Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12.

Am J Hum Genet
Authors
Keywords
Abstract

We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.

Year of Publication
2012
Journal
Am J Hum Genet
Volume
90
Issue
3
Pages
524-32
Date Published
2012 Mar 09
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2012.01.010
PubMed ID
22365150
PubMed Central ID
PMC3309197
Links
Grant list
R01-AR057108 / AR / NIAMS NIH HHS / United States
P60 AR048095 / AR / NIAMS NIH HHS / United States
R01 AR057202 / AR / NIAMS NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
K01 DK080188 / DK / NIDDK NIH HHS / United States
R01 AR057108 / AR / NIAMS NIH HHS / United States
K01 AR060848 / AR / NIAMS NIH HHS / United States
R01-AR056768 / AR / NIAMS NIH HHS / United States
R01 AR056768 / AR / NIAMS NIH HHS / United States
U01-GM092691 / GM / NIGMS NIH HHS / United States