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

Nature Genetics volume 43, pages 561564 (2011) | Download Citation

  • A Corrigendum to this article was published on 28 September 2011

This article has been updated

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.

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Change history

  • 22 September 2011

    In the version of this article initially published, there were several errors in the P values reported in the Adiponectin and HOMA-IR columns of Table 3. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The MuTHER study was funded by the Wellcome Trust Program grant # 081917. Genotyping of TwinsUK samples was provided by the Wellcome Trust Sanger Institute and the National Eye Institute via a US National Institutes of Health (NIH)/Center for Inherited Disease Research (CIDR) genotyping project. TwinsUK also receives support from the ENGAGE project grant agreement HEALTH-F4-2007-201413 and from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St. Thomas' National Health Service Foundation Trust in partnership with King's College London. T.D.S. is an NIHR senior investigator and European Research Council (ERC) senior investigator. M.I.M. is supported by the Oxford NIHR Biomedical Research Centre. Additional support was provided by the Louis-Jeantet Foundation to E.T.D. and A.C.N. and via NIH-NIMH grant R01 MH090941 to E.T.D. and M.I.M.

Author information

Author notes

    • Kerrin S Small
    • , Åsa K Hedman
    • , Elin Grundberg
    • , Kari Stefansson
    • , Emmanouil T Dermitzakis
    • , Panos Deloukas
    • , Timothy D Spector
    •  & Mark I McCarthy

    These authors contributed equally to this work.

Affiliations

  1. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Kerrin S Small
    • , Elin Grundberg
    • , Nicole Soranzo
    • , Kourosh R Ahmadi
    •  & Timothy D Spector
  2. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Kerrin S Small
    • , Elin Grundberg
    • , So-Youn Shin
    • , Nicole Soranzo
    •  & Panos Deloukas
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Åsa K Hedman
    • , Cecilia M Lindgren
    •  & Mark I McCarthy
  4. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Alexandra C Nica
    •  & Emmanouil T Dermitzakis
  5. deCODE genetics, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Augustine Kong
    • , Unnur Thorsteindottir
    •  & Kari Stefansson
  6. Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

    • Unnur Thorsteindottir
    •  & Kari Stefansson
  7. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Hannah B Richards
    •  & Mark I McCarthy
  8. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy

Consortia

  1. the MuTHER Consortium

    A full list of members is provided in the Supplementary Note.

    the GIANT Consortium

    the MAGIC Investigators

    the DIAGRAM Consortium

Authors

    Contributions

    K.S.S., Å.K.H., E.G., G.T. and A.C.N. analyzed data. G.T., A.K., S.-Y.S., H.B.R., N.S. and C.M.L. contributed reagents, materials and analysis tools. U.T., K.R.A., K.S., E.T.D., P.D., M.I.M. and T.D.S. conceived and designed the experiments. K.S.S. and M.I.M. wrote the paper with contributions from Å.K.H. and E.G. All authors read and approved the manuscript before submission.

    Competing interests

    The author declare no competing financial interests.

    Corresponding author

    Correspondence to Mark I McCarthy.

    Supplementary information

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    1. 1.

      Supplementary Text and Figures

      Supplementary Figures 1 and 2, Supplementary Table 1 and Supplementary Note.

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    DOI

    https://doi.org/10.1038/ng.833

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