Title |
Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion
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Published in |
Nature Genetics, December 2012
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DOI | 10.1038/ng.2507 |
Pubmed ID | |
Authors |
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 Daly, Johanna Kuusisto, Laura J Scott, Hyun Min Kang, Francis S Collins, Gonçalo R Abecasis, Richard M Watanabe, Michael Boehnke, Markku Laakso, Karen L Mohlke |
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. |
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Student > Ph. D. Student | 61 | 24% |
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Other | 18 | 7% |
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Unknown | 22 | 9% |
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