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Nat Commun. 2018 Aug 15;9(1):3268. doi: 10.1038/s41467-018-05512-x.

Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.

Yao C1,2, Chen G1,2, Song C1,2,3,4, Keefe J1,2, Mendelson M1,2,5, Huan T1,2, Sun BB6, Laser A7,8, Maranville JC9, Wu H10, Ho JE11, Courchesne P1,2, Lyass A1,12, Larson MG1,13, Gieger C7,8,14, Graumann J15, Johnson AD1,2, Danesh J6,16,17, Runz H9, Hwang SJ1,2, Liu C1,2, Butterworth AS6,18, Suhre K19, Levy D20,21.

Author information

1
Framingham Heart Study, Framingham, 01702, MA, USA.
2
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
3
Department of Medical Sciences, Uppsala University, 75105, Uppsala, Sweden.
4
Department of Immunology, Genetics and Pathology, Uppsala University, 75105, Uppsala, Sweden.
5
Department of Cardiology, Boston Children's Hospital, Boston, 02115, MA, USA.
6
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
7
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
8
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
9
MRL, Merck & Co., Inc, Kenilworth, 07033, NJ, USA.
10
Computer Science and Networking, Wentworth Institute of Technology, Boston, 02115, MA, USA.
11
Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, 02114, MA, USA.
12
Department of Mathematics and Statistics, Boston University, Boston, 02115, MA, USA.
13
Department of Biostatistics, Boston University School of Public Health, Boston, 02118, MA, USA.
14
German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
15
Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, Ludwigstr. 43, D-61231, Bad Nauheim, Germany.
16
British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
17
Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1RQ, UK.
18
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
19
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar.
20
Framingham Heart Study, Framingham, 01702, MA, USA. levyd@nih.gov.
21
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892, MD, USA. levyd@nih.gov.

Abstract

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

PMID:
30111768
PMCID:
PMC6093935
DOI:
10.1038/s41467-018-05512-x
[Indexed for MEDLINE]
Free PMC Article

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