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Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics.
Lundby, Alicia; Rossin, Elizabeth J; Steffensen, Annette B; Acha, Moshe Rav; Newton-Cheh, Christopher; Pfeufer, Arne; Lynch, Stacey N; Olesen, Søren-Peter; Brunak, Søren; Ellinor, Patrick T; Jukema, J Wouter; Trompet, Stella; Ford, Ian; Macfarlane, Peter W; Krijthe, Bouwe P; Hofman, Albert; Uitterlinden, André G; Stricker, Bruno H; Nathoe, Hendrik M; Spiering, Wilko; Daly, Mark J; Asselbergs, Folkert W; van der Harst, Pim; Milan, David J; de Bakker, Paul I W; Lage, Kasper; Olsen, Jesper V.
Affiliation
  • Lundby A; 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
  • Rossin EJ; 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].
  • Steffensen AB; The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
  • Acha MR; 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Newton-Cheh C; 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.
  • Pfeufer A; Institute of Human Genetics, Technical University of Munich, Munich, Germany.
  • Lynch SN; 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Olesen SP; The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
  • Brunak S; 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.
  • Ellinor PT; 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Jukema JW; 1] Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN - Netherlands Heart Institute, Utrecht, the Netherlands.
  • Trompet S; 1] Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
  • Ford I; Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
  • Macfarlane PW; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
  • Krijthe BP; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands.
  • Hofman A; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands.
  • Uitterlinden AG; 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.
  • Stricker BH; 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 N
  • Nathoe HM; Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Spiering W; Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Daly MJ; 1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Asselbergs FW; 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 Sc
  • van der Harst P; University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • Milan DJ; 1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • de Bakker PI; 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 Med
  • Lage K; 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, Massachu
  • Olsen JV; 1] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2].
Nat Methods ; 11(8): 868-74, 2014 Aug.
Article in En | MEDLINE | ID: mdl-24952909
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proteomics / Genome-Wide Association Study Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Nat Methods Journal subject: TECNICAS E PROCEDIMENTOS DE LABORATORIO Year: 2014 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Proteomics / Genome-Wide Association Study Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Nat Methods Journal subject: TECNICAS E PROCEDIMENTOS DE LABORATORIO Year: 2014 Type: Article Affiliation country: United States