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

被引：205

作者：

Huyghe, Jeroen R. ^{[1
]}

Jackson, Anne U. ^{[1
]}

Fogarty, Marie P. ^{[2
]}

Buchkovich, Martin L. ^{[2
]}

Stancakova, Alena ^{[3
,4
]}

Stringham, Heather M. ^{[1
]}

Sim, Xueling ^{[1
]}

Yang, Lingyao ^{[1
]}

Fuchsberger, Christian ^{[1
]}

Cederberg, Henna ^{[3
,4
]}

Chines, Peter S. ^{[5
]}

Teslovich, Tanya M. ^{[1
]}

Romm, Jane M. ^{[6
]}

Ling, Hua ^{[6
]}

McMullen, Ivy ^{[6
]}

Ingersoll, Roxann ^{[6
]}

Pugh, Elizabeth W. ^{[6
]}

Doheny, Kimberly F. ^{[6
]}

Neale, Benjamin M. ^{[7
,8
,9
]}

Daly, Mark J. ^{[7
,8
,9
]}

Kuusisto, Johanna ^{[3
,4
]}

Scott, Laura J. ^{[1
]}

Kang, Hyun Min ^{[1
]}

Collins, Francis S. ^{[5
]}

Abecasis, Goncalo R. ^{[1
]}

Watanabe, Richard M. ^{[10
,11
]}

Boehnke, Michael ^{[1
]}

Laakso, Markku ^{[3
,4
]}

Mohlke, Karen L. ^{[2
]}

机构：

[1] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[2] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[3] Univ Eastern Finland, Dept Med, Kuopio, Finland

[4] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[5] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA

[6] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD USA

[7] Broad Inst MIT & Harvard, Cambridge, MA USA

[8] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[9] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[10] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[11] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 02期

基金：

美国国家卫生研究院; 芬兰科学院;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COMMON VARIANTS; GLYCEMIC TRAITS; GLUCOSE; PROTEIN; EXPRESSION; RELEASE; GTPASES; FAMILY;

D O I：

10.1038/ng.2507

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：197 / 201

页数：5

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