title: 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.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Asa K
authors.initials: AK
authors.lastname: Hedman
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteindottir
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Hannah B
authors.initials: HB
authors.lastname: Richards
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Kourosh R
authors.initials: KR
authors.lastname: Ahmadi
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051703:Sp Transcription Factors / Q000235:genetics*
chemical_list: D008076:Cholesterol, HDL; C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; D051703:Sp Transcription Factors