Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese

Abstract Aims: Genome-wide association studies (GWAS) identified many common type 2 diabetes-associated variants, mostly found at the intronic or intergenic regions. Recent advancement of exome array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exome-chip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population. Methods: An exome-chip association study was conducted by genotyping 5640 Hong Kong Chinese individuals using a custom Asian Exome-chip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 Guangzhou individuals. A combined analysis involving 7189 cases and 10,813 controls was performed. Results: In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and 2 variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes at exome-wide significance (pdiscovery<6.45x10-7). The risk allele (T) of PAX4 rs2233580 was associated with a younger age of diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (pmeta=3.74x10-15) in the combined analysis. Conclusions: We identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. Our findings are suggestive of PAX4 being a possible effector gene of the 7q32 locus previously identified from GWAS amongst Asians.