Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Eyre S

PROVIDER: S-EPMC3605761 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Eyre Steve S Bowes John J Diogo Dorothée D Lee Annette A Barton Anne A Martin Paul P Zhernakova Alexandra A Stahl Eli E Viatte Sebastien S McAllister Kate K Amos Christopher I CI Padyukov Leonid L Toes Rene E M RE Huizinga Tom W J TW Wijmenga Cisca C Trynka Gosia G Franke Lude L Westra Harm-Jan HJ Alfredsson Lars L Hu Xinli X Sandor Cynthia C de Bakker Paul I W PI Davila Sonia S Khor Chiea Chuen CC Heng Khai Koon KK Andrews Robert R Edkins Sarah S Hunt Sarah E SE Langford Cordelia C Symmons Deborah D Concannon Pat P Onengut-Gumuscu Suna S Rich Stephen S SS Deloukas Panos P Gonzalez-Gay Miguel A MA Rodriguez-Rodriguez Luis L Ärlsetig Lisbeth L Martin Javier J Rantapää-Dahlqvist Solbritt S Plenge Robert M RM Raychaudhuri Soumya S Klareskog Lars L Gregersen Peter K PK Worthington Jane J

Nature genetics 20121111 12

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 arthriti ...[more]

PMID: 23143596

Similar Datasets

Project description:Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10(-57); OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10(-17); OR = 4.28) and the DRB1*1501 (combined P = 2.24×10(-35); OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets