Overview

A genome-wide association study meta-analysis in individuals of European and Asian ancestries with 29,880 rheumatoid arthritis cases and 73,758 controls.
 
Meta-analysis was done in three stages.  Stage1 meta-analysis (22 GWAS from 19,234 cases and 61,565 controls of European and Asian ancestry) followed by two-step replication, stage 2 in silico replication (2 GWAS from 3,708 RA cases and 5,535 controls of Europeans and Asians) and stage 3 de novo replication (2 GWAS from 6938 RA cases and 6658 controls of Europeans and Asians).   Meta-analysis was performed for the trans-ethnic study (both Europeans and Asians), European study, and Asian study separately.
 
Approximately 10 million snps were evaluated in this study. Post QC whole-genome imputation was performed using 1000 Genomes Project Phase I data (European and Asian) with Minimac (release 2011-10-27).  The combined analysis identified 42 novel RA risk loci, at a genome-wide level of significance (P < 5.0 x 10-8), in any of the trans-ethnic, European or Asian meta-analyses.  The study also confirms 59 known RA risk loci, at a suggestive level of association (P < 5.0 x 10-6) from previous studies, increasing the total number of confirmed RA risk loci to 101 (including the MHC region), out of which 5 loci demonstrated population-specific associations.
Study Type
Whole Genome Association Study
Samples
GroupPhenotypePopulationCasesControlsFamiliesTrios
DiscoveryRA1923461565--
ReplicationRA1064612193--
Exclusion Criteria
GWAS QC Criteria: 
 
Samples were excluded due to:
  • Stage1 : Call rate < 0.95 (European) and < 0.90 (Asian)
  • Stage2 : Call rate < 0.95 (European & Asian)
SNPs were excluded due to:
  • Stage1: Call rate < 0.95 (European) and < 0.90 (Asian)
  • Stage2: Call rate < 0.95 (European & Asian
  • Stage1: MAF < 0.01 (European & Asian)
  • Stage2: MAF < 0.01 (European) and < 0.05  (Asian)
  • Stage1: Deviation from  Hardy-Weinberg equilibrium, p < 10-6 (European) and p < 10-7 (Asian)
  • Stage2: Deviation from  Hardy-Weinberg equilibrium, p < 10-4 (European) and p < 10-3 (Asian)
QC criteria for Stage3 de novo replication study were described in Stahl et al., Okada et al.
 
Imputation QC Criteria:
 
Excluded imputed SNPs with
  • MAF < 0.005 in RA cases and controls 
  • Low imputation score, Rsq < 0.5 for genome-wide array and < 0.7 for Immunochip for each study.

 

Study Association

RegionLocationGene(s)MarkerAlleleMAFP ValueOdds Ratio
1p13.1chr1:116642505-116755112CD2  rs624988C > T0.4001.20e-05C1.06 (1.03-1.09)D
1p13.2chr1:113296527-114009223PTPN22  rs2476601G > A0.0906.60e-170C1.81 (1.74-1.90)D
1p34.3chr1:38136523-38238517LINC01343  rs12140275A > T0.1902.00e-09C1.10 (1.06-1.14)D
1p34.3chr1:37731957-38002404INPP5B  MTF1  rs28411352C > T0.2502.80e-12C1.12 (1.08-1.15)D
1p36.13chr1:17240113-17353103PADI4  rs2301888G > A0.4201.30e-18C1.13 (1.10-1.17)D
1p36.23chr1:7777818-8136946TNFRSF9  rs227163T > C0.4203.90e-04C1.03 (1.01-1.06)D
1p36.32chr1:2431888-2879054MMEL1  TNFRSF14  rs187786174G > A0.3307.80e-14C1.13 (1.09-1.16)D
1q21.3chr1:154335188-154679688IL6R  rs2228145A > C0.4003.70e-09C1.08 (1.05-1.11)D
1q23.1chr1:157513710-157848760FCRL3  rs2317230G > T0.4202.20e-07C1.08 (1.05-1.11)D
1q23.3chr1:161306153-161514258FCGR2A  rs72717009C > T0.1001.10e-07C1.13 (1.08-1.19)D
1q23.3chr1:161513789-161737712FCGR2B  rs75409195G > C0.2908.20e-05C1.15 (1.08-1.22)D
1q23.3chr1:160724085-160963275CD244  LY9  rs4656942G > A0.2508.40e-02C1.03 (1.00-1.06)D
1q25.1chr1:173329925-173871661rs2105325C > A0.2106.90e-13C1.11 (1.08-1.15)D
1q31.3chr1:198570898-198867217PTPRC  rs17668708C > T0.1101.70e-05C1.12 (1.06-1.18)D
2p14chr2:65170461-65489960SPRED2  rs1858037T > A0.4803.30e-15C1.12 (1.09-1.15)D
2p15chr2:62167375-62271077B3GNT2  rs13385025G > A0.1708.80e-07C1.11 (1.06-1.16)D
2p16.1chr2:60694033-61616575REL  rs34695944T > C0.2701.70e-15C1.12 (1.08-1.15)D
2p23.1chr2:30192259-30240054LBH  rs10175798A > G0.4601.10e-09C1.09 (1.06-1.12)D
2q11.2chr2:99928492-100425222AFF3  rs9653442T > C0.4601.60e-18C1.11 (1.08-1.14)D
2q13chr2:110225473-111045908ACOXL  rs6732565A > G0.3902.70e-08C1.08 (1.04-1.11)D
2q32.3chr2:190990148-191143008STAT4  rs11889341C > T0.2503.60e-19C1.14 (1.11-1.18)D
2q33.1chr2:200781905-201640992CASP8  CFLAR  rs6715284C > G0.1001.80e-09C1.14 (1.08-1.20)D
2q33.2chr2:203750711-203951852CTLA4  rs3087243G > A0.4003.10e-25C1.14 (1.11-1.17)D
2q33.2chr2:203581104-203854006CD28  rs1980422T > C0.1903.00e-14C1.12 (1.09-1.16)D
3p14.3chr3:58170449-58544384PXK  DNASE1L3  ABHD6  rs73081554C > T0.0704.60e-08C1.18 (1.11-1.25)D
3p24.1chr3:27639513-27794554EOMES  rs3806624G > A0.4408.60e-09C1.09 (1.05-1.12)D
3p24.3chr3:16837707-17112238PLCL2  rs4452313A > T0.3501.60e-10C1.09 (1.06-1.12)D
3q22.3chr3:135890168-137099199IL20RB  rs9826828G > A0.0208.60e-10C1.42 (1.25-1.62)D
4p11chr4:47951498-48970634TEC  rs2664035G > A0.3709.50e-08C1.06 (1.03-1.09)D
4p15.2chr4:26027183-26130530SMIM20  rs11933540T > C0.3108.80e-17C1.15 (1.11-1.19)D
4p16.1chr4:10696641-10915159CLNK  rs13142500T > C0.4903.00e-09C1.10 (1.07-1.14)D
4q21.21chr4:78552886-78960359ANXA3  rs10028001A > T0.4003.40e-04C1.06 (1.03-1.09)D
4q27chr4:122041679-122644147IL21  IL2  rs45475795A > G0.0703.50e-06C1.14 (1.08-1.20)D
5q11.2chr5:56136421-56175811ANKRD55  rs7731626G > A0.2907.30e-24C1.21 (1.17-1.26)D
5q21.1chr5:102699259-103415498C5orf30  rs2561477G > A0.3109.60e-11C1.09 (1.06-1.12)D
5q31.1chr5:131110726-132444068CSF2  IL3  rs657075G > A0.1707.50e-07C1.09 (1.05-1.13)D
6p21.1chr6:44257254-44326129NFKBIE  rs2233424C > T0.1201.40e-19C1.26 (1.20-1.33)D
6p21.31chr6:36375944-36646035ETV7  rs2234067C > A0.1001.60e-09C1.15 (1.10-1.20)D
6p23chr6:14040786-14142258CD83  rs74984480C > T0.0903.10e-07C1.15 (1.09-1.21)D
6p25.3chr6:384546-467748IRF4  rs9378815C > G0.4201.70e-10C1.10 (1.07-1.13)D
6q21chr6:106150492-106380042ATG5  rs9372120T > G0.1607.60e-10C1.10 (1.06-1.14)D
6q23.3chr6:137709334-137966423TNFAIP3  rs7752903T > G0.0402.00e-29C1.38 (1.30-1.46)D
6q23.3chr6:137568133-137806067TNFAIP3  rs17264332A > G0.2103.90e-20C1.17 (1.13-1.22)D
6q25.1chr6:149315830-149932104PPIL4  rs9373594T > C0.3703.00e-09C1.10 (1.06-1.14)D
6q25.3chr6:158907321-159123547TAGAP  rs2451258T > C0.2602.70e-11C1.11 (1.07-1.14)D
6q27chr6:166937632-167134466RP11-517H2.6  CCR6  rs1571878T > C0.4505.00e-35C1.17 (1.14-1.20)D
7p15.1chr7:28080094-28222707JAZF1  rs67250450T > C0.4203.70e-09C1.09 (1.05-1.13)D
7q21.2chr7:92434186-92805872CDK6  rs4272A > G0.1905.00e-09C1.10 (1.06-1.13)D
7q32.1chr7:128911686-129137466IRF5  rs3778753A > G0.3901.10e-14C1.12 (1.09-1.15)D
8p23.1chr8:11426026-11546260BLK  rs2736337T > C0.3603.10e-13C1.11 (1.08-1.14)D
8q21.13chr8:80159381-80417925TPD52  rs998731T > C0.4401.90e-08C1.07 (1.04-1.11)D
8q22.3chr8:101367069-101475028GRHL2  rs678347A > G0.4201.60e-08C1.08 (1.05-1.11)D
8q24.21chr8:128484980-128585383PVT1  rs1516971T > C0.1101.30e-10C1.12 (1.07-1.17)D
9p13.3chr9:34648421-34975511CCL19  CCL21  rs11574914G > A0.2602.60e-15C1.12 (1.09-1.16)D
9q33.2chr9:120584375-121363046TRAF1  C5  rs10985070A > C0.4505.00e-11C1.08 (1.05-1.11)D
10p11.22chr10:30843546-31191775ZNF438  rs793108C > T0.4901.30e-09C1.07 (1.04-1.10)D
10p14chr10:8954304-9174993rs12413578C > T0.1004.80e-08C1.20 (1.12-1.29)D
10p14chr10:8041925-8083759GATA3  rs3824660T > C0.3802.00e-08C1.08 (1.05-1.11)D
10p15.1chr10:5988280-6129961IL2RA  rs706778C > T0.4504.60e-14C1.09 (1.06-1.12)D
10p15.1chr10:6346109-6394072PRKCQ  rs947474A > G0.1704.10e-10C1.11 (1.07-1.15)D
10q11.23chr10:48760551-48932543WDFY4  rs2671692A > G0.4802.80e-09C1.08 (1.05-1.11)D
10q21.2chr10:62090031-62395176RTKN2  rs6479800G > C0.1803.60e-08C1.11 (1.06-1.15)D
10q21.2chr10:61937130-62094062ARID5B  rs71508903C > T0.2204.70e-22C1.17 (1.13-1.21)D
10q22.3chr10:79454422-80126158SFTPD  rs726288C > T0.0801.60e-05C1.13 (1.06-1.21)D
11p12chr11:36431719-36737472RAG2  TRAF6  RAG1  rs331463T > A0.1303.40e-07C1.09 (1.05-1.13)D
11q12.2chr11:61753196-61917078FADS2  FADS3  FADS1  rs968567C > T0.1701.80e-08C1.11 (1.06-1.16)D
11q12.2chr11:61067850-61377180CD5  rs508970G > A0.4902.70e-06C1.07 (1.04-1.11)D
11q13.4chr11:72576306-73174077ARAP1  rs11605042A > G0.4904.90e-05C1.06 (1.03-1.10)D
11q21chr11:95537638-95599614CEP57  rs4409785T > C0.1501.20e-11C1.11 (1.07-1.15)D
11q22.3chr11:107973474-108562579ATM  rs138193887A > G0.0801.40e-08C1.21 (1.12-1.30)D
11q23.3chr11:118523399-118918512CXCR5  rs10790268G > A0.1901.10e-15C1.15 (1.11-1.19)D
11q24.3chr11:128558890-128692203ETS1  rs73013527C > T0.4401.20e-10C1.10 (1.07-1.13)D
12q13.2chr12:55958153-56397446CDK2  rs773125A > G0.3501.10e-10C1.09 (1.06-1.12)D
12q14.1chr12:57490018-58092822CDK4  rs1633360C > T0.4909.60e-08C1.07 (1.05-1.10)D
12q24.12chr12:111269993-112590299SH2B3  PTPN11  rs10774624A > G0.5006.80e-09C1.09 (1.06-1.13)D
13q14.11chr13:39618079-39887654COG6  rs9603616C > T0.3201.60e-12C1.11 (1.07-1.14)D
14q23.1chr14:61437664-61536516PRKCH  rs3783782G > A0.0902.20e-09C1.16 (1.10-1.23)D
14q24.1chr14:68090027-68492994RAD51B  rs1950897T > C0.2408.20e-11C1.10 (1.07-1.14)D
14q32.33chr14:104816684-105116187AHNAK2  PLD4  rs2582532C > T0.1402.70e-07C1.14 (1.08-1.22)D
15q14chr15:38522176-38665929RASGRP1  rs8032939T > C0.3501.90e-18C1.12 (1.09-1.16)D
15q23chr15:69667254-69758634DRAIC  rs8026898G > A0.2103.60e-19C1.16 (1.12-1.19)D
16p13.13chr16:11663703-11822505TXNDC11  rs4780401T > G0.4404.10e-08C1.07 (1.04-1.10)D
16q24.1chr16:85956974-85990498IRF8  rs13330176T > A0.3001.40e-12C1.12 (1.08-1.15)D
17p13.2chr17:5212114-5550267C1QBP  rs72634030C > A0.2301.50e-09C1.12 (1.07-1.16)D
17q12chr17:39218393-40025771MED1  rs1877030C > T0.1701.90e-08C1.11 (1.07-1.15)D
17q12chr17:39226421-40083963IKZF3  CSF3  rs59716545T > G0.4002.30e-12C1.10 (1.07-1.13)D
18p11.21chr18:12738414-12926279PTPN2  rs8083786A > G0.2106.30e-18C1.14 (1.10-1.18)D
18q22.2chr18:69838097-69902924CD226  rs2469434T > C0.4008.90e-10C1.06 (1.04-1.09)D
19p13.2chr19:10280033-10517872TYK2  rs34536443G > C0.0504.40e-16C1.46 (1.33-1.60)D
19p13.2chr19:10523588-11048849ILF3  rs147622113C > T0.0308.60e-10C1.47 (1.30-1.67)D
20q13.12chr20:45963997-46172387CD40  rs4239702C > T0.3104.00e-18C1.12 (1.09-1.15)D
21q22.3chr21:44178639-44284761CH507-9B2.1  ICOSLG  AIRE  rs2236668C > T0.3005.70e-07C1.08 (1.05-1.11)D
21q22.3chr21:42389975-42471211UBASH3A  rs1893592A > C0.2707.20e-12C1.11 (1.08-1.15)D
21q22.11chr21:33369949-33841543IFNGR2  rs73194058C > A0.2401.20e-06C1.08 (1.05-1.12)D
21q22.12chr21:34454478-34639390RCAN1  rs147868091C > T0.1003.00e-07C1.12 (1.07-1.17)D
21q22.12chr21:35316695-35450246RUNX1  rs8133843A > G0.4102.70e-09C1.09 (1.06-1.12)D
22q11.21chr22:21454896-21649639YDJC  UBE2L3  rs11089637T > C0.2602.10e-09C1.08 (1.05-1.12)D
22q12.3chr22:37142288-37166071IL2RB  rs3218251T > A0.2102.10e-05C1.07 (1.03-1.10)D
22q13.1chr22:39259042-39371656SYNGR1  rs909685T > A0.4501.40e-16C1.12 (1.09-1.16)D
MHCchr6:32371299-32684804HLA-DRB1  rs9268839A > G0.4501.00e-250C2.30 (2.23-2.36)D
Xq21.1chrX:78745152-79369242P2RY10  rs201408742C > A0.3303.50e-08C1.16 (1.09-1.22)D
Xq28chrX:153866773-154120938IRAK1  rs5987194G > C0.3605.20e-16C1.16 (1.12-1.20)D

Criteria

GDXHsS00035 meets the following criteria:

Criteria Name
Details
Disease Tags
Study for a Disease 

Publications

PMIDTitleFirst AuthorJournalDisease(s)Date