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Genomic prediction of coronary heart disease

Gad Abraham, Aki S. Havulinna, Oneil G. Bhalala, Sean G. Byars, Alysha M. De Livera, Laxman Yetukuri, Emmi Tikkanen, Markus Perola, Heribert Schunkert, Eric J. Sijbrands, Aarno Palotie, Nilesh J. Samani, Veikko Salomaa, Samuli Ripatti, Michael Inouye
doi: https://doi.org/10.1101/041483
Gad Abraham
1Centre for Systems Genomics, School of BioSciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia
PhD
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Aki S. Havulinna
3National Institute for Health and Welfare, Helsinki, Finland
DSc
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Oneil G. Bhalala
1Centre for Systems Genomics, School of BioSciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia
PhD
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Sean G. Byars
1Centre for Systems Genomics, School of BioSciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia
PhD
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Alysha M. De Livera
1Centre for Systems Genomics, School of BioSciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia
4Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria 3010, Australia
PhD
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Laxman Yetukuri
5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
PhD
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Emmi Tikkanen
5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
PhD
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Markus Perola
3National Institute for Health and Welfare, Helsinki, Finland
5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
MD, PhD
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Heribert Schunkert
6Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Munich, Germany
MD
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Eric J. Sijbrands
7Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands
MD, PhD
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Aarno Palotie
5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
8Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
9Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
10Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
MD, PhD
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Nilesh J. Samani
11Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Rd., Leicester, LE3 9QP, United Kingdom
12National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, United Kingdom
MD, FRCP
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  • For correspondence: minouye@unimelb.edu.au samuli.ripatti@helsinki.fi veikko.salomaa@thl.fi njs@leicester.ac.uk
Veikko Salomaa
3National Institute for Health and Welfare, Helsinki, Finland
MD, PhD
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  • For correspondence: minouye@unimelb.edu.au samuli.ripatti@helsinki.fi veikko.salomaa@thl.fi njs@leicester.ac.uk
Samuli Ripatti
5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
13Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
14Department of Public Health, University of Helsinki, Helsinki, Finland
PhD
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  • For correspondence: minouye@unimelb.edu.au samuli.ripatti@helsinki.fi veikko.salomaa@thl.fi njs@leicester.ac.uk
Michael Inouye
1Centre for Systems Genomics, School of BioSciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia
5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
PhD
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  • For correspondence: minouye@unimelb.edu.au samuli.ripatti@helsinki.fi veikko.salomaa@thl.fi njs@leicester.ac.uk
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Abstract

Background Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of a genomic risk score (GRS) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear.

Methods We generated a GRS of 49,310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested this using five prospective population cohorts (three FINRISK cohorts, combined n=12,676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n=3,406, 587 incident CHD events).

Results The GRS was strongly associated with time to CHD event (FINRISK HR=1.74, 95% CI 1.61-1.86 per S.D. of GRS; Framingham HR=1.28, 95% CI 1.18-1.38), and was largely unchanged by adjustment for clinical risk scores or individual risk factors, including family history. Integration of the GRS with clinical risk scores (FRS and ACC/AHA13 score) improved prediction of CHD events within 10 years (meta-analysis C-index: +1.5-1.6%, P<0.001), particularly for individuals ≥60 years old (meta-analysis C-index: +4.6-5.1%, P<0.001). Men in the top 20% of the GRS had 3-fold higher risk of CHD by age 75 in FINRISK and 2-fold in FHS, and attaining 10% cumulative CHD risk 18y earlier in FINRISK and 12y earlier in FHS than those in the bottom 20%. Furthermore, high genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking.

Conclusions A GRS based on a large number of SNPs substantially improves CHD risk prediction and encodes decades of variation in CHD risk not captured by traditional clinical risk scores.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 26, 2016.
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Genomic prediction of coronary heart disease
Gad Abraham, Aki S. Havulinna, Oneil G. Bhalala, Sean G. Byars, Alysha M. De Livera, Laxman Yetukuri, Emmi Tikkanen, Markus Perola, Heribert Schunkert, Eric J. Sijbrands, Aarno Palotie, Nilesh J. Samani, Veikko Salomaa, Samuli Ripatti, Michael Inouye
bioRxiv 041483; doi: https://doi.org/10.1101/041483
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Genomic prediction of coronary heart disease
Gad Abraham, Aki S. Havulinna, Oneil G. Bhalala, Sean G. Byars, Alysha M. De Livera, Laxman Yetukuri, Emmi Tikkanen, Markus Perola, Heribert Schunkert, Eric J. Sijbrands, Aarno Palotie, Nilesh J. Samani, Veikko Salomaa, Samuli Ripatti, Michael Inouye
bioRxiv 041483; doi: https://doi.org/10.1101/041483

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