SynthesisGenome biology2025
Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.
Abstract readMeta-Analysis
In one paragraph
Synthesis in Genome biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
5 citing papers in PubMed.
- MetaSTAARlite: an all-in-one tool for biobank-scale whole-genome sequencing meta-analysis.Nature computational science · 2026Article
- Exome-wide association study of blood lipids in 1,158,017 individuals from diverse populations.Nature genetics · 2026Article
- Genetic factors contributing to atherosclerosis.Current opinion in cardiology · 2026Review
- Rare coding and noncoding variants map 1,342 diseases and biomarkers in 490,549 whole genomes.medRxiv : the preprint server for health sciences · 2026Article
- Sex differences in LDL-C genetic architecture and statin efficacy in All of Us.medRxiv : the preprint server for health sciences · 2026Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
83 authors.
Margaret Sunitha SelvarajCenter for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Xihao LiDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Zilin LiDepartment of Biostatistics Harvard T.H. Chan School of Public Health,, Boston, MA, 02115, USA.
Eric Van BurenDepartment of Biostatistics Harvard T.H. Chan School of Public Health,, Boston, MA, 02115, USA.
Sara HaidermotaCenter for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Darina PostupakaCenter for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Whitney HornsbyCenter for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Brian E CadeDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Ren-Hua ChungInstitute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.
Joanne E CurranDepartment 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 DamrauerDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Lisa de Las FuentesDepartment 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 VriesHuman Genetics Center, Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, , Houston, TX, USA.
Ravindranath DuggiralaDepartment of Health and Behavioral Sciences, College of Arts and Sciences,, Texas A&M University-San Antonio, San Antonio, TX, 78224, USA.
Barry I FreedmanSection on Nephrology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
MariaElisa GraffDepartment of Epidemiology, UNC,, Chapel Hill, NC, USA.
Xiuqing GuoThe 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 HidalgoDepartment of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Lifang HouDepartment of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
Ryan IrvinDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA.
Renae JudyDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Rita R KalyaniDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
Tanika N KellyDivision of Nephrology, Department of Medicine, University of Illinois Chicago, Chicago, 60612, IL, USA.
Iain R KonigsbergDepartment of Biomedical Informatics School of Medicine, University of Colorado, Aurora, CO, USA.
Brian G KralDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
Lydia Coulter KweeDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Daniel LevyFramingham Heart Study, Framingham, MA, USA.
Changwei LiDepartment of Epidemiology, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Ani W ManichaikulDepartment of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Lisa Warsinger MartinDivision of Cardiology, Department of Medicine, George Washington University, Washington DC, USA.
May E MontasserDepartment of Medicine, University of Maryland School of Medicine,, Baltimore, MD, USA.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, , Houston, TX, USA.
Take NaseriNaseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
Kari E NorthDepartment of Epidemiology and Population Health Albert, Einstein College of Medicine, Bronx, 10461, NY, USA.
Jeffrey R O'ConnellDepartment of Medicine, University of Maryland School of Medicine,, Baltimore, MD, USA.
Nicholette D PalmerDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, 27157, NC, USA.
Patricia A PeyserDepartment of Epidemiology, School of Public Healt, University of Michigan, Ann Arbor, MI, USA.
Alex P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Svati H ShahDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Roelof A J SmitThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai,, New York, NY, USA.
Jennifer A SmithDepartment of Epidemiology, School of Public Healt, University of Michigan, Ann Arbor, MI, USA.
Kent D TaylorThe 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.
Hemant TiwariDepartment of Biostatistics, University of Alabama at Birmingham, Birmingham, 35294, AL, USA.
Michael Y TsaiDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
Satupa'itea VialiOceanian University of Medicine, Apia, Samoa.
Zhe WangDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA.
Yuxuan WangDepartment of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave, Boston, 02118, MA, USA.
Wei ZhaoDepartment of Epidemiology, School of Public Healt, University of Michigan, Ann Arbor, MI, USA.
Donna K ArnettProvost, University of South Carolina, Columbia, 29208, SC, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, 78520, TX , USA.
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, , Houston, TX, USA.
Donald W BowdenDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, 27157, NC, USA.
Jenna C CarlsonDepartments of Human Genetics and Biostatistics, School of Public Health,, University of Pittsburgh, Pittsburgh, PA, USA.
Yii-Der Ida ChenThe 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.
Patrick T EllinorCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, , Cambridge, MA , 02141, USA.
Myriam FornageBrown Foundation Institute of Molecular Medicine McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, 7722, TX, USA.
Jiang HeDepartment of Epidemiology, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nancy Heard-CostaFramingham Heart Study, Framingham, MA, USA.
Robert C KaplanDepartment of Epidemiology, UNC,, Chapel Hill, NC, USA.
Sharon L R KardiaDepartment of Epidemiology, School of Public Healt, University of Michigan, Ann Arbor, MI, USA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
William E KrausDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Leslie A LangeDepartment of Biomedical Informatics School of Medicine, University of Colorado, Aurora, CO, USA.
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai,, New York, NY, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine,, Baltimore, MD, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Daniel J RaderDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Susan RedlineDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Stephen S RichDepartment of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Lisa R YanekDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.
Richard GibbsBaylor College of Medicine Human Genome Sequencing Center, Houston, 77030, TX, USA.
Stacey GabrielBroad Institute, Cambridge, 02142, MA, USA.
Karine A Viaud-MartinezIllumina Laboratory Services, Illumina,. Inc., , San Diego, 92122, CA, USA.
Susan K DutcherThe McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 63110, MO, USA.
Soren GermerNew York Genome Center, New York, 10013, NY, USA.
Ryan KimPsomagen, Inc. (formerly Macrogen USA), Rockville, MD, USA.
Jerome I RotterThe 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.
Xihong LinDepartment of Biostatistics Harvard T.H. Chan School of Public Health,, Boston, MA, 02115, USA.
Gina M Peloso *Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave, Boston, 02118, MA, USA. gpeloso@bu.edu.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Pradeep Natarajan *Center for Genomic Medicine, Cardiovascular Research Center, , Massachusetts General Hospital Simches Research Center, 185 Cambridge Street, CPZN 5.238,, Boston, MA, 02114, USA. pnatarajan@mgh.harvard.edu.
Funding
Infrastructure for mentored access to CHS data and specimensR01HL172803 · UNIVERSITY OF WASHINGTON · 2025 to 2025
$1.4MImaging and multi-omics analyses to identify molecular subtypes of distinct emphysema patternsR01HL167072 · BRIGHAM AND WOMEN'S HOSPITAL · 2025 to 2025
$838kHispanic Latino Lipid ConsortiumR01HL142302 · VANDERBILT UNIVERSITY MEDICAL CENTER · 2025 to 2025
$652kEnhanced Machine Learning Tools for Complex Data Evaluation and Integration in Advancing Health OutcomesR01HL173044 · UNIV OF NORTH CAROLINA CHAPEL HILL · 2025 to 2025
$642kWhole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemiasR01HL142711 · MASSACHUSETTS GENERAL HOSPITAL · 2025 to 2025
$641kStatistical Methods for Integrative Analysis of Large-Scale Multi-Ethnic Whole Genome Sequencing Studies and Biobanks of Common DiseasesR01HL163560 · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2025 to 2025
$498kNational Institutes of Health (NIH) R01HL142711NHLBI NIH HHS P50 HL118006NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL142302NHLBI NIH HHS R01 HL163560NHLBI NIH HHS R01 HL167072NHLBI NIH HHS R01 HL172803NHLBI NIH HHS R01 HL173044NHLBI TOPMed fellowship 75N92021F00229NIBIB NIH HHS R01 EB015611
Abstract
backgroundRare 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.
resultsHere, 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.
conclusionsThis 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.
Indexed as
Cholesterol, LDLWhole Genome SequencingGenetic VariationGenome, HumanGenome-Wide Association StudyHumansPolymorphism, Single NucleotideCholesterol, LDL
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LicenceCC BY-NC-ND
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.