Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture?

Elbein SC, Gamazon ER, Das SK, Rasouli N, Kern PA, Cox NJ
Am J Hum Genet. 2012 91 (3): 466-77

PMID: 22958899 · PMCID: PMC3512001 · DOI:10.1016/j.ajhg.2012.08.002

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.

Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

MeSH Terms (20)

Adipose Tissue Adult Diabetes Mellitus, Type 2 Female Gene Expression Profiling Gene Expression Regulation Glucose Humans Insulin-Secreting Cells Insulin Resistance Liver Male Middle Aged Muscles Organ Specificity Polymorphism, Single Nucleotide Quantitative Trait Loci Risk Factors Transcriptome Young Adult

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