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Nat Methods. 2014 Aug;11(8):868-74. doi: 10.1038/nmeth.2997. Epub 2014 Jun 22.

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

Author information

1
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].
2
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].
3
The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
4
1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
5
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.
6
Institute of Human Genetics, Technical University of Munich, Munich, Germany.
7
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.
8
1] Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN - Netherlands Heart Institute, Utrecht, the Netherlands.
9
1] Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
10
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
11
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
12
1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands.
13
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.
14
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.
15
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
16
Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
17
1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
18
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.
19
University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
20
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].
21
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].
22
1] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2].

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.

PMID:
24952909
PMCID:
PMC4117722
DOI:
10.1038/nmeth.2997
[Indexed for MEDLINE]
Free PMC Article

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