Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics

Research output: Contribution to journalJournal article – Annual report year: 2014Researchpeer-review

  • Author: Lundby, Alicia

    University of Copenhagen, Denmark

  • Author: Rossin, Elizabeth J.

    Massachusetts General Hospital, United States

  • Author: Steffensen, Annette B.

    University of Copenhagen, Denmark

  • Author: Acha, Moshe Ray

    Massachusetts General Hospital, United States

  • Author: Newton-Cheh, Christopher

    Massachusetts General Hospital, United States

  • Author: Pfeufer, Arne

    Technical University of Munich, Germany

  • Author: Lyneh, Stacey N.

    Massachusetts General Hospital, United States

  • Author: Olesen, Søren-Peter

    University of Copenhagen, Denmark

  • Author: Brunak, Søren

    Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark

  • Author: Ellinor, Patrick T.

    Massachusetts General Hospital, United States

  • Author: Jukema, J. Wouter

    Leiden University, Netherlands

  • Author: Trompet, Stella

    Leiden University, Netherlands

  • Author: Ford, Ian

    University of Glasgow, United Kingdom

  • Author: Macfarlane, Peter W.

    University of Glasgow, United Kingdom

  • Author: Krijthe, Bouwe P.

    Erasmus MC University Medical Center, Netherlands

  • Author: Hofman, Albert

    Erasmus MC University Medical Center, Netherlands

  • Author: Uitterlinden, Andre G.

    Erasmus MC University Medical Center, Netherlands

  • Author: Stricker, Bruno H.

    Erasmus MC University Medical Center, Netherlands

  • Author: Nathoe, Hendrik M.

    University Medical Centre Utrecht, Netherlands

  • Author: Spiering, Wilko

    University Medical Centre Utrecht, Netherlands

  • Author: Daly, Mark J.

    Massachusetts General Hospital, United States

  • Author: Asselbergs, Folkert W.

    University College London, Netherlands

  • Author: van der Harst, Pim

    University of Groningen, Netherlands

  • Author: Milan, David J.

    Massachusetts General Hospital, United States

  • Author: de Bakker, Paul I. W.

    University Medical Centre Utrecht, United States

  • Author: Lage, Kasper

    University of Copenhagen

  • Author: Olsen, Jesper V.

    University of Copenhagen, Denmark

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Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LOTS). We integrated the LOTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LOTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics.
Original languageEnglish
JournalNature Methods
Volume11
Issue number8
Pages (from-to)868-874
Number of pages7
ISSN1548-7091
DOIs
Publication statusPublished - 2014
CitationsWeb of Science® Times Cited: No match on DOI
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