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

Margaret Sunitha Selvaraj, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
Xihao Li, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Zilin Li, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Akhil Pampana, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
David Y. Zhang, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Joseph Park, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Stella Aslibekyan, Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Joshua C. Bis, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Jennifer A. Brody, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Brian E. Cade, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Lee-Ming Chuang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Ren-Hua Chung, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, 350, Taiwan.
Joanne E. Curran, Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, 78520, USA.
Lisa de Las Fuentes, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA.
Paul S. de Vries, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Ravindranath Duggirala, Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, 78520, USA.
Barry I. Freedman, Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
Mariaelisa Graff, Department of Epidemiology, UNC Chapel Hill, Chapel Hill, NC, USA.
Xiuqing Guo, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Nancy Heard-Costa, Department of Neurology, Boston university School of Medicine, Boston, MA, USA.
Bertha Hidalgo, Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Chii-Min Hwu, Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Marguerite R. Irvin, Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Tanika N. Kelly, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA.
Brian G. Kral, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Leslie Lange, Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Xiaohui Li, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Martin Lisa, Department of Medicine, George Washington University, Washingron, DC, USA.
Steven A. Lubitz, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
Ani W. Manichaikul, Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Preuss Michael, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
May E. Montasser, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Document Type

Journal Article

Publication Date

10-11-2022

Journal

Nature communications

Volume

13

Issue

1

DOI

10.1038/s41467-022-33510-7

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.

Department

Medicine

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