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 β-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 β-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.
|Number of pages||12|
|Journal||American Journal of Human Genetics|
|State||Published - Sep 7 2012|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health grants DK039311 (S.C.E. and S.K.D.), DK80327 (P.A.K.), DK71349 (P.A.K.), U01 HL084715 (N.J.C.), P60 DK20595 (N.J.C.), U01 DK085501 (N.J.C.), U01 GM61393 (N.J.C.), R01 MH090937 (N.J.C.); VA merit grant (N.R.); a generous grant from the Sturgis Foundation to the University of Arkansas for Medical Sciences (UAMS); and the Research Service of the Department of Veterans Affairs. The project was supported in part by award number 1UL1RR029884 to UAMS from the National Center for Research Resources. We thank the dedicated staff of the Clinical Research Center at UAMS for support of the clinical studies and assistance with data management. We also acknowledge technical assistance from Neeraj K. Sharma and Kurt A. Langberg for the extraction, quality control, and management of DNA and RNA samples used in this study.
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