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

ABSTRACT: 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 (PHeterogeneity?=?9.6?×?10(-9) at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta?=?1.37 and PMeta?=?4.2?×?10(-13) in Asians; ORMeta?=?1.00 and PMeta?=?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.

SUBMITTER: Kim K

PROVIDER: S-EPMC4897688 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Kim Kwangwoo K Bang So-Young SY Ikari Katsunori K Yoo Dae Hyun DH Cho Soo-Kyung SK Choi Chan-Bum CB Sung Yoon-Kyoung YK Kim Tae-Hwan TH Jun Jae-Bum JB Kang Young Mo YM Suh Chang-Hee CH Shim Seung-Cheol SC Lee Shin-Seok SS Lee Jisoo J Chung Won Tae WT Kim Seong-Kyu SK Choe Jung-Yoon JY Momohara Shigeki S Taniguchi Atsuo A Yamanaka Hisashi H Nath Swapan K SK Lee Hye-Soon HS Bae Sang-Cheol SC

Scientific reports 20160608

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 ( ...[more]

PMID: 27272985

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Project description:Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker.Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p?=?3×10(-3)); IL2-21 (rs13119723, p?=?0.008); HLA-DRB1 (rs660895, p?=?2.56×10(-5); rs6457617, p?=?1.6×10(-09); rs13192471, p?=?6.7×10(-16)); TNFA1P3 (rs9321637, p?=?0.03); CCL21 (rs13293020, p?=?0.01); IL2RA (rs2104286, p?=?1.9×10(-4)) and ZEB1 (rs2793108, p?=?0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent allelic heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ?50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants.

Dataset Information

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

Publications

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

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