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Genome-wide Association Study Of Plasma Proteins Identifies Putatively Causal Genes, Proteins, And Pathways For Cardiovascular Disease

Chen Yao, George Chen, Ci Song, Michael Mendelson, Tianxiao Huan, Annika Laser, Hongsheng Wu, Jennifer E. Ho, Paul Courchesne, Asya Lyass, Martin G. Larson, Christian Gieger, Johannes Graumann, Andrew D. Johnson, Shih-Jen Hwang, Chunyu Liu, Karsten Suhre, Daniel Levy
doi: https://doi.org/10.1101/136523
Chen Yao
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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George Chen
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Ci Song
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
3Department of Medical Sciences, Uppsala University, 75105 Uppsala, Sweden
4Department of Immunology, Genetics and Pathology, Uppsala University, 75105 Uppsala, Sweden
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Michael Mendelson
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
5Department of Cardiology, Boston Children’s Hospital, Boston, MA
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Tianxiao Huan
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Annika Laser
6Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
7Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
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Hongsheng Wu
8Computer Science and Networking, Wentworth Institute of Technology, Boston, MA
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Jennifer E. Ho
9Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA
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Paul Courchesne
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Asya Lyass
1Framingham Heart Study, Framingham, MA
10Department of Mathematics and Statistics, Boston University, Boston, MA
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Martin G. Larson
1Framingham Heart Study, Framingham, MA
11Department of Biostatistics, Boston University School of Public Health, Boston, MA
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Christian Gieger
6Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
7Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
12German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
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Johannes Graumann
13Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, Ludwigstr. 43, D—61231 Bad Nauheim, Germany
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Andrew D. Johnson
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Shih-Jen Hwang
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Chunyu Liu
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Karsten Suhre
14Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar
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Daniel Levy
1Framingham Heart Study, Framingham, MA
2Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Summary

Identifying genetic variants associated with circulating protein concentrations (pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a GWAS knowledge gap for hitherto unexplained SNP-disease associations. We conducted GWAS of 71 high-value proteins for cardiovascular disease in 6,861 Framingham Heart Study participants followed by external replication. We comprehensively mapped thousands of pQTLs, including functional annotations and clinical-trait associations, and created an integrated plasma-protein-QTL searchable database. We next identified 15 proteins with pQTLs coinciding with coronary heart disease (CHD)-related variants from GWAS or tested causal for CHD by Mendelian randomization; most of these proteins were associated with new-onset cardiovascular disease events in Framingham participants with long-term follow-up. Identifying pQTLs and integrating them with GWAS results yields insights into genes, proteins, and pathways that may be causally associated with disease and can serve as therapeutic targets for treatment and prevention.

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Posted May 12, 2017.
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Genome-wide Association Study Of Plasma Proteins Identifies Putatively Causal Genes, Proteins, And Pathways For Cardiovascular Disease
Chen Yao, George Chen, Ci Song, Michael Mendelson, Tianxiao Huan, Annika Laser, Hongsheng Wu, Jennifer E. Ho, Paul Courchesne, Asya Lyass, Martin G. Larson, Christian Gieger, Johannes Graumann, Andrew D. Johnson, Shih-Jen Hwang, Chunyu Liu, Karsten Suhre, Daniel Levy
bioRxiv 136523; doi: https://doi.org/10.1101/136523
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Genome-wide Association Study Of Plasma Proteins Identifies Putatively Causal Genes, Proteins, And Pathways For Cardiovascular Disease
Chen Yao, George Chen, Ci Song, Michael Mendelson, Tianxiao Huan, Annika Laser, Hongsheng Wu, Jennifer E. Ho, Paul Courchesne, Asya Lyass, Martin G. Larson, Christian Gieger, Johannes Graumann, Andrew D. Johnson, Shih-Jen Hwang, Chunyu Liu, Karsten Suhre, Daniel Levy
bioRxiv 136523; doi: https://doi.org/10.1101/136523

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