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Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author

Listed:
  • Seyedeh M. Zekavat

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

  • Sanni Ruotsalainen

    (University of Helsinki)

  • Robert E. Handsaker

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Maris Alver

    (University of Tartu
    Estonian Genome Center)

  • Jonathan Bloom

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit)

  • Timothy Poterba

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit)

  • Cotton Seed

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit)

  • Jason Ernst

    (University of California, Los Angeles)

  • Mark Chaffin

    (Broad Institute of MIT and Harvard)

  • Jesse Engreitz

    (Broad Institute of MIT and Harvard)

  • Gina M. Peloso

    (Boston University School of Public Health)

  • Ani Manichaikul

    (University of Virginia)

  • Chaojie Yang

    (University of Virginia)

  • Kathleen A. Ryan

    (University of Maryland School of Medicine)

  • Mao Fu

    (University of Maryland School of Medicine)

  • W. Craig Johnson

    (University of Washington)

  • Michael Tsai

    (University of Minnesota)

  • Matthew Budoff

    (Los Angeles Biomedical Research Institute)

  • Ramachandran S. Vasan

    (NHLBI Framingham Heart Study
    Boston university Schools of Medicine and Public health)

  • L. Adrienne Cupples

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

  • Jerome I. Rotter

    (Harbor-UCLA Medical Center)

  • Stephen S. Rich

    (University of Virginia)

  • Wendy Post

    (Johns Hopkins University School of Medicine)

  • Braxton D. Mitchell

    (University of Maryland School of Medicine)

  • Adolfo Correa

    (University of Mississippi Medical Center)

  • Andres Metspalu

    (Estonian Genome Center)

  • James G. Wilson

    (University of Mississippi Medical Center)

  • Veikko Salomaa

    (National Institute for Health and Welfare)

  • Manolis Kellis

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

  • Mark J. Daly

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit)

  • Benjamin M. Neale

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit)

  • Steven McCarroll

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Ida Surakka

    (University of Helsinki)

  • Tonu Esko

    (Broad Institute of MIT and Harvard
    Estonian Genome Center)

  • Andrea Ganna

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit)

  • Samuli Ripatti

    (Broad Institute of MIT and Harvard
    University of Helsinki
    University of Helsinki)

  • Sekar Kathiresan

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

  • Pradeep Natarajan

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

Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

Suggested Citation

  • Seyedeh M. Zekavat & Sanni Ruotsalainen & Robert E. Handsaker & Maris Alver & Jonathan Bloom & Timothy Poterba & Cotton Seed & Jason Ernst & Mark Chaffin & Jesse Engreitz & Gina M. Peloso & Ani Manich, 2018. "Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04668-w
    DOI: 10.1038/s41467-018-04668-w
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