Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Natarajan, Pradeep; Pampana, Akhil; Graham, Sarah E.; Ruotsalainen, Sanni E.; Perry, James A.; Vries, Paul S.; Broome, Jai G.; Pirruccello, James P.; Honigberg, Michael C.; Aragam, Krishna; Wolford, Brooke; Brody, Jennifer A.; Antonacci-Fulton, Lucinda; Arden, Moscati; Aslibekyan, Stella; Assimes, Themistocles L.; Ballantyne, Christie M.; Bielak, Lawrence F.; Bis, Joshua C.; Cade, Brian E.; Do, Ron; Doddapaneni, Harsha; Emery, Leslie S.; Hung, Yi-Jen; Irvin, Marguerite R.; Khan, Alyna T.; Lange, Leslie; Lee, Jiwon; Lemaitre, Rozenn N.; Martin, Lisa W.; Metcalf, Ginger; Montasser, May E.; Moon, Jee-Young; Muzny, Donna; O’Connell, Jeffrey R.; Palmer, Nicholette D.; Peralta, Juan M.; Peyser, Patricia A.; Stilp, Adrienne M.; Tsai, Michael; Wang, Fei Fei; Weeks, Daniel E.; Yanek, Lisa R.; Wilson, James G.; Abecasis, Goncalo; Arnett, Donna K.; Becker, Lewis C.; Blangero, John; Boerwinkle, Eric; Bowden, Donald W.; Chang, Yi-Cheng; Der I. Chen, Yii-; Choi, Won Jung; Correa, Adolfo; Curran, Joanne E.; Daly, Mark J.; Dutcher, Susan K.; Ellinor, Patrick T.; Fornage, Myriam; Freedman, Barry I.; Gabriel, Stacey; Germer, Soren; Gibbs, Richard A.; He, Jiang; Hveem, Kristian; Jarvik, Gail P.; Kaplan, Robert C.; Kardia, Sharon L. R.; Kenny, Eimear; Kim, Ryan W.; Kooperberg, Charles; Laurie, Cathy C.; Lee, Seonwook; Lloyd-Jones, Don M.; Loos, Ruth J. F.; Lubitz, Steven A.; Mathias, Rasika A.; Martinez, Karine A. Viaud; McGarvey, Stephen T.; Mitchell, Braxton D.; Nickerson, Deborah A.; North, Kari E.; Palotie, Aarno; Park, Cheol Joo; Psaty, Bruce M.; Rao, D. C.; Redline, Susan; Reiner, Alexander P.; Seo, Daekwan; Seo, Jeong-Sun; Smith, Albert V.; Tracy, Russell P.; Vasan, Ramachandran S.; Kathiresan, Sekar; Cupples, L. Adrienne; Rotter, Jerome I.; Morrison, Alanna C.; Rich, Stephen S.; Ripatti, Samuli; Willer, Cristen; Peloso, Gina M.

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Pradeep Natarajan (), Akhil Pampana, Sarah E. Graham, Sanni E. Ruotsalainen, James A. Perry, Paul S. Vries, Jai G. Broome, James P. Pirruccello, Michael C. Honigberg, Krishna Aragam, Brooke Wolford, Jennifer A. Brody, Lucinda Antonacci-Fulton, Moscati Arden, Stella Aslibekyan, Themistocles L. Assimes, Christie M. Ballantyne, Lawrence F. Bielak, Joshua C. Bis, Brian E. Cade, Ron Do, Harsha Doddapaneni, Leslie S. Emery, Yi-Jen Hung, Marguerite R. Irvin, Alyna T. Khan, Leslie Lange, Jiwon Lee, Rozenn N. Lemaitre, Lisa W. Martin, Ginger Metcalf, May E. Montasser, Jee-Young Moon, Donna Muzny, Jeffrey R. O’Connell, Nicholette D. Palmer, Juan M. Peralta, Patricia A. Peyser, Adrienne M. Stilp, Michael Tsai, Fei Fei Wang, Daniel E. Weeks, Lisa R. Yanek, James G. Wilson, Goncalo Abecasis, Donna K. Arnett, Lewis C. Becker, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yi-Cheng Chang, Yii- Der I. Chen, Won Jung Choi, Adolfo Correa, Joanne E. Curran, Mark J. Daly, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Barry I. Freedman, Stacey Gabriel, Soren Germer, Richard A. Gibbs, Jiang He, Kristian Hveem, Gail P. Jarvik, Robert C. Kaplan, Sharon L. R. Kardia, Eimear Kenny, Ryan W. Kim, Charles Kooperberg, Cathy C. Laurie, Seonwook Lee, Don M. Lloyd-Jones, Ruth J. F. Loos, Steven A. Lubitz, Rasika A. Mathias, Karine A. Viaud Martinez, Stephen T. McGarvey, Braxton D. Mitchell, Deborah A. Nickerson, Kari E. North, Aarno Palotie, Cheol Joo Park, Bruce M. Psaty, D. C. Rao, Susan Redline, Alexander P. Reiner, Daekwan Seo, Jeong-Sun Seo, Albert V. Smith, Russell P. Tracy, Ramachandran S. Vasan, Sekar Kathiresan, L. Adrienne Cupples, Jerome I. Rotter, Alanna C. Morrison, Stephen S. Rich, Samuli Ripatti, Cristen Willer and Gina M. Peloso ()
Additional contact information
Pradeep Natarajan: Cardiovascular Research Center, Massachusetts General Hospital
Akhil Pampana: Cardiovascular Research Center, Massachusetts General Hospital
Sarah E. Graham: University of Michigan
Sanni E. Ruotsalainen: University of Helsinki
James A. Perry: University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine
Paul S. Vries: The University of Texas Health Science Center at Houston
Jai G. Broome: University of Washington
James P. Pirruccello: Cardiovascular Research Center, Massachusetts General Hospital
Michael C. Honigberg: Cardiovascular Research Center, Massachusetts General Hospital
Krishna Aragam: Cardiovascular Research Center, Massachusetts General Hospital
Brooke Wolford: University of Michigan
Jennifer A. Brody: University of Washington
Lucinda Antonacci-Fulton: Washington University School of Medicine
Moscati Arden: The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai
Stella Aslibekyan: University of Alabama at Birmingham
Themistocles L. Assimes: Stanford University School of Medicine
Christie M. Ballantyne: Section of Cardiovascular Research, Baylor College of Medicine
Lawrence F. Bielak: University of Michigan
Joshua C. Bis: University of Washington
Brian E. Cade: Brigham and Women’s Hospital, Harvard Medical School
Ron Do: The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai
Harsha Doddapaneni: Human Genome Sequencing Center, Baylor College of Medicine
Leslie S. Emery: University of Washington
Yi-Jen Hung: Division of Endocrine and Metabolism, Tri-Service General Hospital Songshan branch
Marguerite R. Irvin: University of Alabama at Birmingham
Alyna T. Khan: University of Washington
Leslie Lange: University of Colorado Anschutz Medical Campus
Jiwon Lee: Brigham and Women’s Hospital, Harvard Medical School
Rozenn N. Lemaitre: University of Washington
Lisa W. Martin: George Washington University School of Medicine and Healthcare Sciences
Ginger Metcalf: Human Genome Sequencing Center, Baylor College of Medicine
May E. Montasser: University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine
Jee-Young Moon: Albert Einstein College of Medicine
Donna Muzny: Human Genome Sequencing Center, Baylor College of Medicine
Jeffrey R. O’Connell: University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine
Nicholette D. Palmer: Wake Forest School of Medicine
Juan M. Peralta: University of Texas Rio Grande Valley School of Medicine
Patricia A. Peyser: University of Michigan
Adrienne M. Stilp: University of Washington
Michael Tsai: University of Minnesota
Fei Fei Wang: University of Washington
Daniel E. Weeks: University of Pittsburgh, Pittsburgh
Lisa R. Yanek: Johns Hopkins University School of Medicine
James G. Wilson: Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center
Goncalo Abecasis: University of Michigan
Donna K. Arnett: University of Kentucky
Lewis C. Becker: Johns Hopkins University School of Medicine
John Blangero: University of Texas Rio Grande Valley School of Medicine
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Donald W. Bowden: Wake Forest School of Medicine
Yi-Cheng Chang: National Taiwan University Hospital
Yii- Der I. Chen: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Won Jung Choi: Psomagen. Inc. (formerly Macrogen USA)
Adolfo Correa: University of Mississippi Medical Center
Joanne E. Curran: University of Texas Rio Grande Valley School of Medicine
Mark J. Daly: Program in Medical and Population Genetics, Broad Institute
Susan K. Dutcher: Washington University School of Medicine
Patrick T. Ellinor: Program in Medical and Population Genetics, Broad Institute
Myriam Fornage: the University of Texas Health Science Center at Houston
Barry I. Freedman: Section on Nephrology, Wake Forest School of Medicine, Winston-
Stacey Gabriel: Genomics Platform, Broad Institute of Harvard and MIT
Soren Germer: New York Genome Center
Richard A. Gibbs: Human Genome Sequencing Center, Baylor College of Medicine
Jiang He: Tulane University School of Public Health and Tropical Medicine, and Tulane University Translational Science Institute, Tulane University
Kristian Hveem: Norwegian University of Science and Technology
Gail P. Jarvik: University of Washington
Robert C. Kaplan: Albert Einstein College of Medicine
Sharon L. R. Kardia: University of Michigan
Eimear Kenny: The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai
Ryan W. Kim: Psomagen. Inc. (formerly Macrogen USA)
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Cathy C. Laurie: University of Washington
Seonwook Lee: Psomagen. Inc. (formerly Macrogen USA)
Don M. Lloyd-Jones: Northwestern University
Ruth J. F. Loos: The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai
Steven A. Lubitz: Cardiac Arrhythmia Service and Cardiovascular Research Center Massachusetts General Hospital
Rasika A. Mathias: Johns Hopkins University School of Medicine
Karine A. Viaud Martinez: Illumina Laboratory Services, Illumina inc.
Stephen T. McGarvey: Brown University
Braxton D. Mitchell: University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine
Deborah A. Nickerson: University of Washington
Kari E. North: University of North Carolina at Chapel Hill
Aarno Palotie: Program in Medical and Population Genetics, Broad Institute
Cheol Joo Park: Psomagen. Inc. (formerly Macrogen USA)
Bruce M. Psaty: University of Washington
D. C. Rao: Washington University School of Medicine
Susan Redline: Brigham and Women’s Hospital, Harvard Medical School
Alexander P. Reiner: Fred Hutchinson Cancer Research Center
Daekwan Seo: Psomagen. Inc. (formerly Macrogen USA)
Jeong-Sun Seo: Psomagen. Inc. (formerly Macrogen USA)
Albert V. Smith: University of Michigan
Russell P. Tracy: University of Vermont
Ramachandran S. Vasan: Boston University School of Medicine
Sekar Kathiresan: Program in Medical and Population Genetics, Broad Institute
L. Adrienne Cupples: NHLBI Framingham Heart Study
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Stephen S. Rich: University of Virginia
Samuli Ripatti: Program in Medical and Population Genetics, Broad Institute
Cristen Willer: University of Michigan
Gina M. Peloso: Boston University School of Public Health

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Date: 2021
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DOI: 10.1038/s41467-021-22339-1

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