Dataset Information

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

ABSTRACT: To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

SUBMITTER: Stahl EA

PROVIDER: S-EPMC4243840 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

Stahl Eli A EA Raychaudhuri Soumya S Remmers Elaine F EF Xie Gang G Eyre Stephen S Thomson Brian P BP Li Yonghong Y Kurreeman Fina A S FA Zhernakova Alexandra A Hinks Anne A Guiducci Candace C Chen Robert R Alfredsson Lars L Amos Christopher I CI Ardlie Kristin G KG Barton Anne A Bowes John J Brouwer Elisabeth E Burtt Noel P NP Catanese Joseph J JJ Coblyn Jonathan J Coenen Marieke J H MJ Costenbader Karen H KH Criswell Lindsey A LA Crusius J Bart A JB Cui Jing J de Bakker Paul I W PI De Jager Philip L PL Ding Bo B Emery Paul P Flynn Edward E Harrison Pille P Hocking Lynne J LJ Huizinga Tom W J TW Kastner Daniel L DL Ke Xiayi X Lee Annette T AT Liu Xiangdong X Martin Paul P Morgan Ann W AW Padyukov Leonid L Posthumus Marcel D MD Radstake Timothy R D J TR Reid David M DM Seielstad Mark M Seldin Michael F MF Shadick Nancy A NA Steer Sophia S Tak Paul P PP Thomson Wendy W van der Helm-van Mil Annette H M AH van der Horst-Bruinsma Irene E IE van der Schoot C Ellen CE van Riel Piet L C M PL Weinblatt Michael E ME Wilson Anthony G AG Wolbink Gert Jan GJ Wordsworth B Paul BP Wijmenga Cisca C Karlson Elizabeth W EW Toes Rene E M RE de Vries Niek N Begovich Ann B AB Worthington Jane J Siminovitch Katherine A KA Gregersen Peter K PK Klareskog Lars L Plenge Robert M RM

Nature genetics 20100509 6

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of al ...[more]

PMID: 20453842

Similar Datasets

Project description:A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).

Dataset Information

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

Publications

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets