Genetic Risk Factors for Type 2 Diabetes: A Trans-Regulatory Genetic Architecture?

被引：26

作者：

Elbein, Steven C. ^{[2
]}

Gamazon, Eric R. ^{[1
]}

Das, Swapan K. ^{[2
]}

Rasouli, Neda ^{[3
,4
]}

Kern, Philip A. ^{[5
,6
]}

Cox, Nancy J. ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA

[2] Wake Forest Sch Med, Sect Endocrinol & Metab, Dept Internal Med, Winston Salem, NC 27157 USA

[3] Univ Colorado, Div Endocrinol Metab & Diabet, Aurora, CO 80045 USA

[4] Eastern Colorado Vet Hlth Care Syst, Denver, CO 80220 USA

[5] Univ Kentucky, Sch Med, Div Endocrinol, Dept Internal Med, Lexington, KY 40536 USA

[6] Univ Kentucky, Sch Med, Barnstable Brown Diabet & Obes Ctr, Lexington, KY 40536 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2012年 / 91卷 / 03期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; QUANTITATIVE TRAIT LOCI; FASTING GLUCOSE; SUSCEPTIBILITY LOCI; INSULIN-RESISTANCE; COMMON VARIANTS; BETA-CELL; EXPRESSION; MTNR1B; METAANALYSIS;

D O I：

10.1016/j.ajhg.2012.08.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To date, 68 loci have been associated with type 2 diabetes (T2D) or glucose homeostasis traits. We report here the results of experiments aimed at functionally characterizing the SNPs replicated for T2D and glucose traits. We sought to determine whether these loci were associated with transcript levels in adipose, muscle, liver, lymphocytes, and pancreatic beta-cells. We found an excess of trans, rather than cis, associations among these SNPs in comparison to what was expected in adipose and muscle. Among transcripts differentially expressed (FDR < 0.05) between muscle or adipose cells of insulin-sensitive individuals and those of insulin-resistant individuals (matched on BMI), trans-regulated transcripts, in contrast to the cis-regulated ones, were enriched. The paucity of cis associations with transcripts was confirmed in a study of liver transcriptome and was further supported by an analysis of the most detailed transcriptome map of pancreatic p-cells. Relative to location- and allele-frequency-matched random SNPs, both the 68 loci and top T2D-associated SNPs from two large-scale genome-wide studies were enriched for trans eQTLs in adipose and muscle but not in lymphocytes. Our study suggests that T2D SNPs have broad-reaching and tissue-specific effects that often extend beyond local transcripts and raises the question of whether patterns of cis or trans transcript regulation are a key feature of the architecture of complex traits.

引用

页码：466 / 477

页数：12

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