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Nat Commun. 2018 Jul 4;9(1):2606. doi: 10.1038/s41467-018-04668-w.

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

Collaborators (305)

Abe N, Abecasis G, Albert C, Allred NNP, Almasy L, Alonso A, Ament S, Anderson P, Anugu P, Applebaum-Bowden D, Arking D, Arnett DK, Ashley-Koch A, Aslibekyan S, Assimes T, Auer P, Avramopoulos D, Barnard J, Barnes K, Barr RG, Barron-Casella E, Beaty T, Becker D, Becker L, Beer R, Begum F, Beitelshees A, Benjamin E, Bezerra M, Bielak L, Bis J, Blackwell T, Blangero J, Boerwinkle E, Borecki I, Bowler R, Brody J, Broeckel U, Broome J, Bunting K, Burchard E, Cardwell J, Carty C, Casaburi R, Casella J, Chang C, Chasman D, Chavan S, Chen BJ, Chen WM, Chen YI, Cho M, Choi SH, Chuang LM, Chung M, Cornell E, Crandall C, Crapo J, Curran J, Curtis J, Custer B, Damcott C, Darbar D, Das S, David S, Davis C, Daya M, Andrade M, DeBaun M, Deka R, DeMeo D, Devine S, Do R, Duan Q, Duggirala R, Durda P, Dutcher S, Eaton C, Ekunwe L, Ellinor P, Emery L, Farber C, Farnam L, Fingerlin T, Flickinger M, Fornage M, Franceschini N, Fullerton SM, Fulton L, Gabriel S, Gan W, Gao Y, Gass M, Gelb B, Geng XP, Germer S, Gignoux C, Gladwin M, Glahn D, Gogarten S, Gong DW, Goring H, Gu CC, Guan Y, Guo X, Haessler J, Hall M, Harris D, Hawley N, He J, Heavner B, Heckbert S, Hernandez R, Herrington D, Hersh C, Hidalgo B, Hixson J, Hokanson J, Hong E, Hoth K, Hsiung CA, Huston H, Hwu CM, Irvin MR, Jackson R, Jain D, Jaquish C, Jhun MA, Johnsen J, Johnson A, Johnston R, Jones K, Kang HM, Kaplan R, Kardia S, Kaufman L, Kelly S, Kenny E, Kessler M, Khan A, Kinney G, Konkle B, Kooperberg C, Kramer H, Krauter S, Lange C, Lange E, Lange L, Laurie C, Laurie C, LeBoff M, Lee SS, Lee WJ, LeFaive J, Levine D, Levy D, Lewis J, Li Y, Lin H, Lin KH, Liu S, Liu Y, Loos R, Lubitz S, Lunetta K, Luo J, Mahaney M, Make B, Manson J, Margolin L, Martin L, Mathai S, Mathias R, McArdle P, McDonald ML, McFarland S, McGarvey S, Mei H, Meyers DA, Mikulla J, Min N, Minear M, Minster RL, Montasser ME, Musani S, Mwasongwe S, Mychaleckyj JC, Nadkarni G, Naik R, Nekhai S, Nickerson D, North K, O'Connell J, O'Connor T, Ochs-Balcom H, Pankow J, Papanicolaou G, Parker M, Parsa A, Penchev S, Peralta JM, Perez M, Perry J, Peters U, Peyser P, Phillips L, Phillips S, Pollin T, Becker JP, Boorgula MP, Preuss M, Prokopenko D, Psaty B, Qasba P, Qiao D, Qin Z, Rafaels N, Raffield L, Rao DC, Rasmussen-Torvik L, Ratan A, Redline S, Reed R, Regan E, Reiner A, Rice K, Roden D, Roselli C, Ruczinski I, Russell P, Ruuska S, Sakornsakolpat P, Salimi S, Salzberg S, Sandow K, Sankaran V, Scheller C, Schmidt E, Schwander K, Schwartz D, Sciurba F, Seidman C, Sheehan V, Shetty A, Shetty A, Sheu WH, Shoemaker MB, Silver B, Silverman E, Smith J, Smith J, Smith N, Smith T, Smoller S, Snively B, Sofer T, Sotoodehnia N, Stilp A, Streeten E, Sung YJ, Sylvia J, Szpiro A, Sztalryd C, Taliun D, Tang H, Taub M, Taylor K, Taylor S, Telen M, Thornton TA, Tinker L, Tirschwell D, Tiwari H, Tracy R, Vaidya D, VandeHaar P, Vrieze S, Walker T, Wallace R, Walts A, Wan E, Wang FF, Watson K, Weeks DE, Weir B, Weiss S, Weng LC, Willer C, Williams K, Williams LK, Wilson C, Wong Q, Xu H, Yanek L, Yang I, Yang R, Zaghloul N, Zhang Y, Zhao SX, Zhao W, Zheng X, Zhi D, Zhou X, Zody M, Zoellner S.

Author information

1
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
2
Yale School of Medicine, New Haven, CT, 06510, USA.
3
Department of Computational Biology & Bioinformatics, Yale University, New Haven, CT, 06510, USA.
4
Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
5
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
6
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
7
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
8
Estonian Genome Center, Tallinn, Estonia.
9
Analytic and Translational Genetics Unit, Boston, MA, 02142, USA.
10
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
11
Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
12
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22904, USA.
13
Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
14
Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, WA, 98195, USA.
15
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
16
Division of Cardiology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute, Los Angeles, CA, 90509, USA.
17
NHLBI Framingham Heart Study, Framingham, MA, 20892, USA.
18
Sections of Preventive medicine and Epidemiology, and cardiovascular medicine, Departments of Medicine and Epidemiology, Boston university Schools of Medicine and Public health, Boston, MA, 02118, USA.
19
Departments of Pediatrics and Medicine, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, 90509, USA.
20
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
21
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
22
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
23
National Institute for Health and Welfare, Helsinki, Finland.
24
Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA, 02139, USA.
25
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
26
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. skathiresan1@mgh.harvard.edu.
27
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. skathiresan1@mgh.harvard.edu.
28
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. skathiresan1@mgh.harvard.edu.
29
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. skathiresan1@mgh.harvard.edu.
30
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. pnatarajan@mgh.harvard.edu.
31
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. pnatarajan@mgh.harvard.edu.
32
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. pnatarajan@mgh.harvard.edu.
33
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. pnatarajan@mgh.harvard.edu.

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.

PMID:
29973585
PMCID:
PMC6031652
DOI:
10.1038/s41467-018-04668-w
[Indexed for MEDLINE]
Free PMC Article

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