Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Selvaraj, Margaret Sunitha; Li, Xihao; Li, Zilin; Pampana, Akhil; Zhang, David Y.; Park, Joseph; Aslibekyan, Stella; Bis, Joshua C.; Brody, Jennifer A.; Cade, Brian E.; Chuang, Lee-Ming; Chung, Ren-Hua; Curran, Joanne E.; Fuentes, Lisa las; Vries, Paul S.; Duggirala, Ravindranath; Freedman, Barry I.; Graff, Mariaelisa; Guo, Xiuqing; Heard-Costa, Nancy; Hidalgo, Bertha; Hwu, Chii-Min; Irvin, Marguerite R.; Kelly, Tanika N.; Kral, Brian G.; Lange, Leslie; Li, Xiaohui; Lisa, Martin; Lubitz, Steven A.; Manichaikul, Ani W.; Michael, Preuss; Montasser, May E.; Morrison, Alanna C.; Naseri, Take; O’Connell, Jeffrey R.; Palmer, Nicholette D.; Peyser, Patricia A.; Reupena, Muagututia S.; Smith, Jennifer A.; Sun, Xiao; Taylor, Kent D.; Tracy, Russell P.; Tsai, Michael Y.; Wang, Zhe; Wang, Yuxuan; Bao, Wei; Wilkins, John T.; Yanek, Lisa R.; Zhao, Wei; Arnett, Donna K.; Blangero, John; Boerwinkle, Eric; Bowden, Donald W.; Der Ida Chen, Yii-; Correa, Adolfo; Cupples, L. Adrienne; Dutcher, Susan K.; Ellinor, Patrick T.; Fornage, Myriam; Gabriel, Stacey; Germer, Soren; Gibbs, Richard; He, Jiang; Kaplan, Robert C.; Kardia, Sharon L. R.; Kim, Ryan; Kooperberg, Charles; Loos, Ruth J. F.; Viaud-Martinez, Karine A; Mathias, Rasika A.; McGarvey, Stephen T.; Mitchell, Braxton D.; Nickerson, Deborah; North, Kari E.; Psaty, Bruce M.; Redline, Susan; Reiner, Alexander P.; Vasan, Ramachandran S.; Rich, Stephen S.; Willer, Cristen; Rotter, Jerome I.; Rader, Daniel J.; Lin, Xihong; Peloso, Gina M.; Natarajan, Pradeep

Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Y. Zhang, Joseph Park, Stella Aslibekyan, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Lee-Ming Chuang, Ren-Hua Chung, Joanne E. Curran, Lisa las Fuentes, Paul S. Vries, Ravindranath Duggirala, Barry I. Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy Heard-Costa, Bertha Hidalgo, Chii-Min Hwu, Marguerite R. Irvin, Tanika N. Kelly, Brian G. Kral, Leslie Lange, Xiaohui Li, Martin Lisa, Steven A. Lubitz, Ani W. Manichaikul, Preuss Michael, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Muagututia S. Reupena, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Russell P. Tracy, Michael Y. Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T. Wilkins, Lisa R. Yanek, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yii- Der Ida Chen, Adolfo Correa, L. Adrienne Cupples, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Jiang He, Robert C. Kaplan, Sharon L. R. Kardia, Ryan Kim, Charles Kooperberg, Ruth J. F. Loos, Karine A Viaud-Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Deborah Nickerson, Kari E. North, Bruce M. Psaty, Susan Redline, Alexander P. Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen Willer, Jerome I. Rotter, Daniel J. Rader, Xihong Lin, Gina M. Peloso () and Pradeep Natarajan ()
Additional contact information
Margaret Sunitha Selvaraj: Massachusetts General Hospital
Xihao Li: Harvard T.H. Chan School of Public Health
Zilin Li: Harvard T.H. Chan School of Public Health
Akhil Pampana: Broad Institute of Harvard and MIT
David Y. Zhang: University of Pennsylvania
Joseph Park: University of Pennsylvania
Stella Aslibekyan: University of Alabama at Birmingham School of Public Health
Joshua C. Bis: University of Washington
Jennifer A. Brody: University of Washington
Brian E. Cade: Harvard Medical School
Lee-Ming Chuang: National Taiwan University Hospital
Ren-Hua Chung: National Health Research Institutes
Joanne E. Curran: University of Texas Rio Grande Valley School of Medicine
Lisa las Fuentes: Washington University School of Medicine
Paul S. Vries: The University of Texas Health Science Center at Houston
Ravindranath Duggirala: University of Texas Rio Grande Valley School of Medicine
Barry I. Freedman: Wake Forest School of Medicine
Mariaelisa Graff: UNC Chapel Hill
Xiuqing Guo: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Nancy Heard-Costa: Boston university School of Medicine
Bertha Hidalgo: University of Alabama at Birmingham School of Public Health
Chii-Min Hwu: Taipei Veterans General Hospital
Marguerite R. Irvin: University of Alabama at Birmingham School of Public Health
Tanika N. Kelly: Tulane University School of Public Health and Tropical Medicine
Brian G. Kral: Johns Hopkins University School of Medicine
Leslie Lange: University of Colorado Anschutz Medical Campus
Xiaohui Li: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Martin Lisa: George Washington University
Steven A. Lubitz: Massachusetts General Hospital
Ani W. Manichaikul: University of Virginia
Preuss Michael: Icahn School of Medicine at Mount Sinai
May E. Montasser: University of Maryland School of Medicine
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Take Naseri: Government of Samoa
Jeffrey R. O’Connell: University of Maryland School of Medicine
Nicholette D. Palmer: Wake Forest School of Medicine
Patricia A. Peyser: University of Michigan
Muagututia S. Reupena: Lutia i Puava ae Mapu i Fagalele
Jennifer A. Smith: University of Michigan
Xiao Sun: Tulane University School of Public Health and Tropical Medicine
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Russell P. Tracy: Larner College of Medicine at the University of Vermont
Michael Y. Tsai: University of Minneosta
Zhe Wang: Icahn School of Medicine at Mount Sinai
Yuxuan Wang: Boston University School of Public Health
Wei Bao: University of Science and Technology of China
John T. Wilkins: Northwestern University Feinberg School of Medicine
Lisa R. Yanek: Johns Hopkins University School of Medicine
Wei Zhao: University of Michigan
Donna K. Arnett: University of Kentucky College of Public Health
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
Yii- Der Ida Chen: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Adolfo Correa: University of Mississippi Medical Center
L. Adrienne Cupples: Boston University School of Public Health
Susan K. Dutcher: Washington University School of Medicine
Patrick T. Ellinor: Massachusetts General Hospital
Myriam Fornage: The University of Texas Health Science Center at Houston
Stacey Gabriel: Broad Institute
Soren Germer: New York Genome Center
Richard Gibbs: Baylor College of Medicine Human Genome Sequencing Center
Jiang He: Tulane University School of Public Health and Tropical Medicine
Robert C. Kaplan: Albert Einstein College of Medicine
Sharon L. R. Kardia: University of Michigan
Ryan Kim: Psomagen, Inc. (formerly Macrogen USA)
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Karine A Viaud-Martinez: Illumina. Inc
Rasika A. Mathias: Johns Hopkins University School of Medicine
Stephen T. McGarvey: Brown University
Braxton D. Mitchell: University of Maryland School of Medicine
Deborah Nickerson: University of Washington, Department of Genome Sciences
Kari E. North: UNC Chapel Hill
Bruce M. Psaty: University of Washington
Susan Redline: Harvard Medical School
Alexander P. Reiner: Fred Hutchinson Cancer Research Center
Ramachandran S. Vasan: Boston University School of Medicine
Stephen S. Rich: University of Virginia
Cristen Willer: University of Michigan, Internal Medicine
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Daniel J. Rader: University of Pennsylvania
Xihong Lin: Broad Institute of Harvard and MIT
Gina M. Peloso: Boston University School of Public Health
Pradeep Natarajan: Massachusetts General Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Date: 2022
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DOI: 10.1038/s41467-022-33510-7

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