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

Author

Listed:
  • Margaret Sunitha Selvaraj

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Harvard Medical School)

  • 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
    University of Pennsylvania)

  • Joseph Park

    (University of Pennsylvania
    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
    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
    Tulane University Translational Science Institute)

  • 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
    The Broad Institute of MIT and Harvard)

  • 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
    The Broad Institute of MIT and Harvard)

  • 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
    Tulane University Translational Science Institute)

  • Robert C. Kaplan

    (Albert Einstein College of Medicine
    Fred Hutchinson Cancer Research Center)

  • 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
    University of Copenhagen)

  • 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
    Baltimore Veterans Administration Medical Center)

  • Deborah Nickerson

    (University of Washington, Department of Genome Sciences)

  • Kari E. North

    (UNC Chapel Hill)

  • Bruce M. Psaty

    (University of Washington
    University of Washington
    University of Washington)

  • Susan Redline

    (Harvard Medical School)

  • Alexander P. Reiner

    (Fred Hutchinson Cancer Research Center
    University of Washington)

  • Ramachandran S. Vasan

    (Boston University School of Medicine
    Boston University School of Public Health
    Framingham Heart Study)

  • 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
    University of Pennsylvania
    University of Pennsylvania)

  • Xihong Lin

    (Broad Institute of Harvard and MIT
    Harvard T.H. Chan School of Public Health
    Harvard University)

  • Gina M. Peloso

    (Boston University School of Public Health)

  • Pradeep Natarajan

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT
    Harvard Medical School)

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.

Suggested Citation

  • 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, 2022. "Whole genome sequence analysis of blood lipid levels in >66,000 individuals," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33510-7
    DOI: 10.1038/s41467-022-33510-7
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    References listed on IDEAS

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    Cited by:

    1. Ozvan Bocher & Cristen J. Willer & Eleftheria Zeggini, 2023. "Unravelling the genetic architecture of human complex traits through whole genome sequencing," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    2. Nicole Deflaux & Margaret Sunitha Selvaraj & Henry Robert Condon & Kelsey Mayo & Sara Haidermota & Melissa A. Basford & Chris Lunt & Anthony A. Philippakis & Dan M. Roden & Joshua C. Denny & Anjene Mu, 2023. "Demonstrating paths for unlocking the value of cloud genomics through cross cohort analysis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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