Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion

Insulin secretion plays a critical role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion1,2; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5% to 5%) and rare (MAF<0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 non-diabetic Finnish males. We identified low-frequency coding variants associated with fasting proinsulin levels at the SGSM2 and MADD GWAS loci and three novel genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1, and PAM. We also demonstrate that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs nearby and megabases (Mb) away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits

Timing of water plume eruptions on Enceladus explained by interior viscosity structure

International audienc