ASSOCIATION HETEROGENEITY MAPPING IDENTIFIES AN ASIAN-SPECIFIC ASSOCIATION OF THE GTF2I LOCUS WITH RHEUMATOID ARTHRITIS

Abstract

Background Genetic association studies using multiple ancestral cohorts have revealed a large overlap of rheumatoid arthritis (RA)-risk alleles among different ancestries, but there are some exceptional loci showing heterogenic association among populations.

Objectives Here we investigated genetic variants with distinct effects on the development of RA in Asian and European populations.

Methods Ancestry-related association heterogeneity was examined using the association data from large Korean (n=9,299) and European (n=45,790) rheumatoid arthritis cohorts with Immunochip and genome-wide SNP array data. Novel disease associations detected in Koreans were validated using two independent Asian cohorts (n=5,166) and a meta-analysis.

Results We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus and showed that this heterogeneity is due to an Asian-specific association effect (PHeterogeneity =9.6×10-9 at rs73366469 [ORMeta =1.37 and PMeta =4.2×10–13 in Asians; ORMeta =1.00 and PMeta =1.00 in Europeans]) in RA. Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal SNP (rs117026326; linked to rs73366469), whose minor allele is common in Asians but rare in Europeans.

Conclusions We identified the largest effect on Asian RA across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.