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

Jeroen R. Huyghe, Anne U. Jackson, Marie P. Fogarty, Martin L. Buchkovich, Alena Stančáková, Heather M. Stringham, Xueling Sim, Lingyao Yang, Christian Fuchsberger, Henna Cederberg, Peter S. Chines, Tanya M. Teslovich, Jane M. Romm, Hua Ling, Ivy McMullen, Roxann Ingersoll, Elizabeth W. Pugh, Kimberly F. Doheny, Benjamin M. Neale, Mark J. DalyJohanna Kuusisto, Laura J. Scott, Hyun Min Kang, Francis S. Collins, Gonçalo R. Abecasis, Richard M. Watanabe, Michael Boehnke, Markku Laakso, Karen L. Mohlke

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)197-201
Number of pages5
JournalNature genetics
Volume45
Issue number2
DOIs
StatePublished - Feb 1 2013

ASJC Scopus subject areas

  • Genetics

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