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

Kerrin S. Small; Asa K. Hedman; Elin Grundberg; Alexandra C. Nica; Gudmar Thorleifsson; Augustine Kong; Unnur Thorsteindottir; So-Youn Shin; Hannah B. Richards; Nicole Soranzo; Kourosh R. Ahmadi; Cecilia M. Lindgren; Kari Stefansson; Emmanouil T. Dermitzakis; Panos Deloukas; Timothy D. Spector; Mark I. McCarthy

doi:10.1038/ng.833

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

Kerrin S. Small, Asa K. Hedman, Elin Grundberg, Alexandra C. Nica, Gudmar Thorleifsson, Augustine Kong, Unnur Thorsteindottir, So-Youn Shin, Hannah B. Richards, Nicole Soranzo, Kourosh R. Ahmadi, Cecilia M. Lindgren, Kari Stefansson, Emmanouil T. Dermitzakis, Panos Deloukas, Timothy D. Spector, Mark I. McCarthy

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249 Citations (Scopus)

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.

Original language	English
Pages (from-to)	561 - 564
Number of pages	4
Journal	Nature Genetics
Volume	43
Issue number	6
DOIs	https://doi.org/10.1038/ng.833
Publication status	Published - Jun 2011

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Small, K. S., Hedman, A. K., Grundberg, E., Nica, A. C., Thorleifsson, G., Kong, A., Thorsteindottir, U., Shin, S.-Y., Richards, H. B., Soranzo, N., Ahmadi, K. R., Lindgren, C. M., Stefansson, K., Dermitzakis, E. T., Deloukas, P., Spector, T. D., & McCarthy, M. I. (2011). Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nature Genetics, 43(6), 561 - 564. https://doi.org/10.1038/ng.833

@article{d11dc41071d44fb7ae1037ab80b45f61,

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.",

author = "Small, {Kerrin S.} and Hedman, {Asa K.} and Elin Grundberg and Nica, {Alexandra C.} and Gudmar Thorleifsson and Augustine Kong and Unnur Thorsteindottir and So-Youn Shin and Richards, {Hannah B.} and Nicole Soranzo and Ahmadi, {Kourosh R.} and Lindgren, {Cecilia M.} and Kari Stefansson and Dermitzakis, {Emmanouil T.} and Panos Deloukas and Spector, {Timothy D.} and McCarthy, {Mark I.}",

year = "2011",

month = jun,

doi = "10.1038/ng.833",

language = "English",

volume = "43",

pages = "561 -- 564",

journal = "Nature Genetics",

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Small, KS, Hedman, AK, Grundberg, E, Nica, AC, Thorleifsson, G, Kong, A, Thorsteindottir, U, Shin, S-Y, Richards, HB, Soranzo, N, Ahmadi, KR, Lindgren, CM, Stefansson, K, Dermitzakis, ET, Deloukas, P, Spector, TD & McCarthy, MI 2011, 'Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes', Nature Genetics, vol. 43, no. 6, pp. 561 - 564. https://doi.org/10.1038/ng.833

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T1 - Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes

AU - Small, Kerrin S.

AU - Hedman, Asa K.

AU - Grundberg, Elin

AU - Nica, Alexandra C.

AU - Thorleifsson, Gudmar

AU - Kong, Augustine

AU - Thorsteindottir, Unnur

AU - Shin, So-Youn

AU - Richards, Hannah B.

AU - Soranzo, Nicole

AU - Ahmadi, Kourosh R.

AU - Lindgren, Cecilia M.

AU - Stefansson, Kari

AU - Dermitzakis, Emmanouil T.

AU - Deloukas, Panos

AU - Spector, Timothy D.

AU - McCarthy, Mark I.

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

U2 - 10.1038/ng.833

DO - 10.1038/ng.833

M3 - Article

SN - 1546-1718

VL - 43

SP - 561

EP - 564

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

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