 6 12 432376 rs751710770 CAAAA C KDM5A 6 12 432376 rs756310068 CAAA C KDM5A 6 12 498088 rs117819701 G A KDM5A 6 12 51510213 rs77417603 T A TFCP2 6 12 63974439 rs61935050 C T DPY19L2 6 1 26566248 rs775335757 T C CEP85 6 1 26601570 rs11577318 A G CEP85 6 1 27943525 rs2231876 G C FGR 6 13 26155953 rs7335339 G C ATP8A2 6 1 39466786 rs10888613 C G AKIRIN1 6 14 39784010 rs539446066 A ATGTG CTAGE5 6 14 39784010 rs539446066 A ATGTGT G CTAGE5 1.51 2.84 132 1.81 1.71 132 3.62 2.28 132 1.81 2.28 132 1.81 1.71 396 1.81 1.71 396 1.81 1.71 396 D 1.81 2.28 132 1.81 2 24 130 2.26 2.84 132 1.51 2.84 132 2.26 1.9 132 1.81 6.83 264 D 1.81 6.83 264 D 2.53 1.69 420 D 2.53 1.69 420 2.53 1.69 420 2.53 1.69 420 2.53 1,69 420 1.58 1.99 132 2.41 2.24 130 1.81 2.28 264 1.81 2.28 264 1.63 1.71 132 2.41 4.55 132 1.63 2.56 132 1.64 3 128 1.64 3 128 116 2 5 5 116 4 6 6 116 2 4 4 116 1 2 2 348 14 21 21 348 14 21 21 348 14 21 21 116 1 2 2 116 1 2 2 116 2 5 5 116 2 5 5 116 3 5 5 232 1 6 6 232 1 6 6 356 7 10 10 356 7 10 10 356 7 10 10 356 7 10 10 356 7 10 10 116 4 7 6 116 2 4 4 232 2 4 3 232 2 4 3 116 6 9 9 116 1 4 3 116 8 18 18 128 4 12 12 128 4 12 12 46 2017100960 13 Μ 2017 0,0327 0.0387 0.0119 0.0109 0.0268 0.0347 0.0635 0.0109 0.0149 0.0169 0.0337 0.0188 0.0179 0.0129 0.0119 0.0228 0.0129 0.0228 0.0308 0.0248 0.1052 0.0615 2017100960 13M2017 6 14 39784010 rs539446066 A ATGTGT GTG CTAGE5 6 14 39784010 rs539446066 A ATGTGT CTAGE5 1.64 3 128 128 4 12 12 1.64 3 128 128 4 12 12

GTGTG (SEQ ID N0:4) 6 1 47403818 rs79056865 A G CYP4A11 6 15 48512900 rs749613571 G A SLC12A1 6 15 48580692 rs537641866 G A SLC12A1 6 15 48594989 rs755737521 G T SLC12A1 6 1 55076238 rs7535372 C A FAM151A 6 15 55484910 rs3759863 G A RSL24D1 6 15 75628507 C T COMMD4 6 15 75631598 rs200129803 C T COMMD4 6 16 1825689 rs3826055 C T EME2 6 16 1825789 rs746707908 T c EME2 6 16 2017804 rs146108433 T G RNF151 6 16 30455945 rs146596728 A C SEPHS2 6 16 30456188 rs550048089 G A SEPHS2 6 16 31004812 rs12445568 T C STX1B 6 16 67198846 rs115335849 C T HSF4 6 16 733320 A T JMJD8 6 16 733604 rs79868981 G A JMJD8 6 1 67442275 rs11208979 C T MIER1 6 17 16342833 rs11871958 T c LRRC75A- AS1 6 17 18022218 rs765495851 G A MY015A 6 17 18023739 rs766303371 T G MY015A 6 17 18028490 A G MY015A 6 17 18043856 A G MY015A 6 17 18051423 A G MY015A 2.72 1.71 132 116 8 12 12 0.0536 D 10.86 2.28 396 348 1 2 2 D 10.86 2.28 396 348 1 2 2 D 10.86 2.28 396 348 1 2 2 1.62 1.53 130 116 19 26 22 0.1687 1.81 1.55 132 116 11 15 14 0.0685 1.81 2.28 264 232 1 2 2 1.81 2.28 264 232 1 2 2 0.0149 4.53 5.69 264 232 1 5 5 0.0129 4.53 5.69 264 232 1 5 5 D 3.62 2.28 132 116 4 8 7 0.0387 2.72 1.71 264 232 2 3 3 0.0248 2.72 1.71 264 232 2 3 3 1.91 1.8 132 116 12 19 17 0.1002 2.41 1.52 132 116 3 4 4 0.0278 2.72 1.71 264 232 2 3 3 2.72 1.71 264 232 2 3 3 0.0129 1.66 1.93 132 116 13 22 20 0.1171 1.81 2.11 132 116 7 13 13 0.0823 D 2.04 1.71 1056 928 4 6 6 D 2.04 1.71 1056 928 4 6 6 D 2.04 1.71 1056 928 4 6 6 D 2.04 1.71 1056 928 4 6 6 D 2.04 1.71 1056 928 4 6 6 47 2017100960 13M2017 6 17 18057215 rs9916193 C G MY015A 6 17 18064722 rs140029076 C T MY015A 6 17 18071031 rs201763265 C T MY015A 6 17 38511509 rs188616110 C T RARA 6 17 47486684 rs2277637 T c PHB 6 17 67079441 rs143326198 C G ABCA6 6 17 67081193 rs527461596 G C ABCA6 6 17 67109811 rs777203184 T G ABCA6 6 17 67121068 A G ABCA6 6 17 67124939 A C ABCA6 6 1 78420930 rs151051327 T C FUBP1 6 1 78429408 rs2274257 G C FUBP1 6 1 78432563 A G FUBP1 6 18 50432706 rs17389547 A C DCC 6 18 50912515 rs3764494 G A DCC 6 18 50937026 rs11873515 A G DCC 6 19 13318672 CCTGCTGC C CACNA1A TGCTGCT GCTGCTG CTGCTG (SEQ ID N0:5) 2.04 1.71 1056 928 4 6 6 0.0119 D 2.04 1.71 1056 928 4 6 6 D 2.04 1.71 1056 928 4 6 6 4.53 2.84 132 116 2 5 5 0.0149 1.65 1.71 132 116 14 21 17 0.123 D 1.63 2.26 656 580 2 4 4 0.0119 D 1.63 2.26 656 580 2 4 4 D 1.63 2.26 656 580 2 4 4 D 1.63 2,26 656 580 2 4 4 D 1.63 2.26 656 580 2 4 4 1.52 1.76 396 346 13 20 19 0.0109 1.52 1.76 396 346 13 20 19 0.0903 1.52 1.76 396 346 13 20 19 1.81 1.51 396 348 40 53 43 0.0109 1.81 1.51 396 348 40 53 43 0.0238 1.81 1.51 396 348 40 53 43 0.2252 2.45 2.06 708 668 36 70 70

6 19 13318672 rs16054 CCTGCTG C CACNA1A 6 19 13318672 rs370146696 CCTG C CACNA1A 6 19 13318672 rs753460234 C CCTG CACNA1A 6 19 13318672 rs753460234 C CCTGCT G C CACNA1A 6 19 13318672 rs765169827 CCTGCTGC CACNA1A TG CTGCTGCT G 2.45 2.06 708 668 36 70 70 2.45 2.06 708 668 36 70 70 0.0714 2.45 2.06 708 668 36 70 70 2.45 2.06 708 668 36 70 70 2.45 2.06 708 668 36 70 70 48 2017100960 13 Μ 2017 6 19 13394158 (SEQ ID NO:6) T C CACNA1A 6 19 13410044 C G CACNA1A 6 19 13616741 G A CACNA1A 6 19 13616977 rs 15999 G A CACNA1A 6 19 1367226 rs11668809 G A MUM1 6 19 32083223 rs11880125 A G THEG5 6 19 32083250 rs79323410 T C THEG5 6 19 36394245 rs74258162 T C HCST 6 19 38572367 rs562186095 GGCCACC G SIPA1L3 6 19 38572367 rs569252662 G GGCCAC p SIPA1L3 6 19 38590722 C U T SIPA1L3 6 19 39421820 rs2304116 T G MRPS12 6 19 39591919 rs182155157 c G ACP7 6 19 39592099 rs186807855 T C ACP7 6 19 4099225 rs200371894 G A MAP2K2 6 19 4099246 G A MAP2K2 6 19 51582802 rs199715229 C T KLK14 6 19 51585822 rs769468261 G A KLK14 6 19 51729577 rs201473304 ACCCAACA A CD33 6 19 53554075 rs1650983 AC TGGTATCT TT (SEQ ID NO:7) A G ERW-2 6 19 54872594 G A LAIR1 6 19 54872611 A T LAIR1 6 19 54872698 C G LAIR1 D 2.45 2.06 708 668 36 70 70 D 2.45 2.06 708 668 36 70 70 2.45 2.06 708 668 36 70 70 D 2.45 2.06 708 668 36 70 70 0.0159 1.81 2.28 132 116 1 2 2 0.0149 3.02 2.84 264 232 4 10 10 0.0179 3,02 2.84 264 232 4 10 10 0.0179 1.81 3.41 132 116 2 6 6 0.0357 4.66 2.17 392 348 14 27 27 4.66 2.17 392 348 14 27 27 0.0337 D 4.66 2.17 392 348 14 27 27 3.62 2.28 132 116 1 2 2 0.0119 1.92 1.93 264 232 10 17 16 0.0387 1.92 1.93 264 232 10 17 16 0.0179 D 1.81 2.28 264 232 1 2 2 0.0119 D 1.81 2.28 264 232 1 2 2 D 2.72 1.71 264 232 2 3 3 0.0119 2.72 1.71 264 232 2 3 3 2.11 1.99 132 116 4 7 7 0.0258 1.81 4.55 132 116 1 4 4 0.0188 1.81 1.9 396 348 9 15 15 0.0317 1.81 1.9 396 348 9 15 15 0.0308 1.81 1.9 396 348 9 15 15 0.0308 49

6 19 55739813 rs10419308 G A TMEM86B 6 19 57956740 rs148699125 C CA ZNF749 6 19 58118371 rs78803667 G A ZNF530 6 19 6147453 rs16993408 G C ACSBG2 6 19 6161219 rs78713134 C T ACSBG2 6 19 6183085 A ATAG ACSBG2 6 20 31040031 rs2236156 C T NOL4L 6 20 31672812 rs71349705 C T BPIFB4 6 20 31677295 rs 142982767 C T BPIFB4 6 20 34572606 rs6142471 A G CNBD2 6 20 44511257 rs35972756 G A ZSWIM1 6 20 44676727 rs12481488 T A SLC12A5 6 21 43412786 rs200509586 GTCA G ZBTB21 6 21 44293806 rs146400491 G A WDR4 6 21 44488667 C T CBS 6 21 44492252 rs201827340 G A CBS 6 2 169791766 G A ABCB11 6 2 169801131 rs118109635 G A ABCB11 6 2 169853135 A G ABCB11 6 2 175304621 rs67227536 C G GPR155 6 2 175333632 rs28588913 G A GPR155 6 22 25603008 rs13055430 C T CRYBB3 6 22 31521167 rs150867939 C T INPP5J 6 22 31521324 C A INPP5J 6 22 31521552 rs774897780 G A INPP5J 6 22 31522468 rs767028605 G A INPP5J 6 22 31524007 rs769593351 A G INPP5J 6 22 31524578 rs202068549 C T INPP5J 6 22 31530095 G c 1NPP5J 2017100960 13 Μ 2017 1.53 1.79 132 1.81 6.83 132 D 4.53 1.9 132 12.07 1.9 396 12.07 1.9 396 12.07 1.9 396 5.43 132 2.72 1.71 264 2.72 1.71 264 D 1.81 4.55 132 2.72 1.71 132 1.81 2.28 132 5.43 3.41 132 3.02 5.69 132 D 3.62 2.28 264 D 3.62 2.28 264 D 3.02 2.84 396 D 3.02 2.84 396 3.02 2.84 396 3.62 2.28 264 3.62 2.28 264 3.62 3.03 132 D 3.62 2.28 924 D 3.62 2.28 924 D 3.62 2.28 924 D 3.62 2.28 924 D 3.62 2.28 924 D 3.62 2.28 924 D 3.62 2.28 924 7 11 11 0.0704 1 6 6 0.0357 3 5 5 0.0159 6 10 9 0.0119 6 10 9 0.0238 6 10 9 0 3 3 0.0248 2 3 3 2 3 3 0.0179 1 4 3 0.0278 2 3 3 0.0159 2 4 4 0.0238 2 6 6 0.0109 1 5 4 0.0208 2 4 4 2 4 4 0.0129 2 5 5 2 5 5 0.0129 2 5 5 2 4 4 0.0139 2 4 4 0.0248 3 8 8 0.0268 3 6 6 0.0129 3 6 6 3 6 6 3 6 6 3 6 6 3 6 6 3 6 6 50 6 2 232458085 rs 145183277 TGAGA T C2orf57 6 22 32992729 rs191241866 G A SYN3 6 2 237246998 G T IQCA1 6 2 237247013 rs186626813 G A IQCA1 6 2 239344663 rs11904390 T A ASB1 6 22 40801855 rs 188579679 C T SGSM3 6 22 43933284 rs3833393 CCT c EFCAB6 6 22 44131813 C T EFCAB6 6 22 46668317 rs779119363 A G TTC38 6 22 46679924 rs201314224 G C TTC38 6 22 46684341 rs763990471 G A TTC38 6 22 50754445 rs80243206 A T DENND6B 6 22 50756452 rs73439320 A G DENND6B 6 2 27729343 C A GCKR 6 2 27729453 G A GCKR 6 2 28634790 rs 12624279 G A FOSL2 6 2 31412347 rs78Q99670 G A CAPN14 6 2 31414833 G T CAPN14 6 2 31414844 rs147299374 C T CAPN14 6 2 31414959 rs141014145 A G CAPN14 6 2 31422395 rs200657395 TCTC T CAPN14 6 2 47399601 rs4953472 A G CALM2 6 3 107097080 rs138204694 CAAATG C CCDC54 6 3 111828384 rs397949663 G GT C3orf52 6 3 119242443 rs58978800 C T T1MMDC1 6 3 122459290 rs16338 G GAGA HSPBAP1 6 3 122459732 rs35887395 G A HSPBAP1 6 3 169546730 rs149140811 C T LRRIQ4 6 3 183908937 rs765039315 C T ABCF3 2.09 2.84 132 5.43 132 D 2.72 1.71 264 D 2.72 1.71 264 1.97 3.41 132 2.72 132 1.63 2.28 264 D 1.63 2.28 264 3.62 1,71 396 D 3.62 1.71 396 3.62 1.71 396 1.51 2.84 264 1.51 2.84 264 5.43 2.28 264 5.43 2.28 264 1.65 1.63 132 5.07 1.59 660 D 5.07 1.59 660 D 5.07 1.59 660 D 5.07 1.59 660 5.07 1.59 660 3.62 1.71 132 1.81 7.97 132 1.56 1.54 132 1.81 4.55 132 1.93 1.52 264 1.93 1.52 264 2.11 1.99 132 D 5.43 1.71 396 116 6 15 15 116 0 3 3 232 2 3 3 232 2 3 3 116 4 12 12 116 0 6 6 232 2 4 4 232 2 4 4 348 2 3 3 348 2 3 3 348 2 3 3 232 2 5 5 232 2 5 5 232 1 2 2 232 1 2 2 116 21 30 25 580 5 7 7 580 5 7 7 580 5 7 7 580 5 7 7 580 5 7 7 116 4 6 6 116 1 7 7 116 28 38 33 116 1 4 4 232 24 32 30 232 24 32 30 116 4 7 6 348 2 3 3 51 2017100960 13 Μ 2017 0.0536 0.0129 0.0129 0.0595 0.0169 0.0159 0.0198 0.0208 0.1835 0.0179 0.0149 0.0139 0.0327 0.0317 0.2569 0.0258 0.126 0.126 0.0357 6 3 183910604 rs118183801 T C ABCF3 6 3 183911455 A G ABCF3 6 3 187451313 rs 140944763 T A BCL6 6 3 32030579 rs373566244 GT G ZNF860 6 3 50219709 rs12639175 A G SEMA3F 6 4 121719584 rs35363618 T TA PRDM5 6 4 16181283 rs78942971 A G TAPT1 6 4 177109395 rs200650536 T G SPATA4 6 4 177116495 C A SPATA4 6 4 2233893 rs 117602484 A G HAUS3 6 4 2240347 rs376063631 C T HAUS3 6 4 69094459 rs75647314 C A TMPRSS11B 6 4 69096987 rs575638339 C T TMPRSS11B 6 4 71888240 rs67437265 C T DCK 6 4 76447062 rs76333976 G c THAP6 6 4 76581064 rs6823013 C T G3BP2 6 5 140182074 rs17844259 G A PCDHA3 6 5 26886200 rs41271091 C A CDH9 6 5 70898466 T TC MCCC2 6 5 70922542 rs549784997 C T MCCC2 6 6 109721228 rs4946972 A C PPIL6 6 6 109763947 rs35444917 TC T SMPD2 6 6 116783619 rs117361304 T G FAM26F 6 6 136554647 rs2274141 A T MTFR2 6 6 167738715 rs12526096 G A TTLL2 6 6 25691362 rs17492659 C T SCGN 6 6 26507069 rs 188130447 T c BTN1A1 6 6 26509379 rs752379950 C T BTN1A1 6 6 32361841 T c BTNL2 D 5.43 1.71 396 D 5.43 1.71 396 1.55 6.83 132 2.72 1.71 132 1.81 2.28 132 1.77 1.99 132 2.9 2.25 98 2.72 3.39 262 2.72 3.39 262 3.32 1.66 210 D 3.32 1.66 210 2.11 1.59 264 D 2.11 1.59 264 D 1.81 1.82 132 D 1.81 2.28 132 1.81 1.71 132 D 3.62 2.28 132 1.84 1.87 128 1.81 1.71 264 D 1.81 1.71 264 1.93 1.82 132 1.81 1.82 132 2.63 3.03 132 2.02 2.15 112 3.62 3.03 132 1.81 1.99 132 1.81 4.55 264 1.81 4.55 264 1.85 1.67 660 348 2 3 3 348 2 3 3 116 1 6 6 116 2 3 3 116 1 2 2 116 24 42 34 116 3 8 8 232 1 3 3 232 1 3 3 190 2 3 3 190 2 3 3 232 5 7 7 232 5 7 7 116 5 8 8 116 1 2 2 116 2 3 3 116 2 4 4 114 12 20 20 232 2 3 3 232 2 3 3 116 10 16 15 116 10 16 15 116 6 16 16 104 1 2 2 116 3 8 8 116 4 7 7 232 1 4 4 232 1 4 4 580 53 78 74 52 2017100960 13 Μ 2017 0.0169 0.0228 0.0129 0.0129 0.1885 0.0248 0.0149 0.0119 0.0278 0.0387 0.0129 0.0198 0.0179 0.0972 0.0179 0.1032 0.1032 0.0635 0.0407 0.0347 0.0417 0.0208 0.0417

6 6 32361842 G A BTNL2 6 6 32369554 G A BTNL2 6 6 32369586 GAA G BTNL2 6 6 32370969 TG T BTNL2 6 6 36929653 rs 144897670 C T P116 6 6 39330207 rs9349115 C G KIF6 6 6 87994504 rs35259282 C T GJB7 6 6 87994537 rs112552839 G A GJB7 6 7 123267310 rs116956332 C T ASB15 6 7 12727793 rs117537847 G A ARL4A 6 7 40277228 rs76667176 T C SUGCT 6 7 40899963 rs751805172 C G SUGCT 6 7 40899965 rs767692645 C G SUGCT 6 7 72984917 CGTT C TBL2 6 7 73083744 C T VPS37D 6 7 73630406 G A LAT2 6 7 7476098 rs11984435 T C COL28A1 6 7 7491996 rs 148703211 G C COL28A1 6 7 7559695 G C COL28A1 6 8 10677699 rs61757720 A T PINX1 6 8 10692283 rs746583094 G A PINX1 6 8 116599274 rs745384526 G A TRPS1 6 8 116599415 T C TRPS1 6 8 30697414 rs149889016 A G TEX15 6 9 137998709 rs35408956 T A OLFM1 6 9 140248783 rs372878424 G A EXD3 6 9 140249147 rs 143654067 C T EXD3 6 9 5892552 rs 148372841 G c MLANA 6 X 2871176 rs56393981 G A ARSE 1.85 1.67 660 1.85 1.67 660 1.85 1.67 660 1.85 1.67 660 1.81 3.41 132 1.81 132 D 1.81 4.55 264 D 1.81 4.55 264 3.62 2,28 132 1.61 2.03 132 1.51 396 D 1.51 396 D 1.51 396 1.81 2.84 132 5.43 1.71 132 1.97 2.28 132 2.41 2.28 396 D 2.41 2.28 396 D 2.41 2.28 396 2.74 1.72 264 D 2.74 1.72 264 D 5.43 2.28 264 D 5.43 2.28 264 3.62 2.24 130 2.07 2.28 132 1.81 2.28 264 1.81 2.28 264 4.53 5.69 132 2.74 3.41 132 580 53 78 74 580 53 78 74 580 53 78 74 580 53 78 74 116 1 3 3 116 0 7 7 232 1 4 4 232 1 4 4 116 1 2 2 114 4 7 7 348 0 5 5 348 0 5 5 348 0 5 5 116 2 5 5 116 2 3 3 116 6 12 11 348 4 8 8 348 4 8 8 348 4 8 8 230 2 3 3 230 2 3 3 232 1 2 2 232 1 2 2 116 1 2 2 116 4 8 8 232 1 2 2 232 1 2 2 116 1 5 5 116 2 6 5 2017100960 13 Μ 2017 0.0417 0.1171 0.1984 0.0129 0.0367 0.0188 0.0208 0.0466 0.0119 0.0159 0.0129 0.0446 0.0208 0.0109 0.0139 0.0188 0.0367 0.0119 0.0139 0.0262 53 2017100960 13 Μ 2017

49114808 C A FOXP3 8763309 GCTGCTG CTG CTGCGGC TT (SEQ ID NO:8) * FAM9A D 2.06 3.69 5.12 132 116 2 9 130 114 0 4 8 0.0393 4 54 2017100960 13 Μ 2017

Table 6: High priority candidate gene list in Rheumatoid Arthritis disease. Gene SNP p-Value Odd ratio References ABHD6 rs73081554 5.00E-08 1.18 Okada Y,PMID: 24390342 ACOXL rs6732565 3.00E-08 1.07 Okada Y.PMID: 24390342 AFF3 rs9653442|rs116 1.00E- 1.1211.12)1 Okada Y.PMID: 243903421Stahl 76922|rs1086503 5 14|1.00E-14|2.00E-082.00E-06 3.00E-07 .12 EA.PMID: 20453842|Jiang L,PM!D: 24782177|Stahl EA.PMID: 20453842 AHNAK2 rs2582532 1.17 Okada Y.PMID: 24390342 AIRE rs2075876|rs760 426 4.00E- 09|4.40E- 08 9.00E-06 1.18| 1.16 Terao C.PMID: 21505073|Terao C.PMID: 21505073 ANAPC4 rs3816587 1.09 WTCCC.PMID: 17554300 ANKRD55 rs77331626|rs77 7.00E- 1.2111.2111 Okada Y.PMID: 31626|rs6859219 24|8,00E-23| 1.00E- 11 .28 24390342|Okada Y.PMID: 24390342 Stahl EA.PMID: 20453842 ANXA3 rs2867461 1.00E-12 1.13 Okada Y.PMID: 22446963 APOM rs805297 3.00E-10 1.56 Hu HJ.PMID: 21844665 ARAP1 rs3781913 6.00E-10 1.12 Okada Y.PMID: 22446963 ARHGEF3 rs2062583 2.16E-06 0.63 Freudenberg J.PMID: 21452313 ARID5B rs71508903|rs71 1.00E- 1.18| 1.18| 1 Okada Y.PMID: 508903|rs108219 44 08|1.00E- 08|6.00E- 18 .16 24390342|Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 ARL15 rs255758 7.00E-06 1.42 Negi S.PMID: 23918589 ATG5 rs9372120 4.00E-08 1.10 Okada Y.PMID: 24390342 ATM chr11:107967350 1.00E-08 1.21 Okada Y.PMID: 24390342 B3GNT2 rs13385025lrs11 900673 9.00E- 07|1.00E- 08 1.11(1.11 Okada Y.PMID: 24390342jOkada Y.PMID: 22446963 BATF rs7155603 1.00E-07 1.16 Stahl EA.PMID: 20453842 BLK rs2736337|rs160 2.00E- 1.15|0.77| 1 Okada Y.PMID: 0249|rs2736340 07|5.00E-06j 1-22E-05|6.00E-09 ,29|1.19 24390342|Freudenberg J.PMID: 214523131 Freudenberg J.PMID: 21452313|Gregersen PK.PMID: 19503088 BTNL2 rs3763309 2.00E-124 2.30 Orozco G.PMID: 24449572 C1QBP rs72634030 2.00E-09 1.12 Okada Y.PMID: 24390342 C4orf52 rs 11933540 1.00E-16 1.15 Okada Y.PMID: 24390342 C5 rs10985070|rs37 4.00E- 1.09)1.13| Okada Y.PMID: 24390342|Stahl 61847|rs881375 09|2.00E- 07|4.00E- 08 1.00E- 10|4.00E- 08 3.00E-12 NR EA.PMID: 20453842|Gregersen PK.PMID: 19503088 C5orf30 rs2561477|rs262 32 1.09(1.14 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 C6orf10 rs9275406 2.10 Negi S.PMID: 23918589 CASP8 rs6715284 2.00E-09 1.15 Okada Y.PMID: 24390342 CCL19 rs11574914 2.00E-15 1.13 Okada Y.PMID: 24390342 CCL21 rs951005|rs2812 4.00E- 1.19| 1.12| 1 Stahl EA.PMID: 378|rs11574914 10|3.00E- .13 20453842|Raychaudhuri 55 2017100960 13M2017 08|2.00E- S,PMID: 18794853|Okada 15 Y.PMID: 24390342 CCR6 rs1571878|rs309 1.00E- 1.28|1.13| Okada Y.PMID: 24390342|Stahl 3023|rs1854853|r 22|2.00E- NR|NR EA.PMID: 20453842|Jiang S3093024 11|4.00E- 09|2.00E- 10|8.00E- 19 8.00E-10 L,PMID: 247821771Jiang L.PMID: 247821771Kochi Y,PMID: 20453841 CD2 rs624988 1.09 Okada Y,PMID: 24390342 CD226 rs2469434 1.00E-08 NR Okada Y,PMID: 24390342 CD244 rs11265493|rs37 4.10E- 1.28(1.3(1. Suzuki A,PMID: 53389|rs3766379 07|8.00E- 31(1.28)1.3 18794858|Suzuki A.PMID: |rs1319651 |rs668 08|3.00E- 1 18794858|Suzuki A,PMID: 2654 08I6.40E- 18794858 Suzuki A.PMID: 07j7.00E- 18794858|Suzuki A.PMID: 08 18794858 CD247 rs840016 2.00E-06 1.11 Stahl EA.PMID: 20453842 CD28 rs1980422 2.00E-13 1.13 Okada Y.PMID: 24390342 CD40 rs4239702|rs481 1.00E- 1.14(0.85( 1 Okada Y.PMID: 24390342|Stah! 0485 16|3.00E- .15 EA.PMID: 09|8.00E- 20453842|Raychaudhuri 09 S.PMID: 18794853 CD5 rs508970 3.00E-06 1.07 Okada Y.PMID: 24390342 CD83 chr6:14103212|rs 3.00E- 1.16(1.14 Okada Y.PMID: 12529514 06|2.00E- 24390342jOkada Y.PMID: 08 22446963 CDK2 rs773125 1.00E-10 1.09 Okada Y.PMID: 24390342 CDK4 rs1633360 1.00E-07 1.07 Okada Y.PMID: 24390342 CDK5RAP ο rs12379034 1.00E-12 1.34 Jiang L.PMID: 24782177 CDK6 rs4272|rs42041 1.00E- 1.10(1.11 Okada Y.PMID: 08|4.00E- 24390342|Raychaudhuri 06 S.PMID: 18794853 CEP57 rs4409785 1.00E-11 1.12 Okada Y.PMID: 24390342 CFLAR rs6715284 2.00E-09 1.15 Okada Y.PMID: 24390342 CLNK rs13142500 2.00E-06 1.10 Okada Y.PMID: 24390342 CLYBL rs9557321 6.00E-08 1.73 Bossini-Castillo L.PMID: 24532677 COG6 rs9603616 2.00E-12 1.10 Okada Y.PMID: 24390342 CSF2 rs657075|rs6570 6.00E- 1.12(1.12 Okada Y.PMID: 75 06|3.00E- 24390342|Okada Y.PMID: 10 22446963 CSF3 chr17:38031857 2.00E-12 1.09 Okada Y.PMID: 24390342 CTLA4 rs3087243]rs308 3.00E- 1.14( 1.15| 1 Okada Y.PMID: 24390342|Stahl 7243|rs231775|rs 25|1.00E- .09|NR EA.PMID: 20453842|Doroth??e 231735 08|6.30E- 07|6.00E- 09 Diogo,PMID:23261300|Gregers en PK.PMID: 19503088 CXCR5 rs10790268 1.00E-15 1.14 Okada Y.PMID: 24390342 56 2017100960 13 Μ 2017 DNASE1L ο rs73081554 5.00E-08 1.18 Okada Y,PMID: 24390342 0 DPP4 rs12617656 1.00E-08 1.24 Jiang L,PMID: 24782177 EOMES rs3806624 3.00E-08 1.08 Okada Y,PMID: 24390342 ETS1 rs73013527|rs49 37362 1.00E- 06|8.00E- 07 1.08|1.Q9 Okada Y,PMID: 24390342jOkada Y.PMID: 22446963 ETV7 rs2234067 1.60E-09 1.15 Okada Y.PMID: 24390342 FADS1 rs968567 2.00E-08 1.12 Okada Y.PMID: 24390342 FADS2 rs968567 2.00E-08 1.12 Okada Y.PMID: 24390342 FADS3 rs968567 2.00E-08 1.12 Okada Y.PMID: 24390342 FAM124A rs3790022 1.00E-06 1.49 Bossini-Castillo L.PMID: 24532677 FCGR2A rs72717009|rs18 01274|rs1181014 3 1.00E-07|2.40E-07| 1.80E-07 1.13| 1.10| 1 .14 Okada Y.PMID: 24390342|Doroth??e Diogo,PMID:23261300|Doroth? ?e Diogo,PMID:23261300 FCRL3 rs2317230 2.00E-07 1.07 Okada Y.PMID: 24390342 FLI1 rs4937362 8.00E-07 1.09 Okada Y.PMID: 22446963 GATA3 rs3824660 2.00E-08 1.08 Okada Y.PMID: 24390342 GATSL3 rs 1043099 7.00E-09 1.19 Orozco G.PMID: 24449572 GCH1 rs3783637 2.00E-06 1.10 Okada Y.PMID: 22446963 GMCL1L rs2961663 4.00E-06 NR Padyukov L.PMID: 21156761 GPR125 rs6448119 7.00E-06 NR Padyukov L.PMID: 21156761 GRHL2 rs678347 2.00E-08 1.08 Okada Y.PMID: 24390342 GRM5 rs518167 2.00E-06 2.24 Bossini-Castillo L.PMID: 24532677 Η LA rs12194148|rs21 57337 5.00E- 58j9.00E- 52 NR|NR Padyukov L.PMID: 211567611Padyukov L.PMID: 21156761 HLA-B rs2596565 9.00E-09 1.40 Bossini-Castillo L.PMID: 24532677 HLA- rs9271348|rs645 5.00E- 1.28|NR|2, Bossini-Castillo L.PMID: DQA1 7617|rs9275406 07j1.00E- 09|3,00E- 12 10 24532677|Julia A.PMID: 18668548]Negi S.PMID: 23918589 HLA- rs12525220|rs64 2.00E- 2.87|NR|2. Jiang L.PMID: 24782177|Julia DQA2 57617|rs9275406 13| 1.00E-09|3,0QE-12 2.00E-13|3. OOE-12 1.00E- 10 A.PMID: 18668548|Negi S.PMID: 23918589 HLA- DQB1 rs12525220|rs92 75406 2.87|2.10 Jiang L.PMID: 24782177|Negi S.PMID: 23918589 HLA- rs9268839|rs926 2.47|2.47|2 Okada Y.PMID: DRB1 8839|rs6910071 |r s7765379|rs1319 2471|rs660895jrs 6457620|rs61567 2|rs9271348 250|1,00E- 250|1.00E- 299|5.00E- 23|2.00E- 58|1.00E- ,88|2.51|N R|3.62|2.5 5|NR|1.28 24390342|Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Freudenberg J.PMID: 21452313|Kochi Y.PMID: 20453841 |Plenge RM.PMID: 57 2017100960 13 Μ 2017 108|4.00E- 186|8.00E- 27|5.00E- 07 IFNGR2 rs73194058 1.00E-06 IGFBP1 rs6956740 5.00E-07 IKZF3 chr17:38031857|r 2.00E- S2872507 12|9.00E- 07 IL2 rs45475795|rs13 4.00E- 119723 06|7.00E- 07 IL20RB rs9826828 9.00E-10 IL21 rs45475795|rs13 4.00E- 119723 06|7.00E- 07 IL2RA rs706778|rs7067 5.00E- 78|rs2228150|rs2 14|1.00E- 104286 11|6.60E- 06|1.00E- 06 IL2RB rs3218251 6.00E-06 IL3 rs657075 6.00E-06 IL6R rs2228145 4.00E-09 IL6ST rs6859219 1.00E-11 INPP5B rs28411352 3.00E-12 intergenic rs12413578 5.00E-08 IRAKI rs5987194 3.00E-12 IRF4 rs9378815 1.00E-07 IRF5 chr7:128580042|r 1.00E- s10488631 |rs380 14|4.00E- 7306 1113.00E-07 IRF8 rs13330176|rs22 1.00E- 80381 12|2.00E- 06 JAZF1 rs67250450 3.00E-09 KCNIP4 rs6448119 7.00E-06 KIF3 rs17374222 2.00E-06 KIF5A rs1678542|rs167 1.00E- 8542 07|9.00E- 08 LBH rs10175798 1.00E-09 LOC10050 6023 rs2105325 3.00E-11 LOC10050 rs8133843 2.00E-08 6403 17804836|Raychaudhuri S.PMID: 18794853|WTCCC,PMID: 175543001 Bossini-Castillo L.PMID: 24532677 1.08 Okada Y.PMID: 24390342 NR Padyukov L.PMID: 21156761 1.09| 1.10 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 1.14|1.12 Okada Y.PMID: 243903421Stahl EA.PMID: 20453842 1.44 Okada Y.PMID: 24390342 1 _14| 1.12 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 1.10| 1.14| 1 ,25|1.19 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Doroth??e Diogo,PMID:23261300|Orozco G.PMID:24449572 1.08 Okada Y.PMID: 24390342 1.12 Okada Y.PMID: 24390342 1.08 Okada Y.PMID: 24390342 1.28 Stahl EA.PMID: 20453842 1.11 Okada Y.PMID: 24390342 NR Okada Y.PMID: 24390342 1.16 Okada Y.PMID: 24390342 1.09 Okada Y.PMID: 24390342 1.12| 1.19| 1 .44 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Padyukov L.PMID: 21156761 1.12| 1.12 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 1.11 Okada Y.PMID: 24390342 NR Padyukov L.PMID: 21156761 1.13 Stahl EA.PMID: 20453842 1.20)1.12 Orozco G.PMID: 24449572|Raychaudhuri S.PMID: 18794853 1.08 Okada Y.PMID: 24390342 1.12 Okada Y.PMID: 24390342 1.09 Okada Y.PMID: 24390342 58 2017100960 13 Μ 2017 LOC14583 7 rs8026898 4.00E-19 LOC33944 2 rs12140275 2.00E-09 MED1 rs1877030 2.00E-08 MHC rs7748270|rs645 1.00E- 7617|rs12525220 16|5.00E-75 |2.00E-13 MICA rs2596565 9.00E-09 MMEL1 chr1:2523811|rs3 5.00E- 890745 09|1.00E- 07 MTF1 rs28411352 3.00E-12 NFKBIE rs2233424|rs223 1.00E- 3434 19|6.00E-19 |1.00E-15 OLIG3 rs2230926|rs692 2.00E- 0220|rs10499194 06|1,00E-07 |1.00E-09 P2RY10 chrX:78464616 4.00E-08 PADI4 rs2301888|rs224 1.00E- 0335 18|2.00E- 08 PDE2A rs3781913 6.00E-10 PIP4K2C rs1678542 9.00E-08 PLCL2 rs4452313 2.00E-10 PLD4 rs2582532|rs284 3.00E- 1277 07|2.00E- 14 POU3F1 rs12131057 4.00E-07 PPIL4 rs9373594 3.00E-09 PRKCB1 rs7404928 4.00E-06 PRKCH rs3783782|rs195 2.00E- 7895 09|4.00E- 07 PRKCQ rs947474|rs4750 3.00E- 316 10|2.00E- 06|4.00E- 06 PTPN11 rs10774624 7.00E-09 PTPN2 rs8083786]rs284 2.00E- 7297 11 J2.00E-08 PTPN22 rs2476601|rs247 9.00E- 6601|rs6679677 170|9.00E- 74]0|1.00E- 08|6.00E- 1.15 1.11 Okada Y,PMID: 24390342

Okada Y.PMID: 24390342 1-09 Okada Y.PMID: 24390342 2.0112.36|2 Jiang L,PMID: .87 24782177|WTCCC,PMID: 175543001Jiang L.PMID: 24782177 1.40 Bossini-Castillo L.PMID: 24532677 1.10| 1.12 Okada Y.PMID: 24390342|Raychaudhuri S.PMID: 18794853 1.11 Okada Y.PMID: 24390342 1.26)1.19 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963|Myouzen K.PMID: 23028356 1.31)1.22) 1 Kochi Y.PMID: .33 204538411Plenge RM.PMID: 17982456|Plenge RM.PMID: 17982456 1.11 Okada Y.PMID: 24390342 1.13|1.50 Okada Y.PMID: 24390342|Freudenberg J.PMID: 21452313 1.12 Okada Y.PMID: 22446963 1.12 Raychaudhuri S.PMID: 18794853 NR Okada Y.PMID: 24390342 1.17)1.15 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 1.16 Stahl EA.PMID: 20453842 1.09 Okada Y.PMID: 24390342 1.08 Okada Y.PMID: 22446963 1.14)1.09 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 1.12)1.15)1 Okada Y.PMID: 24390342|Stahl .14 EA.PMID: 204538421Raycha ud h u ri S.PMID: 18794853 1.09 Okada Y.PMID: 24390342 1.18)1.10 Okada Y.PMID: 24390342|Okada Y.PMID: 22446963 1.80)1.94)1 Okada Y.PMID: 24390342|Stahi .82|1.79|1. EA.PMID: 20453842|Doroth??e 98 Diogo,PMID:23261300|Padyuko v L.PMID: 59 2017100960 13 Μ 2017 42I6.00E- 25 PVT1 rs1516971 1.00E-10 ΡΧΚ rs73081554|rs13 5.00E- 315591 08)5.00E-08 RAD51B rs1950897 5.00E-08 RAG1 rs331463 1.00E-07 RAG2 rs331463 1.00E-07 RASGRP1 rs8032939 2.00E-18 RBPJ rs874040|rs6448 1.00E- 432 16|4.00E- 07 RCAN1 chr21:35928240 3.00E-07 REL rs34695944|rs13 2.00E- 031237|rs130175 15|8.00E- 99 07|2.00E- 12 RNASEH2 Β rs3790022 1.00E-06 RPS12P4 rs4305317 2.00E-06 RTKN2 rs6479800|rs312 4.00E- 5734 06|5.00E- 09 RUNX1 rs8133843 2.00E-08 SALL3 rs2002842 6 00E-06 SFTPD rs726288 9.00E-09 SH2B3 rs10774624|rs31 7.00E- 84504 09|6.00E- 06 SMIM21 rs1943199 2.00E-08 SPRED2 rs1858037|rs934 1.00E- 734 08|5.00E-10j2.00E-08 STAT4 rs118893411 rs75 1.00E- 74865 12|3.00E-07|2.00E-06 SYNGR1 rs909685 1.00E-16 TAGAP rs2451258 2.00E-10 TEC rs2664035 1.00E-07 TNFAIP3 rs7752903|rs692 2.00E- 0220|rs2230926|r 20|9.00E- s10499194 13|1.00E- 07|6.80E- 21156761 |Raychaudhuri S.PMID: 18794853|WTCCC,PMiD: 17554300 1.15 Okada Y.PMID: 24390342 1.18|1.29 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 1.09 Okada Y,PMID: 24390342 1.12 Okada Y.PMID: 24390342 1.12 Okada Y.PMID: 24390342 1.13 Okada Y.PMID: 24390342 1.14| 1.19 Stahl EA.PMID: 20453842|Orozco G.PMID: 24449572 1.11 Okada Y.PMID: 24390342 1.12|1.13| Okada Y.PMID: 24390342|Stahl NR EA.PMID: 20453842|Gregersen PK.PMID: 19503088 1.4925 Bossini-Castiilo L.PMID: 24532677 1.45 Padyukov L.PMID: 21156761 1.19|NR Okada Y.PMID: 24390342jMyouzen K.PMID: 23028356 1.09 Okada Y.PMID: 24390342 1.61 Julia A.PMID: 18668548 1.22 Okada Y.PMID: 24390342 1.09|1.08 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842 1.94 Bossini-Castiilo L.PMID: 24532677 1.19)1.13 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Jiang L.PMID: 24782177 1.12)1.16 Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Kochi Y.PMID: 20453841 1.13 Okada Y.PMID: 24390342 1.10 Okada Y.PMID: 24390342 1.07 Okada Y.PMID: 24390342 1.41)1.22)1 Okada Y.PMID: 24390342|Stahl .3811.33 EA.PMID: 20453842|Plenge RM.PMID: 17982456|Doroth??e Diogo,PMID:23261300|Kochi 60 2017100960 13 Μ 2017 14I2.00E- 06jl.00E- 09 TNFRSF1 chr1:2523811|rs3 5.00E- 4 890745 09I4.00E- 06|1.00E- 06|1.00E- 07 TNFRSF9 rs227163 3.00E-09 TPD52 rs998731 2.00E-08 TRAF1 rs10985070|rs37 4.00E- 61847|rs2239657 09|2.00E- |rs881375|rs2072 07|5.40E- 438 08|4.00E- 08|3.00E- 09 TRAF1-C5 rs3761847 4.00E-14 TRAF6 rs331463 1.00E-07 TRHDE rs12831974 6.00E-06 TXNDC11 rs4780401 4.00E-08 TYK2 rs34536443 5.00E-16 UBASH3A rs1893592|rs112 7.00E- 03203 12|4.00E- 06 UBE2L3 rs11089637 2.00E-07 WDFY4 rs2671692 3.00E-09 YDJC rs11089637 2.00E-07 ZNF438 rs793108 1.00E-09 ZNF774 rs6496667 1.00E-06 Y.PMID: 20453841 |Plenge RM.PMID: 17982456 1.10| 1.12| NR| 1.12 Okada Y.PMID: 24390342|Stahl EA,PMID: 20453842|Orozco G.PMID: 244495721Raychaud h u ri S.PMID: 18794853 1.11 Okada Y,PMID: 24390342 1.08 Okada Y,PMID: 24390342 1.09|1.13|1 ,10|NR|NR Okada Y.PMID: 24390342|Stahl EA.PMID: 20453842|Doroth??e Diogo,PMID:23261300|Gregers en PK,PMID: 19503088|Jiang L.PMID: 24782177 1.32 Plenge RM.PMID: 17804836 1.12 Okada Y.PMID: 24390342 1.27 Freudenberg J.PMID: 21452313 1.07 Okada Y.PMID: 24390342 1.46 Okada Y.PMID: 24390342 1.11|1.11 Okada Y.PMID: 243903421Stahl EA.PMID: 20453842 1.10 Okada Y.PMID: 24390342 1.07 Okada Y.PMID: 24390342 1.10 Okada Y.PMID: 24390342 1.08 Okada Y.PMID: 24390342 1.09 Okada Y.PMID: 22446963 61 2017100960 13M2017

Table 7: Clinical conditions associated with group 2 variants in RA and control comparison. chr pos id ref alt gene LR Clinical conditions reported in ClinVar Function 10 101829514 rs61751507 C T CPN1 T Anaphylotoxin inactivator deficiency Peptide hormone metabolism; Protects the body from potent vasoactive and inflammatory peptides. 11 18291302 rs79681911 G A SAA1 T Serum amyloid a variant Activated TLR4 signaling; Cytokine Signaling in Immune system. 3 133476698 rs41295774 A G TF T Atransferrinemia Vesicle-mediated transport; Iron metabolism in placenta. 5 41862758 rs75134564 G A OXCT1 D Succinyl-CoA acetoacetate transferase deficiency Ketone body metabolism; Regulation of lipid metabolism. 7 44104839 rs77938727 C T PGAM2 D Glycogen storage disease type X Glycosaminoglycan metabolism; Immune response in T lymphocytes. X 38229135 rs72554348 G c OTC Ornithine carbamoltransferase deficiency Carbon metabolism; Viral mRNA Translation. 62 2017100960 13 Μ 2017

Table 8: Pathway analysis for candidate genes conferring susceptibility to RA Pathway P value Genes Based on genes identified in comparison of RA patients and controls ECM-receptor interaction 2.1 x ΙΟ’3 COL4A4, COL6A5. COLJ1A1, COL11A2, HSPG2, ITGB5, LAMCl, THBS1 Protein digestion and absorption 2.3 x ΙΟ 3 ATP1A1, ATP1A4, COL4A4, COL6A5. COL11A1, COL11A2, MME, PRCP Focal adhesion 2.8 x ΙΟ2 RASGRF1, COL4A4, COL6A5, COL11A1, COL11A2, FLNB, ITGB5, LAMCl, MYL5, THBSI Glycerophospholipid metabolism 4.8 x 10-2 CHAT, GPAT4, LPINS, LPCAT1, MBOAT1. PTDSS2 Based on genes only identified in disease duration comparison of RA patients Olfactory transduction 1.2 x ΙΟ 2 OR14C36, OR4A15, OR52N4. OR6C74, OR6C75, OR7G3, OR9K2 63 2017100960 13 Μ 2017

Table 9: Candidate variant list from RA disease duration comparison. grou P chr pos id ref alt gene LR Gene burden ratio KG <1. East Year Asia Year Total No. of alleles in gene <1-Year .7^ Year No. alt alleles in genes <1- 23-Year Year No. of >3- Variant Year allele cases with frequenc alt alleles y KG East Asia 2 10 101829514 rs61751507 C T CPN1 T 2.28 2.26 52 46 1 2 2 0.0248 2 1 115220086 rs121912682 C T AMPD1 D 4.57 52 46 0 3 3 0.0109 2 11 18291302 rs79681911 G A SAA1 PPARGC1 T 3.04 2.26 52 46 1 2 2 0.0198 2 5 149212243 rs7732671 G C B T 1.76 1.88 52 46 3 5 5 0.0625 2 7 138417791 rs3807153 A G ATP6V0A4 T 1.71 52 46 0 3 3 0.0516 2 X 38229135 rs72554348 G C OTC 4.61 4.35 50 46 1 4 3 0.0144 4 10 135086331 rs536126291 C T ADAM 8 9.13 2.26 104 92 1 2 2 0.002 4 10 135087305 rs3810960 G A ADAM 8 9.13 2.26 104 92 1 2 2 0.003 4 10 25144247 rs 199794379 A G PRTFDC1 D 9.13 2.26 104 92 1 2 2 0.004 4 10 25147326 rs 199983667 C A PRTFDC1 D 9.13 2.26 104 92 1 2 2 0.001 4 10 70987060 rs10823320 A G HKDC1 D 18.26 208 184 0 4 4 0.001 4 10 70992606 rs575180113 G A HKDC1 D 18.26 208 184 0 4 4 0.003 4 10 71002935 rs185650169 C T HKDC1 18.26 208 184 0 4 4 0.0069 4 10 71021004 rs143285779 C T HKDC1 D 18.26 208 184 0 4 4 0.001 4 1 100174455 rs192583899 T c FRRS1 3.04 2.26 104 92 1 2 2 0.003 4 1 100177969 rs187278122 A G FRRS1 3.04 2.26 104 92 1 2 2 0.006 4 11 130060344 rs199819888 C T ST14 1.52 2.26 156 138 1 2 2 0.003 4 11 130064039 rs76687780 C G ST14 1.52 2.26 156 138 1 2 2 0.006 4 1 11826069 rs560354825 G C C1orf167 D 6.09 1.51 156 138 3 4 4 0.002 4 1 11826663 rs374366683 G A C1orf167 6.09 1.51 156 138 3 4 4 0.004 4 1 11844289 rs76627351 C T C1orf167 6,09 1.51 156 138 3 4 4 0.0079 64 1 6638995 rs150612979 C T TAS1R1 D 4.57 2.26 104 92 1 2 2 0.006 16 70916556 rs9932260 G A HYDIN 18.26 1.51 52 46 3 4 4 0.002 17 10398298 rs140873918 G T MYH1 D 3.04 2.26 416 368 2 4 4 0.002 * λ * Jk 4^ 4s* Jk 45* 4^ 45* 45* 45* 45* 45* 45* 45* 45* 45* 45* jk 45* Jk Jk Jk 45* 45* jk j* _V „A -A _* CD CD CD CD CD CD cn cn cn cn cn cn 45* 45* 45* IO 663878' ΟΊ cn cn cn ro ΓΟ -4 45* 45* CO CO CO CO hO ro CO ro CO -si o CO -4 o 176853472 -sj -4 -4 fv -4 --4 -4 -vj -4 -4 CO 00 00 CO CO CO 45* _* _i. CD _1 CO 45* 45* 45* +* CD CO CO CO CO 4* 45* ro cn cn 00 00 00 -si -4 -4 O O cn -4 -4 -4 CO CO 00 CO CO CO CO CD _* CO 00 -4 o CO CO cn —* CD _* —A _ —*ί cn co co CD 45* cn CO 45* cn 45* hO 00 CD ISO CD -i. CD CO CO CO CD _* —sj IO 00 -si —*i o CO o CD CD -4 CD CD CO 00 4* ΓΟ 45* CO -si 00 00 45* ro 45* 00 ro O ro 45s* -4 O CO CD CD 45* 45* 45* CO 00 O cn o o CO CO CO -si cn 00 00 O CO CD -4 O 00 CD IO CO o cn ro 45* 00 00 CD -4 CD “k CO cn CD ”5 ~Λ —j ”Λ *z —! —ϊ ~Λ CO CO co CO CO CO CO CO CO CO CO CO CO CO __ CO CO CO CO CO CO CO -4 CO CD CO o N. CO co CO ho CD IO _1 CO cn JO _* ro -A ro to _i, CO cn _* _i. _i _ik ro cn ro ro o -vj o 45* -4 CO O 00 o _Ik 00 o o 45* -s| 45* _A 45* 45* _1 o CO o o -A o CD 45* CD o ro _1 CD cn o o 00 _i. CO 45* cn 4^ 00 _Sl CO o ro _* CO "sj _y 00 cn 00 o cn 00 00 CO CO 00 cn 00 45* CO CO o CO cn CD o _λ. IO o “-4 _^ CO 00 -si _*. 45* 45* CD CO CO -si CD O CO CD _i. _i. _* ro CO CD 00 CO O CO 45* 00 cn CD CO -sj CD CO —* o -4 45* 45* CO o 00 45* CO o 4*. CD _A 00 cn -4 CO 45* O CO o CO 00 CO cn _i ro cn CO o _1 H· cn CD -4 CD 00 00 o CO cn o 45* _* CO 00 CD CO cn CO CO ro cn cn -si ro -4 CD _i. ro -sl CO o CO cn -* CD CD ro 45* -4 ro 45* cn CD ro o o 45* 00 00 CD -4 ro

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CD CD CD 00 00 00 o o —* K> o -0 o o no ON o ΜωωωωΚ)ΜΝ)Κ)ΜΚ)Κ)ΜΝ)οοωωωωωΚ!ΜΜΜΚ3ω IO CO CO CO CO IO ro IO IO IO ro ro ro ro co CO CO CO CO co ro IO ro ro ro CO O o o o P o o o o o o o o P o o P P o P P P o o o o O b b b Q o b b b b b b b b b b b o o CD CO CD O CO CO b o o CD CD CD O -4 CO o b b b b O CO o CO o o IO w CD CD o CO o _A o cn o cn o co o ro o o ro o cn o IO o _i. o cn LJ CO CO o ro o CO o CO o K> o -0 2017100960 13 Μ 2017 4 17 10401217 rs148588034 C T MYH1 4 17 10402103 rs3744564 G A MYH1 4 17 10408323 rs534110923 G C MYH1 4 17 10408380 rs191339081 T A MYH1 4 17 10412897 rs534998190 C T MYH1 4 17 10417137 rs141592934 C T MYH1 4 17 10419751 rs535620022 C T MYH1 4 17 10541353 rs201166774 G A MYH3 4 17 10558169 rs374786690 G C MYH3 4 17 26856125 rs188424977 G A FOXN1 4 17 26861343 rs200401045 C T FOXN1 4 17 26864171 rs187814037 C T FOXN1 4 17 46878711 rs184362955 G A TTLL6 4 17 48245315 rs186669379 C T SGCA 4 17 48245924 rs200945974 G A SGCA 4 17 48246530 rs138254713 G A SGCA 4 17 67079395 rs117323775 G T ABCA6 4 17 67121109 rs200376492 A G ABCA6 4 17 73827216 rs140184929 C T UNC13D 4 17 73839609 rs527842266 C G UNC13D 4 18 72179676 rs201407255 C T CNDP2 4 18 72185883 rs201217537 G A CNDP2 4 19 38934191 rs192495718 C G RYR1 4 19 38948941 rs573737900 C T RYR1 4 19 38964364 rs551509462 G C RYR1 4 19 38981375 rs78851466 A G RYR1 4 19 39014545 rs200939091 G A RYR1 4 19 39014556 rs370630840 C T RYR1 4 19 39018329 rs538497899 C T RYR1 D 3.04 2.26 416 368 2 4 4 0.0069 D 3.04 2.26 416 368 2 4 4 0.003 D 3.04 2.26 416 368 2 4 4 0.005 D 3.04 2.26 416 368 2 4 4 0.005 D 3.04 2.26 416 368 2 4 4 0.002 3.04 2.26 416 368 2 4 4 0.0069 3.04 2.26 416 368 2 4 4 0.001 2.28 2.26 104 92 1 2 2 0.006 2.28 2.26 104 92 1 2 2 0.002 D 3.04 2.26 156 138 1 2 2 0.002 3.04 2.26 156 138 1 2 2 0.001 D 3.04 2.26 156 138 1 2 2 0.005 D 13.7 52 46 0 3 3 0.001 D 1.83 2.26 156 138 1 2 2 0.006 D 1.83 2.26 156 138 1 2 2 0.001 D 1.83 2.26 156 138 1 2 2 0.0079 D 9.13 2.26 104 92 1 2 2 0.001 D 9.13 2.26 104 92 1 2 2 0.0079 D 9.13 2.26 104 92 1 2 2 0.006 9.13 2.26 104 92 1 2 2 0.002 4.57 2.26 104 92 1 2 2 0.003 4.57 2.26 104 92 1 2 2 0.0069 1.96 364 322 0 3 3 0.004 1.96 364 322 0 3 3 0.001 D 1.96 364 322 0 3 3 0.004 1.96 364 322 0 3 3 0.0089 1.96 364 322 0 3 3 0.002 D 1.96 364 322 0 3 3 0.001 D 1.96 364 322 0 3 3 0.001 66 2017100960 13 Μ 2017

4 19 8140232 rs145316149 G A FBN3 4 19 8150331 rs142940013 G A FBN3 4 19 8155130 rs183278638 G A FBN3 4 19 8188820 rs145435433 C T FBN3 4 19 8979212 rs 149481309 C T MUC16 4 19 9002496 rs553074376 C T MUC16 4 19 9043416 rs17417801 G A MUC16 4 19 9056878 rs200934751 GAGA G MUC16 4 20 21142998 rs191064527 G A KIZ 4 20 21143067 rs116937124 T C KIZ 4 20 39788407 rs201733074 T C PLCG1 GACCAGAAC 4 20 39797820 rs547025579 L/ (SEQ ID NO:9) G PLCG1 4 20 39798092 rs183538599 C T PLCG1 4 21 10908822 rs546417233 T c TPTE 4 21 10908886 rs532224827 T c TPTE 4 21 10920159 rs557556075 G T TPTE 4 21 10970067 rs547492558 T c TPTE 4 21 43621840 rs564785493 T A ABCG1 4 21 43636306 rs 149713099 c T ABCG1 4 2 170038100 rs140572511 G A LRP2 4 2 170038761 rs3213760 C T LRP2 4 2 170042008 rs563916043 C T LRP2 4 2 170058290 rs138382534 C T LRP2 4 2 170163815 rs 142594441 C T LRP2 4 2 179404792 rs556524594 C T TTN 4 2 179425208 rs142478636 G T TTN 4 2 179430305 rs185887755 G A TTN 4 2 179437342 rs567446185 C T TTN D 3.04 2.26 208 184 1 2 2 0.004 D 3.04 2.26 208 184 1 2 2 0.004 D 3.04 2.26 208 184 1 2 2 0.002 D 3.04 2.26 208 184 1 2 2 0.006 5.71 2.83 208 184 2 5 5 0.0089 5.71 2.83 208 184 2 5 5 0.006 5.71 2.83 208 184 2 5 5 0.0079 5.71 2.83 208 184 2 5 5 0.0069 1.96 156 138 0 3 3 0.004 1.96 156 138 0 3 3 0.006 3.04 4.52 156 138 1 4 4 0.0079 3.04 4.52 156 138 1 4 4 0.0069 3.04 4.52 156 138 1 4 4 0.0079 9.13 2.26 208 184 1 2 2 0.002 9.13 2.26 208 184 1 2 2 0.002 9.13 2.26 208 184 1 2 2 0.002 9.13 2.26 208 184 1 2 2 0.003 9.13 2.26 104 92 1 2 2 0.001 9.13 2.26 104 92 1 2 2 0.0079 D 11.41 260 230 0 5 5 0.002 D 11.41 260 230 0 5 5 0.004 11.41 260 230 0 5 5 0.001 D 11.41 260 230 0 5 5 0.003 D 11.41 260 230 0 5 5 0.001 4.57 1.7 416 368 2 3 3 0.001 D 4.57 1.7 416 368 2 3 3 0.004 D 4.57 1.7 416 368 2 3 3 0.003 D 4.57 1.7 416 368 2 3 3 0.001 67 2017100960 13 Μ 2017

4 2 179481839 rs144688960 C A 4 2 179504772 rs551963261 C T 4 2 179577222 rs 186857044 C A 4 2 179585717 rs367826445 C T 4 2 203058233 rs 13024221 T C 4 2 203059076 rs141298049 G A 4 22 31522450 rs150976596 G A 4 22 31522715 rs370874308 A T 4 22 32614713 rs78144589 C T 4 22 32631002 rs554791323 T c 4 2 70031769 rs193084283 A G 4 2 70039849 rs 184226986 G A 4 2 71801442 rs147483765 C T 4 2 71901318 rs573892877 C G 4 2 71901432 rs144355449 C T 4 3 130282510 rs150427289 T C 4 3 130286067 rs145020873 A G 4 3 130289976 rs200963433 C T 4 3 130346196 rs117951912 G A 4 3 148904379 rs555339346 C G 4 3 148917507 rs17847018 T C 4 3 148930242 rs563241895 A T 4 3 183822730 rs560673114 C o > H —I o 4 3 183823729 rs187832026 G T 4 3 183823919 rs532417196 T C 4 3 2928719 rs184171731 A C 4 3 3080611 rs10510251 G C 4 3 3081959 rs339284 T C 4 3 62309627 rs 1881268 G C TTN 4.57 1.7 416 368 2 3 3 0.001 TTN 4.57 1.7 416 368 2 3 3 0.001 TTN D 4.57 1.7 416 368 2 3 3 0.001 TTN D 4.57 1.7 416 368 2 3 3 0.002 KIAA2012 9.13 2.26 104 92 1 2 2 0.003 KIAA2012 9.13 2.26 104 92 1 2 2 0.006 INPP5J D 4.57 3.39 104 92 1 3 3 0.0099 INPP5J 4.57 3.39 104 92 1 3 3 0.003 SLC5A4 6.85 3.39 104 92 1 3 3 0.0099 SLC5A4 D 6.85 3.39 104 92 1 3 3 0.001 ANXA4 1.83 2.26 104 92 1 2 2 0.0079 ANXA4 1.83 2.26 104 92 1 2 2 0.0079 DYSF D 3.04 2.26 156 138 1 2 2 0.002 DYSF 3.04 2.26 156 138 1 2 2 0.001 DYSF 3.04 2.26 156 138 1 2 2 0.003 COL6A6 2.28 1.51 208 184 3 4 4 0.0089 COL6A6 D 2.28 1.51 208 184 3 4 4 0.0099 COL6A6 D 2.28 1.51 208 184 3 4 4 0.004 COL6A6 D 2.28 1.51 208 184 3 4 4 0.0069 CP D 9.13 2.26 156 138 1 2 2 0.001 CP D 9.13 2.26 156 138 1 2 2 0.003 CP D 9.13 2.26 156 138 1 2 2 0.002 HTR3E 2.28 2.26 156 138 1 2 2 0.0089 HTR3E D 2.28 2.26 156 138 1 2 2 0.0069 HTR3E D 2.28 2.26 156 138 1 2 2 0.001 CNTN4 6.85 1.7 156 138 2 3 3 0.003 CNTN4 6.85 1.7 156 138 2 3 3 0.003 CNTN4 6.85 1.7 156 138 2 3 3 0.002 C3orf14 4.57 104 92 0 3 3 0.001 68 2017100960 13 Μ 2017

4 3 62317022 rs186089632 C A C3orf14 4 4 106158550 rs141975400 G T TET2 4 4 6596385 rs3216941 AC A MAN2B2 4 4 983115 rs143381873 G A SLC26A1 4 4 983342 rs201608921 C T SLC26A1 4 4 983810 rs563866785 G A SLC26A1 4 4 984938 rs139024319 G A SLC26A1 4 5 1495038 rs201521332 G A LPCAT1 4 5 180477285 rs200884524 C T BTNL9 4 5 180483533 rs373494500 T c BTNL9 4 6 169622491 rs138932100 G A THBS2 4 6 169623562 rs182173220 G A THBS2 4 6 169628312 rs368102843 C T THBS2 4 6 169646282 rs76393784 A T THBS2 4 6 35438350 rs187631484 C T MIR7111 4 6 35438350 rs187631484 C T RPL10A 4 6 43160731 rs568565110 C G CUL9 4 6 43170522 rs200509434 G T CUL9 4 6 43172581 rs80345623 G A CUL9 4 6 49416648 rs199555550 G A MUT 4 6 49425591 rs200908035 T C MUT 4 6 49425720 rs528689712 T C MUT 4 7 100357429 rs374243234 c T ZAN 4 7 100363045 rs184742914 A T ZAN 4 7 100389715 rs369936309 C T ZAN 4 7 128483506 rs200215903 G A FLNC 4 7 128485314 rs199917473 G A FLNC 4 7 128490926 rs140857707 C T FLNC 4 7 128497224 rs180834558 G T FLNC 4.57 104 92 0 3 3 0.003 4.57 2.26 52 46 1 2 2 0.005 9.13 2.26 52 46 1 2 2 0.006 D 4.57 2.26 208 184 1 2 2 0.005 D 4.57 2.26 208 184 1 2 2 0.002 D 4.57 2.26 208 184 1 2 2 0.001 D 4.57 2.26 208 184 1 2 2 0.002 9.55 2.36 52 44 1 2 2 0.0069 4.57 104 92 0 3 3 0.001 4.57 104 92 0 3 3 0.0069 D 2.28 2.26 208 184 1 2 2 0.006 D 2.28 2.26 208 184 1 2 2 0.001 D 2.28 2.26 208 184 1 2 2 0.001 2.28 2.26 208 184 1 2 2 0.002 4.57 2.26 52 46 1 2 2 0.0069 4.57 2.26 52 46 1 2 2 0.0069 9.13 2.26 156 138 1 2 2 0.001 D 9.13 2.26 156 138 1 2 2 0.0069 D 9.13 2.26 156 138 1 2 2 0.0099 13.7 156 138 0 3 3 0.0079 D 13.7 156 138 0 3 3 0.0079 D 13.7 156 138 0 3 3 0.001 3.04 2.26 156 138 1 2 2 0.001 3.04 2.26 156 138 1 2 2 0.003 D 3.04 2.26 156 138 1 2 2 0.003 D 2.28 3.39 208 184 1 3 3 0.005 2.28 3.39 208 184 1 3 3 0.003 D 2.28 3.39 208 184 1 3 3 0.002 D 2.28 3.39 208 184 1 3 3 0.0099 69 2017100960 13 Μ 2017 4 7 149481919 rs561989729 C G SSPO 4 7 149484595 rs532285725 A G SSPO 4 7 149484976 rs372638209 G A SSPO 4 7 149486719 rs185269282 C G SSPO 4 7 149489049 rs189781142 G T SSPO 4 7 149490676 rs4725314 C T SSPO 4 7 149491991 rs550645855 G A SSPO 4 7 149492720 rs573097199 G A SSPO 4 7 149493767 rs118118675 G A SSPO 4 7 149494380 rs376898523 C T SSPO 4 7 149501078 rs147663076 C A SSPO 4 7 149502637 rs375487670 C T SSPO 4 7 149503944 rs191161538 C T SSPO 4 7 149506195 rs73727627 C T SSPO 4 7 149509035 rs189816441 A G SSPO 4 7 149509064 rs73727632 T C SSPO 4 7 149509079 rs73727633 T C SSPO 4 7 149509381 rs757724 c T SSPO 4 7 149509407 rs146934333 G C SSPO 4 7 149509691 rs73727635 G A SSPO 4 7 149515870 rs371607382 G A SSPO 4 7 149518144 rs577743302 A C SSPO 4 7 149519649 rs58369703 G C SSPO 4 7 149519705 rs55857423 G A SSPO 4 7 149519711 rs547007891 G T SSPO 4 7 149521545 rs143632762 G A SSPO 4 17 67246623 rs559974558 G A ABCA5 4 17 67247973 rs201343208 G A ABCA5 4 17 67250466 rs199641093 C T ABCA5 2.79 2.71 1484 1312 5 12 12 0.002 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.002 2.79 2.71 1484 1312 5 12 12 0.003 2.79 2.71 1484 1312 5 12 12 0.002 2.79 2.71 1484 1312 5 12 12 0.001 2.79 2.71 1484 1312 5 12 12 0.003 2.79 2.71 1484 1312 5 12 12 0.001 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.002 2.79 2.71 1484 1312 5 12 12 0.005 2.79 2.71 1484 1312 5 12 12 0.0069 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.001 2.79 2.71 1484 1312 5 12 12 0.006 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.0089 2.79 2.71 1484 1312 5 12 12 0.004 2.79 2.71 1484 1312 5 12 12 0.001 2.79 2.71 1484 1312 5 12 12 0.001 2.79 2.71 1484 1312 5 12 12 0.003 2.79 2.71 1484 1312 5 12 12 0.003 2.79 2.71 1484 1312 5 12 12 0.005 2.79 2.71 1484 1312 5 12 12 0.001 D 2.9 1.5 652 580 6 8 8 0.001 D 2.9 1.5 652 580 6 8 8 0.001 D 2.9 1.5 652 580 6 8 8 0.004 70 2017100960 17 67299017 rs201944918 A G ABCA5 D 2,9 1.5 652 580 6 8 17 67305519 rs199888749 G A ABCA5 D 2.9 1.5 652 580 6 8 17 73827216 rs140184929 C T UNC13D D 5.43 264 232 0 3 17 73839609 rs527842266 C G UNC13D 5.43 264 232 0 3 17 7701543 rs141742705 G A DNAH2 D 1.81 2.28 396 348 1 2 17 7705344 rs8073196 G C DNAH2 1.81 2.28 396 348 1 2 17 7736250 rs201527036 G A DNAH2 1.81 2.28 396 348 1 2 17 79684531 rs201577202 C T SLC25A10 3.62 1.52 264 232 3 4 17 79684871 rs77609145 A T SLC25A10 D 3.62 1.52 264 232 3 4 18 2707800 rs 184984483 C T SMCHD1 5.48 3.37 258 230 1 3 18 2777922 rs527648000 C T SMCHD1 5.48 3.37 258 230 1 3 18 28911778 rs147775289 T c DSG1 D 5.43 1.71 528 464 2 3 18 28934293 rs149191001 c T DSG1 D 5.43 1.71 528 464 2 3 18 28934674 rs 181411154 G A DSG1 D 5.43 1.71 528 464 2 3 18 28934927 rs148488583 C G DSG1 D 5.43 1.71 528 464 2 3 18 580853 rs114933134 G A CETN1 D 3.62 132 116 0 4 18 61160178 rs370525785 T C SERPINB5 3.62 2.28 264 232 1 2 18 61170818 rs185364126 G A SERPINB5 D 3.62 2.28 264 232 1 2 18 61305002 rs201297323 T C SERPINB4 D 1.81 3.41 264 232 1 3 18 61305289 rs188021365 A T SERPINB4 1.81 3.41 264 232 1 3 1 87380851 rs546745 A G HS2ST1 3.62 2.28 264 232 1 2 1 87563514 rs143260332 G A HS2ST1 3.62 2.28 264 232 1 2 18 76886315 rs200431802 C T ATP9B D 3.62 2.28 264 232 1 2 18 77096664 rs201172611 G A ATP9B D 3.62 2.28 264 232 1 2 18 9549345 rs 199964908 G A PPP4R1 2.72 1.71 132 116 2 3 19 14071095 rs140301367 G A DCAF15 5.43 3.41 132 116 1 3 7 149521647 rs564348526 C T SSPO 2.79 2.71 1484 1312 5 12 7 149521654 rs578088844 G A SSPO 2.79 2.71 1484 1312 5 12 7 149522951 rs200469643 C T SSPO 2.79 2.71 1484 1312 5 12 71 2017100960 13 Μ 2017

4 7 75192236 C A HIP1 4 7 75210547 A T HIP1 4 8 110439252 rs375463553 C A PKHD1L1 4 8 110463357 rs202241413 C T PKHD1L1 4 8 110493660 rs139600051 A G PKHD1L1 4 8 110527435 rs559437602 C T PKHD1L1 4 8 145736896 rs557256260 C T RECQL4 4 8 145738985 rs536831548 G c RECQL4 4 8 145741388 rs200097701 C G RECQL4 4 8 145741602 rs34633809 C T RECQL4 4 8 145742799 rs34642881 T C RECQL4 4 8 17400906 rs 12680645 G A SLC7A2 4 8 17407821 rs188973136 C G SLC7A2 4 8 17417839 rs201373242 A G SLC7A2 4 9 439392 rs117109271 A G DOCK8 4 9 441423 rs188141951 C T DOCK8 4 X 1460714 C T IL3RA 4 X 1471130 G T IL3RA 5 2 113342071 rs528909726 G A CHCHD5 5 3 63898360 rs576518931 G GGCAGCA ATXN7 5 4 46994972 rs34464680 G GAA GABRA4 6 10 122618148 rs2241846 G C WDR11 6 10 35485028 rs137918654 G T CREM 6 10 44788826 rs58189594 C T C10orf142 CH17- 6 10 47087078 rs2229967 G T 360D5.1 6 10 47087078 rs2229967 G T NPY4R CH17- 6 10 47087403 rs781881744 T c 360D5.1 6 10 47087403 rs781881744 T c NPY4R 72 4.57 2.26 104 92 1 2 2 0.0089 4.57 2.26 104 92 1 2 2 0.001 4.57 2.26 208 184 1 2 2 0.005 4.57 2.26 208 184 1 2 2 0.003 4.57 2.26 208 184 1 2 2 0.005 4.57 2.26 208 184 1 2 2 0.002 2.28 1.7 260 230 2 3 3 0.001 2.28 1.7 260 230 2 3 3 0.001 2.28 1.7 260 230 2 3 3 0.005 2.28 1.7 260 230 2 3 3 0.0089 2.28 1.7 260 230 2 3 3 0.0079 3.42 1.7 156 138 2 3 3 0.0079 3.42 1.7 156 138 2 3 3 0.006 3.42 1.7 156 138 2 3 3 0.001 3.42 3.39 104 92 1 3 3 0.0099 3.42 3.39 104 92 1 3 3 0.003 9.33 2.31 104 90 1 2 2 0.001 9.33 2.31 104 90 1 2 2 0.004 38 40 0 2 1 0.002 1.76 38 36 3 5 4 0.004 1.41 1.81 70 54 5 7 6 0.0089 1.57 1.67 50 46 15 23 19 0.3472 2.74 3.39 52 46 1 3 2 0.0347 1.87 3.39 52 46 3 9 8 0.1121 1.86 1.83 260 230 13 21 21 1.86 1.83 260 230 13 21 21 1.86 1.83 260 230 13 21 21 1.86 1.83 260 230 13 21 21 2017100960 13 Μ 2017 CH17- 6 10 47087499 rs114592738 G A 360D5.1 6 10 47087499 rs114592738 G A NPY4R CH17- 6 10 47087520 rs 115443559 G A 360D5.1 6 10 47087520 rs115443559 G A NPY4R CH17- 6 10 47087609 rs79871698 G A 360D5.1 6 10 47087609 rs79871698 G A NPY4R 6 10 7747155 rs76983422 G C ITIH2 6 1 100617938 rs78161968 T C LRRC39 6 1 100618085 rs773979041 A G LRRC39 6 1 100620728 rs78962557 G A LRRC39 6 1 109456983 rs141562079 C T GPSM2 6 1 109465156 rs199964596 TCAA T GPSM2 6 1 109465165 rs35029887 ACTT A GPSM2 6 11 118886656 rs7131534 G A RPS25 6 11 13410690 rs375824034 TGAAA T BTBD10 6 11 16812551 rs116885602 C T PLEKHA7 6 11 16863087 rs452745 A G PLEKHA7 6 1 118530450 rs184368389 T C SPAG17 6 1 12082881 rs11588779 C T MIIP 6 11 22232870 rs78987921 G A AN05 6 11 22239801 C T AN05 6 11 32636495 rs145888197 T c CCDC73 6 1 145414790 G c HFE2 6 1 145456731 rs6694055 G c POLR3GL 6 1 145527604 rs2274620 A G ITGA10 6 1 145534221 G T ITGA10 73 1.86 1.83 260 230 13 21 21 1.86 1.83 260 230 13 21 21 1.86 1.83 260 230 13 21 21 0.0179 1.86 1.83 260 230 13 21 21 0.0179 1.86 1.83 260 230 13 21 21 0.0923 1.86 1.83 260 230 13 21 21 0.0923 2.74 1.7 52 46 2 3 3 0.0397 1,68 2.29 156 136 3 6 6 0.0446 1.68 2.29 156 136 3 6 6 1.68 2.29 156 136 3 6 6 0.0198 2.28 6.78 156 138 1 6 6 0.0258 2.28 6.78 156 138 1 6 6 0.0129 2.28 6.78 156 138 1 6 6 1.52 1.7 52 46 2 3 3 0.0704 2.49 1.7 52 46 4 6 6 0.0675 1.61 1.85 100 90 6 10 9 0.0456 1.61 1.85 100 90 6 10 9 0.1617 4.57 3.39 52 46 1 3 3 0.0179 4.57 3.39 52 46 2 6 6 0.0685 4.57 2.26 104 92 1 2 2 0.0109 4.57 2.26 104 92 1 2 2 1.52 2.26 52 46 1 2 2 0.0377 4.57 2.26 52 46 1 2 2 0.0129 1.83 2.26 52 46 1 2 2 0.0119 1.62 2.94 260 230 5 13 12 0.0208 1.62 2.94 260 230 5 13 12 2017100960 13 Μ 2017 6 1 145536082 rs2274616 G A ITGA10 6 1 145541806 rs77912414 T C ITGA10 6 1 152484245 rs2282298 c T LCE5A 6 11 55136125 rs117954374 c T OR4A15 6 11 551644 rs113026126 c T LRRC56 6 11 5776484 rs4910844 A T OR52N4 6 1 15834360 rs2020902 A G CASP9 6 1 15860803 rs11583306 C T DNAJC16 6 1 159799808 rs 10430458 C T SLAMF8 6 1 159858290 rs3795334 T A CFAP45 6 11 61048196 rs78505441 G C VWCE 6 11 61071331 rs28720346 C T DDB1 6 11 62365619 rs11231155 A G MTA2 6 11 62369881 rs35156678 G A EML3 6 1 16382911 rs72474563 A G CLCNKB 6 11 67771408 rs188940236 C T UNC93B1 6 1 168105581 rs200664972 A AG GPR161 6 11 71710425 rs373342292 CTCA C iL18BP 6 1 177247693 rs138799872 C T BRINP2 6 11 797714 T A PAN 01 6 11 798082 rs201547522 C CT PAN 01 6 11 798222 rs572464433 T TCGC PAN 01 6 1 180240510 rs2764449 T C LHX4 6 1 180243593 rs200119009 c T LHX4 6 1 180243601 G A LHX4 6 1 201356001 CCCA * LAD1 6 1 201356001 rs398053706 CCCA c LAD1 6 1 201356004 ACC * LAD1 6 1 201356004 rs552300739 ACC A LAD1 74 1.62 2.94 260 230 5 13 12 0.0704 1.62 2.94 260 230 5 13 12 0.0119 2.28 3.39 52 46 1 3 3 0.0228 2.08 2.83 52 46 2 5 5 0.0585 2.54 1.88 52 46 3 5 5 0.0476 1.56 2.64 52 46 6 14 10 0.1974 3.04 2.26 52 46 1 2 2 0.0317 2.74 1.7 52 46 2 3 3 0.0466 3.42 1.7 52 46 2 3 3 0.0317 1.52 2.83 52 46 2 5 5 0.0556 1.83 2.26 52 46 1 2 2 0.0268 1.83 2.26 52 46 1 2 2 0.0258 1.83 2.26 52 46 2 4 4 0.0526 2.03 2.26 52 46 2 4 4 0.0437 9.13 2.26 52 46 2 4 4 0.0357 1.62 2.2 44 40 2 4 4 0.0308 1.83 4.52 52 46 1 4 4 0.0516 3.65 52 46 0 4 4 0.0198 4.57 2.26 52 46 1 2 2 0.0119 7.72 2.83 154 136 2 5 5 7.72 2.83 154 136 2 5 5 0.0248 7.72 2.83 154 136 2 5 5 2.28 156 138 0 3 3 0.0139 2.28 156 138 0 3 3 2.28 156 138 0 3 3 4.38 1.92 184 160 12 20 20 4.38 1.92 184 160 12 20 20 0.0575 4.38 1.92 184 160 12 20 20 4.38 1.92 184 160 12 20 20 0.0486

6 1 210267893 rs144713062 TGAA T SYT14 6 12 110923012 rs142702785 A G FAM216A 6 12 113592306 rs200344876 G GC CFAP73 6 1 2117557 rs547643542 G A FAAP20 6 12 122243731 rs557334621 C T SETD1B 6 12 122255354 rs541427059 TGCG T SETD1B 6 12 122265770 rs117774166 G A SETD1B TGCACGCTG G (SEQ ID 6 12 12630665 rs 142947418 NO:10) T DUSP16 6 12 12630675 rs201941751 GCACGC G DUSP16 6 12 12630681 rs200271649 TGGGC T DUSP16 6 12 12633287 rs10845555 A G DUSP16 6 1 2130262 rs 144802031 C G FAAP20 6 12 14923935 rs199781231 T TC HIST4H4 6 12 16377347 rs117974895 C T SLC15A5 6 1 224008913 rs3738370 G A TP53BP2 6 1 228289872 rs373634959 G A C1orf35 6 1 22924364 rs72651347 G A EPHA8 6 1 22927298 rs569320402 C T EPHA8 6 1 234509972 rs73099933 A G COA6 6 1 247719769 rs56043070 G A GCSAML 6 1 248512939 rs201185608 AC A OR14C36 6 12 49721122 rs73309977 C T TROAP 6 12 51510213 rs77417603 T A TFCP2 6 12 52156281 rs187002252 A G SCN8A 6 12 53427826 rs140133257 G T EIF4B 6 12 54756528 rs77759698 A G GPR84 6 12 55523586 rs398102299 AT A OR9K2 75 2017100960 13M2017 3.2 3.96 52 46 2 7 6 0.0655 2.74 52 46 0 3 3 0.0149 3.42 3.39 52 46 1 3 3 0.0169 3.65 1.51 104 92 6 8 7 0.0139 2.28 2.26 156 138 1 2 2 2.28 2.26 156 138 1 2 2 0.0129 2.28 2.26 156 138 1 2 2 0.0188 1.55 1.64 178 154 48 68 57 0.13 1.55 1.64 178 154 48 68 57 0.2698 1.55 1.64 178 154 48 68 57 0.2698 1.55 1.64 178 154 48 68 57 0.4097 3.65 1.51 104 92 6 8 7 0.0754 1.52 2.26 52 46 1 2 2 0.0198 2.28 1.7 52 46 2 3 3 0.0337 1.89 1.51 52 46 9 12 11 0.1925 2.28 2.26 52 46 1 2 2 0.0139 2.28 1.7 104 92 2 3 3 0.0179 2.28 1.7 104 92 2 3 3 2.5 2.89 52 42 3 7 7 0.0804 2.28 3.39 52 46 1 3 3 0.0327 1.76 1.88 52 46 3 5 5 0.0615 1.96 3.39 52 46 1 3 3 0.0397 2.28 2.26 52 46 2 4 4 0.0228 1.83 2.26 52 46 1 2 2 0.0179 2.74 52 46 0 3 3 0.0228 1.76 5.65 52 46 1 5 5 0.0347 1.66 3.01 52 46 3 8 7 0.1141

6 12 55641255 rs4522268 C T 6 12 55759191 rs398102300 AT A 6 12 58007149 rs141337782 G C 6 1 26524503 rs199601379 C T 6 1 26526554 rs6700024 G A 6 12 70928745 rs3752702 G A 6 12 95456367 rs138805411 T C 6 13 76457183 rs9530477 T C 6 14 35182348 rs35515423 GA G 6 14 94750501 rs77844573 A G 6 14 94756458 rs2232699 A T 6 15 101013123 rs 1566775 G A 6 15 101601367 rs148929418 C CACTT 6 15 28947605 rs3893142 C A 6 15 60803458 rs779626945 C T 6 15 60919432 rs73424068 C T 6 15 78458485 rs3816253 T C 6 16 1272750 rs113856625 G A 6 16 1273444 rs61587627 G T 6 16 13297242 rs13331224 C T 6 16 1825689 rs3826055 C T 6 16 1825789 rs746707908 T c 6 1 6266793 rs72853039 G c 6 16 28998111 rs4788115 T A 6 16 30455945 rs 146596728 A C 6 16 30456188 rs550048089 G A 2017100960 13 Μ 2017 OR6C74 1.96 3.39 52 46 3 9 8 0.1171 OR6C75 2.28 3.96 52 46 2 7 7 0.0724 ARHGEF2 5 1.52 2.83 52 46 2 5 4 0.1151 CATSPER 4 D 1.71 3.39 104 92 1 3 2 CATSPER 4 1.71 3.39 104 92 1 3 2 0.0208 PTPRB 3.04 2.26 52 46 1 2 2 0.0486 NR2C1 D 4.57 4.52 52 46 1 4 4 0.0208 LM07DN 1,66 1.88 52 46 12 20 15 0.3284 CFL2 1.55 1.7 46 44 8 13 11 0.2034 SERPINA1 0 1.6 1.98 104 92 4 7 7 0.0258 SERPINA1 0 D 1.6 1.98 104 92 4 7 7 0.0298 CERS3 4.57 2.26 52 46 1 2 2 0.0258 LRRK1 3.26 2.26 52 46 5 10 10 0.1409 GOLGA8M 1.75 1.53 46 40 3 4 4 0.0675 RORA D 2.28 104 92 0 3 3 RORA 2.28 104 92 0 3 3 0.0149 IDH3A 1.64 1.58 52 46 10 14 11 0.1885 TPSG1 D 2.13 3.96 104 92 2 7 7 TPSG1 D 2.13 3.96 104 92 2 7 7 0.0972 SHISA9 1.64 1.57 48 46 6 9 9 0.1042 EME2 6.85 1.7 104 92 2 3 3 0.0129 EME2 6.85 1.7 104 92 2 3 3 RNF207 1.71 3.39 52 46 2 6 6 0.0972 LAT 1.74 2.26 52 46 4 8 8 0.1359 SEPHS2 4.57 2.26 104 92 1 2 2 0.0248 SEPHS2 4.57 2.26 104 92 1 2 2 76 2017100960 13 Μ 2017 1.72 2.75 104 92 14 34 28 0.1825 1.72 2.75 104 92 14 34 28 0.3046 1.96 156 138 0 9 9 0.0556 1.96 156 138 0 9 9 0.0556 1.96 156 138 0 9 9 0.0556 2.03 52 46 0 4 4 0.0397 1.71 1.7 156 138 14 21 17 0.2669 1.71 1.7 156 138 14 21 17 0.0218 1.71 1.7 156 138 14 21 17 0.0129 3.04 2.26 52 46 1 2 2 0.0268 2.54 2.83 52 46 2 5 5 0.0595 1.68 52 46 0 7 7 0.0962 4.57 2.26 52 46 1 2 2 0.0109 1.9 2.83 208 184 2 5 5 1.9 2.83 208 184 2 5 5 1.9 2.83 208 184 2 5 5 0.0407 1.9 2.83 208 184 2 5 5 1.56 1.7 156 138 20 30 27 0.0198 1.56 1.7 156 138 20 30 27 0.3224 1.56 1.7 156 138 20 30 27 0.0952 1.63 1.88 104 92 6 10 9 0.0169 1.63 1.88 104 92 6 10 9 0.0962 2.28 4.52 104 92 1 4 4 2.28 4.52 104 92 1 4 4 0.0357 2.28 1.51 208 184 3 4 4 2.28 1.51 208 184 3 4 4 0.0258 2.28 1.51 208 184 3 4 4 2.28 1.51 208 184 3 4 4 1.7 1.75 164 194 30 62 53

6 16 3075701 rs2717664 C T THOC6 6 16 3075999 rs2245000 C G THOC6 6 16 3554840 rs80187466 G T CLUAP1 6 16 3558283 rs59492947 A T CLUAP1 6 16 3580565 rs79684678 T C CLUAP1 6 16 5077897 rs112669475 G A NAG PA 6 16 57736047 rs72795521 G A DRC7 6 16 57756907 rs113469607 C A DRC7 6 16 57757046 rs139945134 C T DRC7 6 1 6647702 rs183072854 G A ZBTB48 6 16 67180171 rs7184692 T C C16orf70 6 16 83998662 rs733728 A G OSGIN1 6 16 84801966 rs189466547 T C USP10 6 17 27067480 rs750108245 G A NEK8 6 17 27067558 rs565763400 C T NEK8 6 17 27068005 rs147832976 TGAG T NEK8 6 17 27068012 rs757972103 G T NEK8 6 17 34182099 rs149317141 G GT HEATR9 6 17 34185535 rs35283303 AG A HEATR9 6 17 34192406 G A HEATR9 6 17 36895514 rs72819704 A G PCGF2 6 17 36896534 rs2075Q57 C T PCGF2 6 17 37824838 GCAA G PNMT 6 17 37826201 rs60871117 C T PNMT 6 17 48753044 rs371874263 C T ABCC3 6 17 48755450 rs11568583 A G ABCC3 6 17 48761020 rs572541933 G A ABCC3 6 17 48765100 rs756871504 C T ABCC3 6 17 4906146 rs 10533622 GC G KIF1C 77

6 17 4906146 rs146311497 GCC G 6 17 4906146 rs763524690 G GC 6 17 4907374 rs766141834 G A 6 17 4924097 rs4790725 C G 6 17 59667953 rs17610181 G A 6 17 64876769 rs376464596 C T 6 17 64876770 rs142916987 G A 6 17 64880788 rs2286677 G A 6 17 76130947 rs62079073 G T 6 17 8109965 rs144397670 G A 6 17 8110079 rs139322514 G A 6 17 8113270 rs766965552 A G 6 17 8113544 C G 6 18 33694444 rs148550301 A G 6 1 89523927 rs60070945 C T 6 19 10426524 rs79442975 G A 6 19 12875807 rs115585485 A C 6 19 1917687 rs138069352 C G 6 1 92798945 rs78196083 C T 6 19 32083223 rs11880125 A G 6 19 32083250 rs79323410 T C 6 19 39905903 rs3859551 A G 6 19 39906985 rs10401595 T C 6 19 39907573 rs763779951 c G 6 19 39915627 rs200639701 A G 6 19 39915764 A G 6 19 39948307 rs2304215 C T 6 19 40327312 rs3760924 A G 6 19 42603776 rs1205817 A G 2017100960 13 Μ 2017 KIF1C 1.7 1.75 164 194 30 62 53 0.3244 KIF1C 1.7 1.75 164 194 30 62 53 KIF1C 1.7 1.75 164 194 30 62 53 KIF1C 1.7 1.75 164 194 30 62 53 0.0446 NACA2 1.77 1.94 52 46 7 12 11 0.1667 CACNG5 D 2.09 1.55 156 138 8 11 9 CACNG5 D 2.09 1.55 156 138 8 11 9 CACNG5 2.09 1.55 156 138 8 11 9 0.126 TMC8 1.52 1.58 52 46 5 7 7 0.0804 AURKB 1.71 3.36 206 184 1 3 3 0.0159 AURKB 1.71 3.36 206 184 1 3 3 AURKB 1.71 3.36 206 184 1 3 3 AURKB 1.71 3.36 206 184 1 3 3 SLC39A6 4.57 52 46 0 3 3 0.0298 GBP1 1.71 2.03 52 46 5 9 9 0.12 FDX1L 1.83 2.26 52 46 1 2 2 0.0397 HOOK2 1.96 3.39 52 46 1 3 3 0.0238 SCAMP4 1.71 3.39 52 46 1 3 3 0.0437 RPAP2 1.52 2.26 52 46 1 2 2 0.0456 THEG5 4.57 1.7 104 92 4 6 6 0.0179 THEG5 4.57 1.7 104 92 4 6 6 0.0179 PLEKHG2 1.64 1.7 260 230 4 6 6 0.0387 PLEKHG2 1.64 1.7 260 230 4 6 6 0.0387 PLEKHG2 D 1.64 1.7 260 230 4 6 6 PLEKHG2 D 1.64 1.7 260 230 4 6 6 PLEKHG2 D 1.64 1.7 260 230 4 6 6 SUPT5H 1.52 2.26 52 46 1 2 2 0.0129 FBL 2.28 2.54 52 46 4 9 8 0.0992 POU2F2 1.52 1.7 52 46 8 12 11 0.1865 78 6 19 43268140 rs11355507 AG A PSG8 6 19 45296846 rs66944506 A AC CBLC 6 19 45297454 rs1903831 A C CBLC 6 19 47290651 rs3826793 G T SLC1A5 6 19 48735017 rs140826611 C CTT CARD8 6 19 49956688 rs78750735 T c ALDH16A1 6 19 49965131 rs76844851 G A ALDH16A1 6 19 49965131 rs76844851 G C ALDH16A1 6 19 49965132 rs79109084 G C ALDH16A1 6 19 51330423 rs61752560 C G KLK15 6 19 51582802 rs199715229 C T KLK14 D 6 19 51585822 rs769468261 G A KLK14 6 19 54578105 C T TARM1 6 19 58118371 rs78803667 G A ZNF530 D 6 19 7688614 rs2335521 T C ACACTGGGG GTGAGGCA GGGGGAGAG AAAGGGGCCTG XAB2 6 19 7935408 A CAGGGGGAG AGAAAGGGG CCTGCACTG G GGGTGAGGG (SEQ ID (SEQ ID NO:11) PRR36 6 19 7935423 rs759755075 NO:12) C PRR36 6 19 7936105 A T PRR36 6 19 7937299 C T PRR36 6 19 829555 rs 144713752 C G AZU1 6 19 9236698 rs111279560 G GATGGT OR7G3 2017100960 13 Μ 2017 1.96 1.7 52 46 2 3 3 0.0188 1.68 1.98 104 92 4 7 7 0.0962 1.68 1.98 104 92 4 7 7 0.0863 1.56 1.63 52 46 9 13 11 0.2212 2.28 1.51 52 46 3 4 4 0.0575 1.8 1.72 208 180 39 58 52 1.8 1.72 208 180 39 58 52 0.3313 1.8 1.72 208 180 39 58 52 0.0149 1.8 1.72 208 180 39 58 52 0.3313 2.28 1.81 52 46 5 8 7 0.1032 4.57 2.26 104 92 1 2 2 0.0119 4.57 2.26 104 92 1 2 2 2.74 52 46 0 3 3 0.0268 6.85 3.39 52 46 1 3 3 0.0159 2.85 5.65 52 46 1 5 5 0.0407 6.49 6.74 218 194 1 6 6 6.49 6.74 218 194 1 6 6 6.49 6.74 218 194 1 6 6 6.49 6.74 218 194 1 6 6 2.74 52 46 0 3 3 0.0129 1.51 1.64 152 134 18 26 22 0.3651 79

6 19 9236916 rs75266995 AG A 6 19 9236969 rs61751875 G A 6 20 23584368 rs118095359 G A 6 20 31672812 rs71349705 C T 6 20 31677295 rs142982767 C T 6 20 32005736 rs116972153 G A 6 20 4228485 rs3746669 G T 6 20 44180813 rs 17348421 G A 6 20 44511257 rs35972756 G A 6 20 44676727 rs12481488 T A 6 20 50307365 rs117858424 A G 6 2 121997127 rs147546143 G GACGGT 6 2 128466446 G A 6 2 128477849 rs774069217 C T 6 2 128522203 rs117753184 A T 6 2 128522852 G A 6 21 34860749 CAATTA C 6 21 42615293 rs2252576 C T 6 21 43412786 rs200509586 GTCA G 6 2 153515710 rs141445791 A C 6 2 153515879 rs767401165 A G 6 2 169791766 G A 6 2 169801131 rs118109635 G A 6 2 169853135 A G 6 2 175304621 rs67227536 C G 6 2 175333632 rs28588913 G A 6 2 202498027 rs78297522 T C 6 22 19420778 rs3747064 T A 6 22 24313530 rs199896117 GGA G 2017100960 13 Μ 2017 OR7G3 1.51 1.64 152 134 18 26 22 0.0317 OR7G3 1.51 1.64 152 134 18 26 22 0.0357 CST9 1.83 2.26 52 46 1 2 2 0.0129 BPIFB4 6.85 104 92 0 3 3 BPIFB4 6.85 104 92 0 3 3 0.0179 SNTA1 1.52 1.7 52 46 2 3 3 0.0238 ADRA1D 1.5 2.26 52 46 11 22 17 0.2887 WFDC8 2.28 2.83 52 46 2 5 4 0.0585 ZSWIM1 4.57 2.26 52 46 1 2 2 0.0159 SLC12A5 3.42 3.39 52 46 1 3 3 0.0238 ATP9A 1.66 2.26 52 46 2 4 4 0.0476 TFCP2L1 2.03 2.26 52 46 2 4 4 0.0565 WDR33 D 1.9 208 184 0 5 5 WDR33 D 1.9 208 184 0 5 5 WDR33 1.9 208 184 0 5 5 0.0258 WDR33 1.9 208 184 0 5 5 DNAJC28 1.9 2.83 52 46 4 10 9 0.1667 BACE2 1.52 2.83 52 46 2 5 4 0.0675 ZBTB21 11.41 5.65 52 46 1 5 5 0.0109 PRPF40A 1.56 104 90 0 4 4 0.0278 PRPF40A 1.56 104 90 0 4 4 ABCB11 D 4.57 3.39 156 138 1 3 3 ABCB11 D 4.57 3.39 156 138 1 3 3 0.0129 ABCB11 4.57 3.39 156 138 1 3 3 GPR155 6.85 3.39 104 92 1 3 3 0.0139 GPR155 6.85 3.39 104 92 1 3 3 0.0248 TMEM237 1.96 1.7 52 46 2 3 3 0.0298 MRPL40 1.52 4.52 52 46 1 4 4 0.0714 DDTL 2.28 2.26 52 46 1 2 2 0.0278 80

6 22 24919647 rs118163237 G A 6 2 231077154 rs41309096 G A 6 2 30862980 rs 12466818 C T 6 2 31412347 rs78099670 G A 6 2 31414833 G T 6 2 31414844 rs147299374 C T 6 2 31414959 rs141014145 A G 6 2 31422395 rs200657395 TCTC T 6 2 55491007 rs369772725 G GA 6 2 98128073 G * 6 2 98128073 rs373085949 G A 6 2 98164184 rs13001728 C G 6 3 100593675 rs79152576 T C 6 3 107097080 rs 138204694 CAAATG C 6 3 111780629 rs73853301 C T 6 3 111780630 rs73853302 C T 6 3 120428621 rs 11720353 T c 6 3 122002576 rs117375173 A G 6 3 122002644 rs768660050 G T 6 3 133331230 rs71317417 C T 6 3 182871464 rs500288 A G 6 3 196296182 rs79085393 G C 6 3 46714821 rs11130104 C G 6 3 56682841 rs71621834 A C 6 3 58620105 rs76752946 G C 6 4 141458699 rs149594258 A C 6 4 184367558 rs10533201 TCTG T 2017100960 13 Μ 2017 UPB1 D 1.83 2.26 52 46 1 2 2 0.0188 SP110 1.83 1.7 52 46 4 6 6 0.0883 LCLAT1 1.52 1.98 52 46 8 14 11 0.2222 CAPN14 7.3 1.51 260 230 3 4 4 0.0179 CAPN14 D 7.3 1.51 260 230 3 4 4 CAPN14 D 7.3 1.51 260 230 3 4 4 CAPN14 D 7.3 1.51 260 230 3 4 4 0.0149 CAPN14 7.3 1.51 260 230 3 4 4 0.0139 MTIF2 2.75 5.18 44 34 1 4 4 0.0486 ANKRD36 B 1.86 2.71 116 110 14 36 33 ANKRD36 B 1.86 2.71 116 110 14 36 33 ANKRD36 B 1.86 2.71 116 110 14 36 33 0.1796 ABI3BP 2.28 2.26 52 46 1 2 2 0.0139 CCDC54 2.61 4.52 52 46 1 4 4 0.0317 TMPRSS7 3.04 4.52 104 92 2 8 6 0.0258 TMPRSS7 3.04 4.52 104 92 2 8 6 0.0258 RABL3 1.68 1.58 52 46 5 7 7 0.127 CASR D 1.71 6.78 104 92 1 6 6 0.0446 CASR D 1.71 6.78 104 92 1 6 6 TOPBP1 2.28 2.26 52 46 1 2 2 0.0437 LAMP3 3.42 1.7 52 46 2 3 3 0.0317 FBX045 1.9 1.88 52 46 3 5 5 0.0665 ALS2CL 1.56 1.88 52 46 18 30 20 0.3571 FAM208A 3.18 2.36 52 44 2 4 4 0.0327 FAM3D 2.61 4.52 52 46 1 4 4 0.0308 ELMOD2 1.96 3.39 52 46 1 3 3 0.0208 CDKN2AIP 1.66 2.01 52 46 9 16 13 0.244 81 2017100960 13 Μ 2017 1.65 1.84 52 46 8 13 11 0.1726 1.52 2.83 260 230 2 5 5 1.52 2.83 260 230 2 5 5 0.0238 1.52 2.83 260 230 2 5 5 1.52 2.83 260 230 2 5 5 1.52 2.83 260 230 2 5 5 1.71 104 92 0 3 3 1.71 104 92 0 3 3 0.0149 3.04 2.26 104 92 2 4 4 0.0278 3.04 2.26 104 92 2 4 4 1.96 3.39 52 46 1 3 3 0.0476 1.52 2.26 52 46 4 8 8 0.1012 1.71 1.7 104 92 2 3 3 0.0248 1.71 1.7 104 92 2 3 3 3.42 3.39 104 92 1 3 3 0.0159 3.42 3.39 104 92 1 3 3 1.62 1.98 104 92 12 21 19 0.119 1.62 1.98 104 92 12 21 19 0.2153 1.76 2.79 154 138 2 5 4 1.76 2.79 154 138 2 5 4 1.76 2.79 154 138 2 5 4 0.0694 3.42 3.39 104 92 1 3 2 3.42 3.39 104 92 1 3 2 0.0109 1.76 1.91 104 92 16 27 25 0.1845 1.76 1.91 104 92 16 27 25 0.1468 2.71 4.52 156 138 2 8 8 0.0248 2.71 4.52 156 138 2 8 8 0.0308 2.71 4.52 156 138 2 8 8 6 4 20751278 rs2322688 A G KCNIP4 6 4 48517296 rs757286932 C A FRYL 6 4 48545814 rs10517225 A T FRYL 6 4 48546796 rs78799039 A G FRYL 6 4 48549674 rs776615697 GAGA G FRYL 6 4 48559138 rs779161058 AG A FRYL 6 4 48993993 rs749533750 CTTG C CWH43 6 4 49034669 rs147750792 CA C CWH43 TMPRSS1 6 4 69094459 rs75647314 C A 1B TMPRSS1 6 4 69096987 rs575638339 C T 1B 6 4 70078281 rs62298955 G C UGT2B11 6 4 77940418 rs28541859 T A SEPT11 6 5 151784206 rs145273801 G A NMUR2 6 5 151784490 rs762380505 C A NMUR2 6 5 170221307 rs117380156 G A GABRP 6 5 170236578 rs558177227 C T GABRP 6 5 74998426 rs 17649248 G A POC5 6 5 75008193 rs2047059 T C POC5 6 6 106978193 rs 17495742 A G AIM1 6 6 106991361 rs61741114 T C AIM1 6 6 107016343 rs3747789 T G AIM1 6 6 10927469 rs770638323 A G SYCP2L 6 6 10935424 rs181416897 C T SYCP2L 6 6 142487469 rs225656 C A VTA1 6 6 142510676 rs3830800 GTATT G VTA1 6 6 26410148 rs77721150 T C BTN3A1 6 6 26410227 rs7770214 G A BTN3A1 6 6 26410266 T C BTN3A1 82 2017100960 13 Μ 2017 2.85 2.83 52 46 4 10 9 0.1448 3.42 52 46 0 3 3 0.0218 1.76 2.83 52 46 2 5 4 0.0595 2.11 3.39 156 138 2 6 5 2.11 3.39 156 138 2 6 5 0.0198 2.11 3.39 156 138 2 6 5 0.0595 2.08 52 46 0 5 4 0.0615 2.15 1.51 52 46 6 8 8 0.0972 3.04 2.26 52 46 1 2 2 0.0129 2.08 5.65 52 46 1 5 5 0.0496 1.52 3.39 52 46 1 3 3 0.0407 4.57 52 46 0 3 3 0.0149 2.28 2.26 104 92 1 2 2 0.0188 2.28 2.26 104 92 1 2 2 2.28 2.26 52 46 1 2 2 0.0139 2.54 5.65 156 138 1 5 5 2.54 5.65 156 138 1 5 5 1.95 1.66 42 38 8 12 10 0.1766 2.74 1.61 148 138 4 6 6 0.0238 2.74 1.61 148 138 4 6 6 0.0139 2.74 1.61 148 138 4 6 6 1.52 1.7 52 46 4 6 6 0.1111 2.28 2.26 52 46 2 4 4 0.0397 4.57 52 46 0 5 5 0.0159 1.79 2.44 44 36 2 4 4 0.0526 2.74 1.7 52 46 2 3 3 0.0337 1.83 2.26 52 46 1 2 2 0.0149 1.83 3.39 156 138 1 3 3 0.0278 1.83 3.39 156 138 1 3 3 0.0139 6 6 28268497 rs2281043 C T PGBD1 6 6 30574428 A G PPP1R10 6 6 30618867 T C C6orf136 6 6 30670948 rs536243116 C T MDC1 6 6 30679289 rs147822906 G C MDC1 6 6 30679510 rs17189329 G A MDC1 6 6 31733650 rs707936 G A VWA7 6 6 31948421 TCTC T STK19 6 6 36929653 rs144897670 C T P116 6 6 397261 rs34318727 G A IRF4 6 6 46133282 rs 16874326 T C ENPP5 6 6 72011086 rs 16880821 C T OGFRL1 6 6 87994504 rs35259282 C T GJB7 6 6 87994537 rs112552839 G A GJB7 6 7 100230618 rs41303468 A T TFR2 6 7 140125701 rs760033770 G A RAB19 6 7 140125753 rs771901851 G A RAB19 6 7 140174292 rs10709936 CA C MKRN1 6 7 142562051 rs143667567 C CCCTCCT EPHB6 6 7 142562051 rs143667567 C CCCT EPHB6 6 7 142565743 rs8177158 G A EPHB6 6 7 156468559 rs3823617 T C RNF32 6 7 28534518 rs77306029 c T CREB5 6 7 72984917 CGTT c TBL2 6 8 17104886 rs 145945235 G A VPS37A 6 8 37791988 rs201462725 GT G GOT1L1 6 8 87163770 rs150698519 G T ATP6V0D2 6 8 95188916 rs67774240 G A CDH17 6 8 95189955 rs138007982 G T CDH17 83 2017100960 13 Μ 2017 6 8 95201518 rs749070399 TAAAAA T CDH17 6 9 100693386 rs201990544 CACT c HEMGN 6 9 101984010 rs201959100 G A ALG2 6 9 127074783 rs139169292 TC T NEK6 6 9 127076271 rs56045213 A G NEK6 6 9 5892552 rs 148372841 G C MLANA 6 9 95411725 rs72756427 G A IPPK 6 X 31089629 rs7057057 C A FTHL17 6 X 49114808 C A FOXP3 1.83 3.39 156 138 1 3 3 6.85 3.39 52 46 1 3 3 0.0129 6.85 52 46 0 3 3 0.0188 1.59 2.26 104 92 8 16 16 0.0923 1.59 2.26 104 92 8 16 16 0.0923 9.13 4.52 52 46 1 4 4 0.0139 2.74 1.7 52 46 2 3 3 0.0476 1.73 2.26 52 46 3 6 5 0.1453 2.88 1.88 52 46 3 5 4 0.0393 84 2017100960 13 Μ 2017

Table 10: Susceptibility genes unique to disease duration with exonic variants in Rheumatoid Arthritis disease. AMPD1 ATXN7 GPR84 OR7G3 PPARGC1B C10orfl42 OR9K2 CST9 ATP6V0A4 CH17-360D5.1 OR6C74 WDR33 HKDC1 NPY4R OR6C75 DNAJC28 Clorfl67 LRRC39 CATSPER4 DDTL SLC01B3 GPSM2 NR2C1 UPB1 MYH1 ITGA10 SERP1NA10 LCLAT1 SGCA LCE5A RORA CASR RYR1 OR4A15 TPSG1 CDKN2AIP KIZ OR52N4 NEKS FRYL TPTE SLAMF8 HEATR9 CWH43 LRP2 MTA2 PNMT NMUR2 DYSF EML3 ABCC3 GABRP COL6A6 GPR161 NACA2 MDC1 CP IL18BP CACNG5 ENPP5 HTR3E PANOl AURKB RAB19 TET2 LHX4 PLEKHG2 EPHB6 THBS2 LAD1 PSG8 GOT1L1 FLNC SYT14 CBLC HEMGN SSPO FAAP20 CARDS ALG2 PKHD1L1 HIST4H4 TARM1 FTHL17 IL3RA OR14C36 PRR36 85

Claims

1. A method of identifying a gene associated with a disease or pathological condition of the disease, comprising the steps of: a) obtaining a first group of exome sequences from a first population of individuals and a second group of exome sequences from a second population of individuals, wherein the first population of individuals suffer from the disease or pathological condition of the disease, and the second population of individuals do not have the disease or pathological condition of the disease; b) identifying one or more variants in the first group of exome sequences by comparing the first group of exome sequences with the second group of exome sequences, and optionally with a public database, to generate a first set of variant data; c) applying a variant quality score calibration tool with a truth sensitivity threshold to remove false-positive variants having a sensitivity lower than the threshold and background variants from the first set of variant data so as to obtain a second set of variant data; d) removing synonymous variants from the second set of variant data to obtain a third set of variant data; and e) identifying one or more deleterious variants from the third set of variant data using a gene burden analysis, optionally generating a fourth set of variant data.

2. The method of claim 1, wherein in step (a), the first and second exome data are obtained by whole-exome sequencing.

3. The method of claim 1 further comprises a step of confirming the ethnicity of the first and second population of individuals via ancestry composition analysis.

4. The method of claim 1, wherein the step (c) comprises a step (i) of applying the variant quality score calibration tool with the truth sensitivity threshold of about 90% to remove the false-positive variants, and removing the background variants having a read depth of less than 5 and a genotype quality of less than 10 from the first set of variant data.

5. The method of claim 4, wherein the applied truth sensitivity threshold is about 99%, the read depth is less than 10 and the genotype quality is less than 20.

6. The method of claim 4, wherein the step (c) further comprises a step (ii) of screening the resultant variants from step c) (i) based on the dataset provided by UCSC genome browser to keep exonic or slicing variants in the second set of variant data.

7. The method of claim 1, wherein the step e) comprises a step (i) of identifying one or more deleterious variants having a gene burden ratio of larger than 1, or being present in the first group of exome sequences in an amount of at least three but absent in the second group of exome sequences.

8. The method of claim 7, wherein the step e) further comprises a step (ii) of grouping the identified one or more deleterious variants whose minor allele frequency is smaller than 0.02, into a rare variant group, and grouping the rest of the identified one or more deleterious variants into a common variant group.

9. The method of claim 1, further comprises after the step e) a step f) of determining a pathogenic gene associated with the disease or pathological condition of the disease from the fourth set of variant data by using a logistic regression model and public accessible database.

10. The method of claim 9, wherein a biological pathway analysis is performed after the step e) or step f) to determine the functional role of the identified one or more deleterious variants.

11. The method of claim 1, wherein a structural analysis using a homology modeling is applied to determine the structure of protein associated with the identified one or more deleterious variants.

12. The method of claim 1, wherein the disease is selected from the group consisting of an autoimmune disease, a neurodegenerative disease, a cardiovascular disease, a cancer, a gastrointestinal disease, an inflammatory disease, or an endocrine disease.

13. The method of claim 1, wherein the disease is rheumatoid arthritis.