Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes

Abstract

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.

Figure 1. KLF14 is a master regulator of gene expression in adipose tissue

p-value distribution of association between the KLF14 cis-eQTL rs4731702 and expression levels of ~24K probes in adipose tissue.

Figure 2. Regional signal plots of the KLF14 locus

Left: signal plot of a representative trans -regulated gene in the MuTHER samples (N = 776). Middle: signal plot for the Type 2 Diabetes GWA meta-analysis performed by the DIAGRAM consortium (stage 1 data only, effective sample size 22,044: rs972283 reached genome-wide significance after further replication). Right: signal plot for the HDL-cholesterol GWA meta-analysis performed by the Lipid Consortium (N = 99,900). Signal plots of all 10 genome-wide significant trans-regulated genes are included in Supplementary Figure 2