期刊
NATURE GENETICS
卷 45, 期 2, 页码 197-201出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2507
关键词
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资金
- Academy of Finland [124243]
- Finnish Heart Foundation
- Finnish Diabetes Foundation
- Tekes [1510/31/06]
- Commission of the European Community [HEALTH-F2-2007-201681]
- US National Institutes of Health [DK093757, DK072193, DK062370, 1Z01 HG000024]
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(1,2); 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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