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Get Free AccessLipoprotein(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.
Seyedeh M. Zekavat, Sanni Ruotsalainen, Robert E. Handsaker, Maris Alver, Jonathan M. Bloom, Timothy Poterba, Cotton Seed, Jason Ernst, Mark Chaffin, J Engreitz, Gina M. Peloso, Ani Manichaikul, Chaojie Yang, Kathleen A. Ryan, Mao Fu, W. Craig Johnson, Michael Tsai, Matthew J. Budoff, Ramachandran S. Vasan, L. Adrienne Cupples, Jerome I. Rotter, Stephen S. Rich, Wendy S. 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, Tõnu Esko, Andrea Ganna, Samuli Ripatti, Sekar Kathiresan, Pradeep Natarajan, Namiko Abe, Gonçalo R. Abecasis, Christine M. Albert, Nicholette Palmer Allred, Laura Almasy, Álvaro Alonso, Seth A. Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum‐Bowden, Dan E. Arking, Donna K. Arnett, Allison E. Ashley‐Koch, Stella Aslibekyan, Tim Assimes, Paul L. Auer, Dimitrios Avramopoulos, John Barnard, Kathleen C. Barnes, R. Graham Barr, Emily Barron‐Casella, Terri H. Beaty, Diane M. Becker, Lewis C. Becker, Rebecca Beer, Ferdouse Begum, Amber L. Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua C. Bis, Thomas W. Blackwell, John Blangero, Eric Boerwinkle, Ingrid B. Borecki, Russell P. Bowler, Jennifer A. Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban G. Burchard, Jonathan Cardwell, Cara L. Carty, Richard Casaburi, James F. Casella, Christy Chang, Daniel I. Chasman, Sameer Chavan, Bo-Juen Chen, Wei‐Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee‐Ming Chuang, Mina K. Chung, Elaine Cornell, Carolyn Crandall, James D. Crapo, Joanne E. Curran, Jeffrey L. Curtis, Brian Custer (2018). Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries. , 9(1), DOI: https://doi.org/10.1038/s41467-018-04668-w.
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Type
Article
Year
2018
Authors
99
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1038/s41467-018-04668-w
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