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

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 () and Pradeep Natarajan ()
Additional contact information
Seyedeh M. Zekavat: Broad Institute of MIT and Harvard
Sanni Ruotsalainen: University of Helsinki
Robert E. Handsaker: Broad Institute of MIT and Harvard
Maris Alver: University of Tartu
Jonathan Bloom: Broad Institute of MIT and Harvard
Timothy Poterba: Broad Institute of MIT and Harvard
Cotton Seed: Broad Institute of MIT and Harvard
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
L. Adrienne Cupples: Boston University School of Public Health
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
Mark J. Daly: Broad Institute of MIT and Harvard
Benjamin M. Neale: Broad Institute of MIT and Harvard
Steven McCarroll: Broad Institute of MIT and Harvard
Ida Surakka: University of Helsinki
Tonu Esko: Broad Institute of MIT and Harvard
Andrea Ganna: Broad Institute of MIT and Harvard
Samuli Ripatti: Broad Institute of MIT and Harvard
Sekar Kathiresan: Broad Institute of MIT and Harvard
Pradeep Natarajan: Broad Institute of MIT and Harvard

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04668-w

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DOI: 10.1038/s41467-018-04668-w

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