Our recent genome-wide association study (GWAS) identified variants strongly associated with type 2 diabetes (T2D) on chromosome 11p15 in American Indians at KCNQ1 (index variant rs2237895, P=2.5×10-8) and TH (rs11564707, P=3.8×10-8). To assess whether these variants influence epigenetic variation we analyzed associations with DNA methylation. Participants included 7659 American Indians (33% with T2D) who had participated in the GWAS, 842 of whom had DNA methylation measured in peripheral blood. Methylation was measured with the Infinium 450k array (Illumina, San Diego, CA). To identify local CpG sites associated with index variants, we analyzed associations for sites within 1 Mb of each gene (2162 sites for KCNQ1, 2325 for TH). Strong associations were identified: the diabetes risk allele at rs2237895 associated with decreased methylation at cg14637411 (β= 1.35 SD per copy, P=2.6×10-169), and the risk allele at rs11564707 associated with increased methylation at cg19878200 (β=0.46 SD, P=1.1×10-21). We further conducted Bayesian functional fine-mapping association of T2D and statistical colocalization of association of methylation at these sites with T2D using CAVIAR- including 1943 variants for KCNQ1 and 2954 variants for TH. Potentially causal variants for T2D were identified for each gene (30 for KCNQ1 and 33 for TH with posterior probability of causality >0.01); all were in strong linkage disequilibrium with the index variant. Strong evidence for colocalization of the association of T2D with methylation at cg14637411 (colocalization posterior probability >0.01, suggesting both traits are influenced by the same causal variants) was seen with 4 KCNQ1 variants: rs60808706, rs2299620, rs2237896 and rs2237897. Evidence for colocalization was weak for cg19878200 and T2D at TH variants. These results support the notion that KCNQ1 variants may influence T2D risk via an epigenetic effect, and they identify candidate functional variants.


R.L. Hanson: None. S. Kobes: None. W. Hsueh: None. Y.L. Muller: None. W.C. Knowler: None. L. Baier: None.


American Diabetes Association (1-12-DNP-01 to R.L.H.)

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