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

Abstract 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 new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. 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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos genetics
Publication Year Start




PMID- 28640878
OWN - NLM
STAT- In-Process
DA  - 20170622
LR  - 20170622
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 13
IP  - 6
DP  - 2017 Jun
TI  - Genetic loci associated with coronary artery disease harbor evidence of selection
      and antagonistic pleiotropy.
PG  - e1006328
LID - 10.1371/journal.pgen.1006328 [doi]
AB  - 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 new candidate adaptive loci that appear to have been 
      directly modified by disease pressures given their significant associations with 
      CAD genetic risk. These candidates were all uniquely and consistently associated 
      with many different male and female reproductive traits suggesting selection may 
      have also targeted these because of their direct effects on fitness. We found
      that CAD loci are significantly enriched for lifetime reproductive success
      relative to the rest of the human genome, with evidence that the relationship
      between CAD and lifetime reproductive success is antagonistic. This supports the 
      presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel
      explanation for the maintenance and high prevalence of CAD in modern humans.
      Lastly, we found that positive selection more often targeted CAD gene regulatory 
      variants using HapMap3 lymphoblastoid cell lines, which further highlights the
      unique biological significance of candidate adaptive loci underlying CAD. 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.
FAU - Byars, Sean G
AU  - Byars SG
AD  - Centre for Systems Genomics, School of BioSciences, The University of Melbourne, 
      Parkville, Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Parkville, Victoria,
      Australia.
FAU - Huang, Qin Qin
AU  - Huang QQ
AUID- ORCID: http://orcid.org/0000-0003-3073-717X
AD  - Centre for Systems Genomics, School of BioSciences, The University of Melbourne, 
      Parkville, Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Parkville, Victoria,
      Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
FAU - Gray, Lesley-Ann
AU  - Gray LA
AD  - Centre for Systems Genomics, School of BioSciences, The University of Melbourne, 
      Parkville, Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Parkville, Victoria,
      Australia.
FAU - Bakshi, Andrew
AU  - Bakshi A
AUID- ORCID: http://orcid.org/0000-0001-5650-7036
AD  - Centre for Systems Genomics, School of BioSciences, The University of Melbourne, 
      Parkville, Victoria, Australia.
FAU - Ripatti, Samuli
AU  - Ripatti S
AD  - Institute of Molecular Medicine Finland, University of Helsinki, Helsinki,
      Finland.
AD  - Department of Public Health, University of Helsinki, Helsinki, Finland.
AD  - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge,
      United Kingdom.
FAU - Abraham, Gad
AU  - Abraham G
AUID- ORCID: http://orcid.org/0000-0003-4853-0118
AD  - Centre for Systems Genomics, School of BioSciences, The University of Melbourne, 
      Parkville, Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Parkville, Victoria,
      Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
FAU - Stearns, Stephen C
AU  - Stearns SC
AD  - Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT,
      United States of America.
FAU - Inouye, Michael
AU  - Inouye M
AD  - Centre for Systems Genomics, School of BioSciences, The University of Melbourne, 
      Parkville, Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Parkville, Victoria,
      Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
LA  - eng
PT  - Journal Article
DEP - 20170622
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
EDAT- 2017/06/24 06:00
MHDA- 2017/06/24 06:00
CRDT- 2017/06/23 06:00
PHST- 2016/08/31 [received]
PHST- 2017/05/02 [accepted]
AID - 10.1371/journal.pgen.1006328 [doi]
AID - PGENETICS-D-16-01943 [pii]
PST - epublish
SO  - PLoS Genet. 2017 Jun 22;13(6):e1006328. doi: 10.1371/journal.pgen.1006328.
      eCollection 2017 Jun.