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Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy

Sean G. Byars, Qinqin Huang, Lesley-Ann Gray, Samuli Ripatti, Gad Abraham, Stephen C. Stearns, Michael Inouye
doi: https://doi.org/10.1101/064758
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
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  • For correspondence: sean.byars@unimelb.edu.au minouye@unimelb.edu.au
Qinqin Huang
1Centre for Systems Genomics, School of BioSciences, The University of Melbourne, Parkville 3010, Victoria, Australia
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Lesley-Ann Gray
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
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Samuli Ripatti
3National Institute for Health and Welfare, Helsinki, Finland
4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
5Department of Public Health, University of Helsinki, Helsinki, Finland
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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
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Stephen C. Stearns
6Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA
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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
3National Institute for Health and Welfare, Helsinki, Finland
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  • For correspondence: sean.byars@unimelb.edu.au minouye@unimelb.edu.au
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Summary

Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified candidate adaptive loci that may have been directly modified by disease pressures given their significant associations with CAD genetic risk. Top candidates were consistently associated with reproductive-traits suggesting antagonistic-pleiotropic tradeoffs with early-life phenotypes and also showed more evidence of gene regulatory effects in HapMap3 lymphoblastoid cell lines than non-adaptive candidates. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.

Highlights

  • Widespread genomic signals of positive selection are present underlying coronary artery disease (CAD) loci

  • Selection peaks that significantly associated with genetic risk suggest loci modified (in)directly by CAD

  • Selection was more often associated with variants important for regulating gene expression

  • CAD loci share many pleiotropic links with early-life traits suggesting antagonistic effects

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 19, 2016.
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Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy
Sean G. Byars, Qinqin Huang, Lesley-Ann Gray, Samuli Ripatti, Gad Abraham, Stephen C. Stearns, Michael Inouye
bioRxiv 064758; doi: https://doi.org/10.1101/064758
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Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy
Sean G. Byars, Qinqin Huang, Lesley-Ann Gray, Samuli Ripatti, Gad Abraham, Stephen C. Stearns, Michael Inouye
bioRxiv 064758; doi: https://doi.org/10.1101/064758

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