Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits.

Original publication

DOI

10.1038/ng.833

Type

Journal article

Journal

Nat Genet

Publication Date

06/2011

Volume

43

Pages

561 - 564

Keywords

Adipose Tissue, Cholesterol, HDL, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Genome-Wide Association Study, Genomic Imprinting, Humans, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sp Transcription Factors