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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-07-04

AUTHORS

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 Manichaikul, Chaojie Yang, Kathleen A. Ryan, Mao Fu, W. Craig Johnson, Michael Tsai, Matthew Budoff, Ramachandran S. Vasan, L. Adrienne Cupples, Jerome I. Rotter, Stephen S. Rich, Wendy Post, Braxton D. Mitchell, Adolfo Correa, Andres Metspalu, James G. Wilson, Veikko Salomaa, Manolis Kellis, Mark J. Daly, Benjamin M. Neale, Steven McCarroll, Ida Surakka, Tonu Esko, Andrea Ganna, Samuli Ripatti, Sekar Kathiresan, Pradeep Natarajan

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. More... »

PAGES

2606

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    9

    Author Affiliations

  • Department of Computational Biology & Bioinformatics, Yale University, 06510, New Haven, CT, USA
  • Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
  • Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA
  • Estonian Genome Center, Tallinn, Estonia
  • Analytic and Translational Genetics Unit, 02142, Boston, MA, USA
  • Department of Biological Chemistry, University of California, Los Angeles, 90095, Los Angeles, CA, USA
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA
  • Department of Biostatistics, Boston University School of Public Health, 02118, Boston, MA, USA
  • Center for Public Health Genomics, University of Virginia, 22904, Charlottesville, VA, USA
  • Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, 21201, Baltimore, MD, USA
  • Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, 98195, Seattle, WA, USA
  • Department of Laboratory Medicine and Pathology, University of Minnesota, 55455, Minneapolis, MN, USA
  • Division of Cardiology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute, 90509, Los Angeles, CA, USA
  • Sections of Preventive medicine and Epidemiology, and cardiovascular medicine, Departments of Medicine and Epidemiology, Boston university Schools of Medicine and Public health, 02118, Boston, MA, USA
  • NHLBI Framingham Heart Study, 20892, Framingham, MA, USA
  • Departments of Pediatrics and Medicine, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 90509, Torrance, CA, USA
  • Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 21205, Baltimore, MD, USA
  • Department of Medicine, University of Maryland School of Medicine, 21201, Baltimore, MD, USA
  • Department of Medicine, University of Mississippi Medical Center, 39216, Jackson, MS, USA
  • National Institute for Health and Welfare, Helsinki, Finland
  • Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, 02139, Cambridge, MA, USA
  • Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  • Cardiovascular Research Center, Massachusetts General Hospital, 02114, Boston, MA, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-04668-w

    DOI

    http://dx.doi.org/10.1038/s41467-018-04668-w

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1105228669

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29973585


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