Whole Exome Sequencing to Identify Genetic Variants Associated with Raised Atherosclerotic Lesions in Young Persons

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dc.contributor.authorHixson, James E.en
dc.contributor.authorJun, Gooen
dc.contributor.authorShimmin, Lawrence C.en
dc.contributor.authorWang, Yizhien
dc.contributor.authorYu, Guoqiangen
dc.contributor.authorMao, Chunhongen
dc.contributor.authorWarren, Andrew S.en
dc.contributor.authorHoward, Timothy D.en
dc.contributor.authorVander Heide, Richard S.en
dc.contributor.authorVan Eyk, Jennifer E.en
dc.contributor.authorWang, Yueen
dc.contributor.authorHerrington, David M.en
dc.contributor.departmentElectrical and Computer Engineeringen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2019-01-08T15:53:29Zen
dc.date.available2019-01-08T15:53:29Zen
dc.date.issued2017-06-22en
dc.description.abstractWe investigated the influence of genetic variants on atherosclerosis using whole exome sequencing in cases and controls from the autopsy study "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)". We identified a PDAY case group with the highest total amounts of raised lesions (n = 359) for comparisons with a control group with no detectable raised lesions (n = 626). In addition to the standard exome capture, we included genome-wide proximal promoter regions that contain sequences that regulate gene expression. Our statistical analyses included single variant analysis for common variants (MAF > 0.01) and rare variant analysis for low frequency and rare variants (MAF < 0.05). In addition, we investigated known CAD genes previously identified by meta-analysis of GWAS studies. We did not identify individual common variants that reached exome-wide significance using single variant analysis. In analysis limited to 60 CAD genes, we detected strong associations with COL4A2/COL4A1 that also previously showed associations with myocardial infarction and arterial stiffness, as well as coronary artery calcification. Likewise, rare variant analysis did not identify genes that reached exomewide significance. Among the 60 CAD genes, the strongest association was with NBEAL1 that was also identified in gene-based analysis of whole exome sequencing for early onset myocardial infarction.en
dc.description.notesThis report is from the "Genomic and Proteomic Architecture of Atherosclerosis" (GPAA) Study (R01HL111362) that is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. This study used data from the PDAY Cardiovascular Specimen and Data Library (HL60808) that is supported by the National Heart, Lung, and Blood Institute. We wish to thank Yu Zhong, Naveed Farhana, and Do-Kyun Kim for their excellent technical work in whole exome sequencing (JEH laboratory), and Yun Gong (JEH laboratory) and Andrew Carroll (DNA Nexus, Inc.) for their computing expertise for data management and allele calling.en
dc.description.sponsorshipNational Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL111362]; National Heart, Lung, and Blood Institute [HL60808]en
dc.format.extent9en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-017-04433-xen
dc.identifier.issn2045-2322en
dc.identifier.other4091en
dc.identifier.pmid28642624en
dc.identifier.urihttp://hdl.handle.net/10919/86636en
dc.identifier.volume7en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectgenome-wide associationen
dc.subjectmyocardial-infarctionen
dc.subjectrisken
dc.subjectpolymorphismsen
dc.subjectdiseaseen
dc.titleWhole Exome Sequencing to Identify Genetic Variants Associated with Raised Atherosclerotic Lesions in Young Personsen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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