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Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Author

Listed:
  • Pradeep Natarajan

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

  • Gina M. Peloso

    (Boston University School of Public Health)

  • Seyedeh Maryam Zekavat

    (Broad Institute of Harvard & MIT
    Yale School of Medicine
    Yale University)

  • May Montasser

    (University of Maryland)

  • Andrea Ganna

    (Broad Institute of Harvard & MIT
    Massachusetts General Hospital)

  • Mark Chaffin

    (Broad Institute of Harvard & MIT)

  • Amit V. Khera

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

  • Wei Zhou

    (University of Michigan)

  • Jonathan M. Bloom

    (Broad Institute of Harvard & MIT
    Massachusetts General Hospital)

  • Jesse M. Engreitz

    (Broad Institute of Harvard & MIT
    Harvard University)

  • Jason Ernst

    (University of California, Los Angeles)

  • Jeffrey R. O’Connell

    (University of Maryland)

  • Sanni E. Ruotsalainen

    (Institute for Molecular Medicine Finland)

  • Maris Alver

    (University of Tartu)

  • Ani Manichaikul

    (University of Virginia)

  • W. Craig Johnson

    (University of Washington)

  • James A. Perry

    (University of Maryland)

  • Timothy Poterba

    (Broad Institute of Harvard & MIT
    Massachusetts General Hospital)

  • Cotton Seed

    (Broad Institute of Harvard & MIT
    Massachusetts General Hospital)

  • Ida L. Surakka

    (Institute for Molecular Medicine Finland)

  • Tonu Esko

    (University of Tartu)

  • Samuli Ripatti

    (Institute for Molecular Medicine Finland)

  • Veikko Salomaa

    (Institute for Molecular Medicine Finland)

  • Adolfo Correa

    (University of Mississippi Medical Center)

  • Ramachandran S. Vasan

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

  • Manolis Kellis

    (Broad Institute of Harvard & MIT
    Massachusetts Institute of Technology)

  • Benjamin M. Neale

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

  • Eric S. Lander

    (Broad Institute of Harvard & MIT)

  • Goncalo Abecasis

    (University of Michigan)

  • Braxton Mitchell

    (University of Maryland)

  • Stephen S. Rich

    (University of Virginia)

  • James G. Wilson

    (University of Mississippi Medical Center
    University of Mississippi Medical Center)

  • L. Adrienne Cupples

    (Boston University School of Public Health
    Framingham Heart Study)

  • Jerome I. Rotter

    (Harbor-UCLA Medical Center)

  • Cristen J. Willer

    (University of Michigan)

  • Sekar Kathiresan

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

Abstract

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

Suggested Citation

  • Pradeep Natarajan & Gina M. Peloso & Seyedeh Maryam Zekavat & May Montasser & Andrea Ganna & Mark Chaffin & Amit V. Khera & Wei Zhou & Jonathan M. Bloom & Jesse M. Engreitz & Jason Ernst & Jeffrey R. , 2018. "Deep-coverage whole genome sequences and blood lipids among 16,324 individuals," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05747-8
    DOI: 10.1038/s41467-018-05747-8
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    Cited by:

    1. Young Jin Kim & Sanghoon Moon & Mi Yeong Hwang & Sohee Han & Hye-Mi Jang & Jinhwa Kong & Dong Mun Shin & Kyungheon Yoon & Sung Min Kim & Jong-Eun Lee & Anubha Mahajan & Hyun-Young Park & Mark I. McCar, 2022. "The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians," Nature Communications, Nature, vol. 13(1), pages 1-13, 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.
    3. 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.

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