title: Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics.
abstract: 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 (LQTS). We integrated the LQTS 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 LQTS 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.
authors: 1] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2] The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark. [3] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4].
authors: Alicia
authors: 0000000216126041
authors: A
authors: Lundby
authors: 1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] MD/PhD Program and Health Sciences and Technology Program, Harvard Medical School, Boston, USA. [4].
authors: Elizabeth J
authors: EJ
authors: Rossin
authors: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
authors: Annette B
authors: AB
authors: Steffensen
authors: 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Moshe Rav
authors: MR
authors: Acha
authors: 1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Christopher
authors: C
authors: Newton-Cheh
authors: Institute of Human Genetics, Technical University of Munich, Munich, Germany.
authors: Arne
authors: A
authors: Pfeufer
authors: 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Stacey N
authors: SN
authors: Lynch
authors: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
authors: Søren-Peter
authors: SP
authors: Olesen
authors: 1] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2] Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors: Søren
authors: S
authors: Brunak
authors: 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Patrick T
authors: 0000000220670533
authors: PT
authors: Ellinor
authors: 1] Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN - Netherlands Heart Institute, Utrecht, the Netherlands.
authors: J Wouter
authors: JW
authors: Jukema
authors: 1] Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors: Stella
authors: S
authors: Trompet
authors: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
authors: Ian
authors: I
authors: Ford
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors: Peter W
authors: PW
authors: Macfarlane
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands.
authors: Bouwe P
authors: BP
authors: Krijthe
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands. [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: André G
authors: AG
authors: Uitterlinden
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands. [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. [4] Inspectorate for Health Care, The Hague, the Netherlands. [5] Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands. [6] Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Bruno H
authors: BH
authors: Stricker
authors: Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Hendrik M
authors: HM
authors: Nathoe
authors: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Wilko
authors: 0000000224936407
authors: W
authors: Spiering
authors: 1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Mark J
authors: MJ
authors: Daly
authors: 1] Durrer Center for Cardiogenetic Research, ICIN - Netherlands Heart Institute, Utrecht, the Netherlands. [2] Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands. [3] Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK.
authors: Folkert W
authors: FW
authors: Asselbergs
authors: University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors: Pim
authors: P
authors: van der Harst
authors: 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: David J
authors: DJ
authors: Milan
authors: 1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. [3] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. [4].
authors: Paul I W
authors: 0000000177357858
authors: PI
authors: de Bakker
authors: 1] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark. [5] Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts, USA. [6].
authors: Kasper
authors: K
authors: Lage
authors: 1] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2].
authors: Jesper V
authors: JV
authors: Olsen
mesh_terms: D000818:Animals; D055106:Genome-Wide Association Study; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D040901:Proteomics; D014982:Xenopus laevis; D015027:Zebrafish