High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

1] Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. [2] National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK. [3].
Nature Genetics (Impact Factor: 29.35). 11/2012; 44(12). DOI: 10.1038/ng.2462
Source: PubMed


Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

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Available from: Luis Rodriguez-Rodriguez, Dec 23, 2013
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    • "Saad et al. Table 1 (continued) SNP Gene Position Method Population Comment Reference rs2476601 PTPN22 113,834,946 Individual-SNP Non-hispanic white children ACPA + or RF+ [81] rs7574865 STAT4 191,099,907 Individual-SNP rs10499194 TNFAIP3 137,681,500 Individual-SNP rs4264222 Dectin-2 8,459,172 Individual-SNP Caucasian (Spain and Portugal) [83] rs4804803 DC-SIGN 7,747,847 Individual-SNP rs1024611 MCP-1 34,252,769 Individual-SNP rs13900 34,256,892 Individual-SNP rs4586 34,256,250 Individual-SNP rs6859219 IL6ST 56,142,753 Individual-SNP BRASS, CANADA, EIRA, NARAC I, NARAC III, WTCCC, CANADA II, Dutch, GENRA, GCI, LUMC, NARAC II, United Kingdom RA Genetics (UKRAG), and NHS ACPA + or RF+ [85] rs934734 SPRED2 65,368,452 Individual-SNP rs26232 C5orf30 103,261,019 Individual-SNP rs874040 RBPJ 26,106,575 Individual-SNP rs3093023 CCR6 167,120,802 Individual-SNP rs10488631 IRF5 128,954,129 Individual-SNP rs13315591 PXK 58,571,114 Individual-SNP rs706778 IL2RA 6,056,986 Individual-SNP rs951005 CCL21 34,743,684 Individual-SNP rs11676922 AFF3 100,190,478 Individual-SNP rs34536443 TYK2 10,352,442 Individual-SNP UK, EIRA, US, Dutch, Swedish Umea, Spanish, BRASS, CANADA, NARAC II, and WTCCC [87] rs13397 IRAK1 153,982,797 Individual-SNP rs8026898 TLE3 69,699,078 Individual-SNP rs8043085 RASGRP1 38,535,939 Individual-SNP rs2240336 PADI4 17,347,907 Individual-SNP rs2228145 IL6R 154,454,494 Individual-SNP rs13330176 IRF8 85,985,481 Individual-SNP rs12764378 ARID5B 62,040,245 Individual-SNP rs9979383 RUNX1 35,343,463 Individual-SNP rs12936409 IKZF3 39,887,396 Individual-SNP rs2872507 39,884,510 Individual-SNP rs883220 POU3F1 38,151,199 Individual-SNP rs2834512 RCAN1 34,539,301 Individual-SNP rs595158 CD5 61,142,109 Individual-SNP rs2275806 GATA3 8,053,377 Individual-SNP rs2240340 PADI4 17,336,144 Individual-SNP Malaysian Epidemiological Investigation of RA (MyEIRA) [89] rs1005753 PADI2 17,118,274 Individual-SNP rs1801131 MTHFR 11,854,476 Individual-SNP Jewish and north Italians [90,91] rs699738 CD2 116,768,525 Haplotype Block UK, EIRA, US, Dutch, Swedish Umea, Spanish, BRASS, CANADA, NARAC II, and WTCCC ACPA + [101] rs624988 116,721,168 rs798036 116,766,208 rs11203366 PADI4 17,331,039 "
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