Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants
Background Genome‐wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant‐based genome‐wide association studies improving our understanding of the genetics of CAD, the contribution of stru...
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2025-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.036499 |
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| author | Kruthika R. Iyer Shoa L. Clarke Rodrigo Guarischi‐Sousa Ketrin Gjoni Adam S. Heath Erica P. Young Nathan O. Stitziel Cecelia Laurie Jai G. Broome Alyna T. Khan Joshua P. Lewis Huichun Xu May E. Montasser Kellan E. Ashley Natalie R. Hasbani Eric Boerwinkle Alanna C. Morrison Nathalie Chami Ron Do Ghislain Rocheleau Donald M. Lloyd‐Jones Rozenn N. Lemaitre Joshua C. Bis James S. Floyd Gregory L. Kinney Donald W. Bowden Nicholette D. Palmer Emelia J. Benjamin Matthew Nayor Lisa R. Yanek Brian G. Kral Lewis C. Becker Sharon L. R. Kardia Jennifer A. Smith Lawrence F. Bielak Arnita F. Norwood Yuan‐I Min April P. Carson Wendy S. Post Stephen S. Rich David Herrington Xiuqing Guo Kent D. Taylor JoAnn E. Manson Nora Franceschini Katherine S. Pollard Braxton D. Mitchell Ruth J. F. Loos Myriam Fornage Lifang Hou Bruce M. Psaty Kendra A. Young Elizabeth A. Regan Barry I. Freedman Ramachandran S. Vasan Daniel Levy Rasika A. Mathias Patricia A. Peyser Laura M. Raffield Charles Kooperberg Alex P. Reiner Jerome I. Rotter Goo Jun Paul S. de Vries Themistocles L. Assimes |
| author_facet | Kruthika R. Iyer Shoa L. Clarke Rodrigo Guarischi‐Sousa Ketrin Gjoni Adam S. Heath Erica P. Young Nathan O. Stitziel Cecelia Laurie Jai G. Broome Alyna T. Khan Joshua P. Lewis Huichun Xu May E. Montasser Kellan E. Ashley Natalie R. Hasbani Eric Boerwinkle Alanna C. Morrison Nathalie Chami Ron Do Ghislain Rocheleau Donald M. Lloyd‐Jones Rozenn N. Lemaitre Joshua C. Bis James S. Floyd Gregory L. Kinney Donald W. Bowden Nicholette D. Palmer Emelia J. Benjamin Matthew Nayor Lisa R. Yanek Brian G. Kral Lewis C. Becker Sharon L. R. Kardia Jennifer A. Smith Lawrence F. Bielak Arnita F. Norwood Yuan‐I Min April P. Carson Wendy S. Post Stephen S. Rich David Herrington Xiuqing Guo Kent D. Taylor JoAnn E. Manson Nora Franceschini Katherine S. Pollard Braxton D. Mitchell Ruth J. F. Loos Myriam Fornage Lifang Hou Bruce M. Psaty Kendra A. Young Elizabeth A. Regan Barry I. Freedman Ramachandran S. Vasan Daniel Levy Rasika A. Mathias Patricia A. Peyser Laura M. Raffield Charles Kooperberg Alex P. Reiner Jerome I. Rotter Goo Jun Paul S. de Vries Themistocles L. Assimes |
| author_sort | Kruthika R. Iyer |
| collection | DOAJ |
| description | Background Genome‐wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant‐based genome‐wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. Method and Results We leveraged SVs detected from high‐coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans‐Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome‐wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E‐09, odds ratio=1.34). The sliding window‐based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E‐10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. Conclusions Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease. |
| format | Article |
| id | doaj-art-7c41aa0e05564b73ae5da986f8896fa1 |
| institution | OA Journals |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-7c41aa0e05564b73ae5da986f8896fa12025-08-20T02:08:36ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-02-0114410.1161/JAHA.124.036499Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural VariantsKruthika R. Iyer0Shoa L. Clarke1Rodrigo Guarischi‐Sousa2Ketrin Gjoni3Adam S. Heath4Erica P. Young5Nathan O. Stitziel6Cecelia Laurie7Jai G. Broome8Alyna T. Khan9Joshua P. Lewis10Huichun Xu11May E. Montasser12Kellan E. Ashley13Natalie R. Hasbani14Eric Boerwinkle15Alanna C. Morrison16Nathalie Chami17Ron Do18Ghislain Rocheleau19Donald M. Lloyd‐Jones20Rozenn N. Lemaitre21Joshua C. Bis22James S. Floyd23Gregory L. Kinney24Donald W. Bowden25Nicholette D. Palmer26Emelia J. Benjamin27Matthew Nayor28Lisa R. Yanek29Brian G. Kral30Lewis C. Becker31Sharon L. R. Kardia32Jennifer A. Smith33Lawrence F. Bielak34Arnita F. Norwood35Yuan‐I Min36April P. Carson37Wendy S. Post38Stephen S. Rich39David Herrington40Xiuqing Guo41Kent D. Taylor42JoAnn E. Manson43Nora Franceschini44Katherine S. Pollard45Braxton D. Mitchell46Ruth J. F. Loos47Myriam Fornage48Lifang Hou49Bruce M. Psaty50Kendra A. Young51Elizabeth A. Regan52Barry I. Freedman53Ramachandran S. Vasan54Daniel Levy55Rasika A. Mathias56Patricia A. Peyser57Laura M. Raffield58Charles Kooperberg59Alex P. Reiner60Jerome I. Rotter61Goo Jun62Paul S. de Vries63Themistocles L. Assimes64Data Science and Biotechnology, Gladstone Institutes San Francisco CA USADepartment of Medicine, Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USADepartment of Medicine, Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USAData Science and Biotechnology, Gladstone Institutes San Francisco CA USADepartment of Epidemiology, Human Genetics Center, School of Public Health The University of Texas Health Science Center at Houston Houston TX USADepartment of Medicine, Division of Cardiology Washington University School of Medicine Saint Louis MO USADepartment of Medicine, Division of Cardiology Washington University School of Medicine Saint Louis MO USADepartment of Biostatistics University of Washington Seattle WA USADepartment of Biostatistics University of Washington Seattle WA USADepartment of Biostatistics University of Washington Seattle WA USADepartment of Medicine University of Maryland School of Medicine Baltimore MD USADepartment of Medicine University of Maryland School of Medicine Baltimore MD USADepartment of Medicine University of Maryland School of Medicine Baltimore MD USADepartment of Medicine University of Mississippi Medical Center Jackson MS USADepartment of Epidemiology, Human Genetics Center, School of Public Health The University of Texas Health Science Center at Houston Houston TX USADepartment of Epidemiology, Human Genetics Center, School of Public Health The University of Texas Health Science Center at Houston Houston TX USADepartment of Epidemiology, Human Genetics Center, School of Public Health The University of Texas Health Science Center at Houston Houston TX USAThe Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY USAThe Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY USAThe Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY USADepartment of Preventive Medicine Northwestern University Chicago IL USADepartment of Medicine, Cardiovascular Health Research Unit University of Washington Seattle WA USADepartment of Medicine, Cardiovascular Health Research Unit University of Washington Seattle WA USADepartment of Medicine, Cardiovascular Health Research Unit University of Washington Seattle WA USADepartment of Epidemiology Colorado School of Public Health Aurora CO USADepartment of Biochemistry Wake Forest University School of Medicine Winston‐Salem NC USADepartment of Biochemistry Wake Forest University School of Medicine Winston‐Salem NC USADepartment of Medicine, Cardiovascular Medicine, Boston Medical Center Boston University Chobanian & Avedisian School of Medicine Boston MA USADepartment of Medicine, Cardiovascular Medicine Boston University Chobanian & Avedisian School of Medicine Boston MA USADepartment of Medicine Johns Hopkins University School of Medicine Baltimore MD USADepartment of Medicine Johns Hopkins University School of Medicine Baltimore MD USADepartment of Medicine Johns Hopkins University School of Medicine Baltimore MD USADepartment of Epidemiology University of Michigan School of Public Health Ann Arbor MI USADepartment of Epidemiology University of Michigan School of Public Health Ann Arbor MI USADepartment of Epidemiology University of Michigan School of Public Health Ann Arbor MI USADepartment of Medicine University of Mississippi Medical Center Jackson MS USADepartment of Medicine University of Mississippi Medical Center Jackson MS USADepartment of Medicine University of Mississippi Medical Center Jackson MS USADepartment of Medicine, Division of Cardiology Johns Hopkins University Baltimore MD USADepartment of Genome Sciences University of Virginia School of Medicine Charlottesville VA USADepartment of Medicine Wake Forest University School of Medicine Winston‐Salem NC USADepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences The Lundquist Institute for Biomedical Innovation at Harbor‐UCLA Medical Center Torrance CA USADepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences The Lundquist Institute for Biomedical Innovation at Harbor‐UCLA Medical Center Torrance CA USADepartment of Medicine Brigham and Women’s Hospital, Harvard Medical School Boston MA USADepartment of Epidemiology University of North Carolina at Chapel Hill Chapel Hill NC USAData Science and Biotechnology, Gladstone Institutes San Francisco CA USADepartment of Medicine University of Maryland School of Medicine Baltimore MD USAThe Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY USABrown Foundation Institute of Molecular Medicine University of Texas Health Science Center at Houston Houston TX USADepartment of Preventive Medicine Northwestern University Chicago IL USADepartment of Medicine, Cardiovascular Health Research Unit University of Washington Seattle WA USADepartment of Epidemiology Colorado School of Public Health Aurora CO USADivision of Rheumatology National Jewish Health Denver CO USADepartment of Internal Medicine, Section on Nephrology Wake Forest University School of Medicine Winston‐Salem NC USAUniversity of Texas Health Sciences Center San Antonio TX USADivision of Intramural Research, Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD USADepartment of Medicine Johns Hopkins University School of Medicine Baltimore MD USADepartment of Epidemiology University of Michigan School of Public Health Ann Arbor MI USADepartment of Genetics University of North Carolina at Chapel Hill Chapel Hill NC USADivision of Public Health Fred Hutchinson Cancer Center Seattle WA USADivision of Public Health Fred Hutchinson Cancer Center Seattle WA USADepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences The Lundquist Institute for Biomedical Innovation at Harbor‐UCLA Medical Center Torrance CA USADepartment of Epidemiology, Human Genetics Center, School of Public Health The University of Texas Health Science Center at Houston Houston TX USADepartment of Epidemiology, Human Genetics Center, School of Public Health The University of Texas Health Science Center at Houston Houston TX USADepartment of Medicine, Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USABackground Genome‐wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant‐based genome‐wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. Method and Results We leveraged SVs detected from high‐coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans‐Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome‐wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E‐09, odds ratio=1.34). The sliding window‐based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E‐10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. Conclusions Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.https://www.ahajournals.org/doi/10.1161/JAHA.124.036499association testingcoronary artery diseasegeneticsstructural variantswhole‐genome sequencing |
| spellingShingle | Kruthika R. Iyer Shoa L. Clarke Rodrigo Guarischi‐Sousa Ketrin Gjoni Adam S. Heath Erica P. Young Nathan O. Stitziel Cecelia Laurie Jai G. Broome Alyna T. Khan Joshua P. Lewis Huichun Xu May E. Montasser Kellan E. Ashley Natalie R. Hasbani Eric Boerwinkle Alanna C. Morrison Nathalie Chami Ron Do Ghislain Rocheleau Donald M. Lloyd‐Jones Rozenn N. Lemaitre Joshua C. Bis James S. Floyd Gregory L. Kinney Donald W. Bowden Nicholette D. Palmer Emelia J. Benjamin Matthew Nayor Lisa R. Yanek Brian G. Kral Lewis C. Becker Sharon L. R. Kardia Jennifer A. Smith Lawrence F. Bielak Arnita F. Norwood Yuan‐I Min April P. Carson Wendy S. Post Stephen S. Rich David Herrington Xiuqing Guo Kent D. Taylor JoAnn E. Manson Nora Franceschini Katherine S. Pollard Braxton D. Mitchell Ruth J. F. Loos Myriam Fornage Lifang Hou Bruce M. Psaty Kendra A. Young Elizabeth A. Regan Barry I. Freedman Ramachandran S. Vasan Daniel Levy Rasika A. Mathias Patricia A. Peyser Laura M. Raffield Charles Kooperberg Alex P. Reiner Jerome I. Rotter Goo Jun Paul S. de Vries Themistocles L. Assimes Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease association testing coronary artery disease genetics structural variants whole‐genome sequencing |
| title | Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants |
| title_full | Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants |
| title_fullStr | Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants |
| title_full_unstemmed | Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants |
| title_short | Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants |
| title_sort | unveiling the genetic landscape of coronary artery disease through common and rare structural variants |
| topic | association testing coronary artery disease genetics structural variants whole‐genome sequencing |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.036499 |
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