Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals

Margaret Sunitha Selvaraj, Center for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Xihao Li, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Zilin Li, Department of Biostatistics Harvard T.H. Chan School of Public Health,, Boston, MA, 02115, USA.
Eric Van Buren, Department of Biostatistics Harvard T.H. Chan School of Public Health,, Boston, MA, 02115, USA.
Sara Haidermota, Center for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Darina Postupaka, Center for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Whitney Hornsby, Center for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, 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, Boston, MA, USA.
Ren-Hua Chung, Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, 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, 78520, TX , USA.
Scott M. Damrauer, Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Lisa de Las Fuentes, Department of Medicine, Cardiovascular Division, Global Health Center, Institute for Public Health, and Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics (I2BD), Washington University School of Medicine, St. Louis, MO, USA.
Paul S. de Vries, Human Genetics Center, Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, , Houston, TX, USA.
Ravindranath Duggirala, Department of Health and Behavioral Sciences, College of Arts and Sciences,, Texas A&M University-San Antonio, San Antonio, TX, 78224, USA.
Barry I. Freedman, Section on Nephrology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
MariaElisa Graff, Department of Epidemiology, UNC,, 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, 90502, USA.
Bertha A. Hidalgo, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Lifang Hou, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
Ryan Irvin, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA.
Renae Judy, Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Rita R. Kalyani, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
Tanika N. Kelly, Division of Nephrology, Department of Medicine, University of Illinois Chicago, Chicago, 60612, IL, USA.
Iain R. Konigsberg, Department of Biomedical Informatics School of Medicine, University of Colorado, Aurora, CO, USA.
Brian G. Kral, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
Lydia Coulter Kwee, Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Daniel Levy, Framingham Heart Study, Framingham, MA, USA.
Changwei Li, Department of Epidemiology, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Ani W. Manichaikul, Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Lisa Warsinger Martin, Division of Cardiology, Department of Medicine, George Washington University, Washington DC, USA.

Document Type

Journal Article

Publication Date

9-9-2025

Journal

Genome biology

Volume

26

Issue

1

DOI

10.1186/s13059-025-03698-0

Abstract

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Department

Medicine

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