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

Nat Genet 2013 Feb 23;45(2):197-201. Epub 2012 Dec 23.

Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

Insulin secretion has a crucial 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 secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.

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http://dx.doi.org/10.1038/ng.2507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727235PMC
February 2013
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