Rare, low-frequency, and common variants in the protein-coding sequence of biological candidate genes from GWASs contribute to risk of rheumatoid arthritis.

Am J Hum Genet
Authors
Keywords
Abstract

The extent to which variants in the protein-coding sequence of genes contribute to risk of rheumatoid arthritis (RA) is unknown. In this study, we addressed this issue by deep exon sequencing and large-scale genotyping of 25 biological candidate genes located within RA risk loci discovered by genome-wide association studies (GWASs). First, we assessed the contribution of rare coding variants in the 25 genes to the risk of RA in a pooled sequencing study of 500 RA cases and 650 controls of European ancestry. We observed an accumulation of rare nonsynonymous variants exclusive to RA cases in IL2RA and IL2RB (burden test: p = 0.007 and p = 0.018, respectively). Next, we assessed the aggregate contribution of low-frequency and common coding variants to the risk of RA by dense genotyping of the 25 gene loci in 10,609 RA cases and 35,605 controls. We observed a strong enrichment of coding variants with a nominal signal of association with RA (p A [p.His266Gln]), and a noncoding variant, rs624988, reside on distinct haplotypes and independently contribute to the risk of RA (p = 4.6 × 10(-6)). Overall, our results indicate that variants (distributed across the allele-frequency spectrum) within the protein-coding portion of a subset of biological candidate genes identified by GWASs contribute to the risk of RA. Further, we have demonstrated that very large sample sizes will be required for comprehensively identifying the independent alleles contributing to the missing heritability of RA.

Year of Publication
2013
Journal
Am J Hum Genet
Volume
92
Issue
1
Pages
15-27
Date Published
2013 Jan 10
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2012.11.012
PubMed ID
23261300
PubMed Central ID
PMC3542467
Links
Grant list
R01-AR057108 / AR / NIAMS NIH HHS / United States
K08 AR060257 / AR / NIAMS NIH HHS / United States
R01 AR059648 / AR / NIAMS NIH HHS / United States
17552 / Arthritis Research UK / United Kingdom
U01 GM092691 / GM / NIGMS NIH HHS / United States
R01-AR059648 / AR / NIAMS NIH HHS / United States
R01 AR057108 / AR / NIAMS NIH HHS / United States
K08AR060257 / AR / NIAMS NIH HHS / United States
U54 LM008748 / LM / NLM NIH HHS / United States
R01-AR056768 / AR / NIAMS NIH HHS / United States
U54-LM008748 / LM / NLM NIH HHS / United States
R01 AR056768 / AR / NIAMS NIH HHS / United States
U01-GM092691 / GM / NIGMS NIH HHS / United States