Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis

作者：Kim Kwangwoo; Bang So Young; Ikari Katsunori; Yoo Dae Hyun; Cho Soo Kyung; Choi Chan Bum; Sung Yoon Kyoung; Kim Tae Hwan; Jun Jae Bum; Kang Young Mo; Suh Chang Hee; Shim Seung Cheol; Lee Shin Seok; Lee Jisoo; Chung Won Tae; Kim Seong Kyu; Choe Jung Yoon; Momohara Shigeki; Taniguchi Atsuo; Yamanaka Hisashi; Nath Swapan K; Lee Hye Soon; Bae Sang Cheol^*

来源：Scientific Reports, 2016, 6(1): 27563.

DOI：10.1038/srep27563

Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran's homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (P-Heterogeneity = 9.6 x 10(-9) at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and P-Meta = 4.2 x 10(-13) in Asians; ORMeta = 1.00 and P-Meta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.

• 出版日期2016-6-8