Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries
Journal
Nature Communications
Journal Volume
9
Journal Issue
1
Pages
2606
Date Issued
2018
Author(s)
Zekavat S.M.
Ruotsalainen S.
Handsaker R.E.
Alver M.
Bloom J.
Poterba T.
Seed C.
Ernst J.
Chaffin M.
Engreitz J.
Peloso G.M.
Manichaikul A.
Yang C.
Ryan K.A.
Fu M.
Johnson W.C.
Tsai M.
Budoff M.
Ramachandran V.S.
Cupples L.A.
Rotter J.I.
Rich S.S.
Post W.
Mitchell B.D.
Correa A.
Metspalu A.
Wilson J.G.
Salomaa V.
Kellis M.
Daly M.J.
Neale B.M.
McCarroll S.
Surakka I.
Esko T.
Ganna A.
Ripatti S.
Kathiresan S.
Natarajan P.
Abe N.
Abecasis G.
Albert C.
Allred N.P.
Almasy L.
Alonso A.
Ament S.
Anderson P.
Anugu P.
Applebaum-Bowden D.
Arking D.
Arnett D.K.
Ashley-Koch A.
Aslibekyan S.
Assimes T.
Auer P.
Avramopoulos D.
Barnard J.
Barnes K.
Barr R.G.
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 B.-J.
Chen W.-M.
Chen Y.-D.I.
Cho M.
Choi S.H.
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.D.
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 S.M.
Fulton L.
Gabriel S.
Gan W.
Gao Y.
Gass M.
Gelb B.
Geng X.
Germer S.
Gignoux C.
Gladwin M.
Glahn D.
Gogarten S.
Gong D.-W.
Goring H.
Gu C.C.
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 C.
Huston H.
Hwu C.M.
Irvin M.R.
Jackson R.
Jain D.
Jaquish C.
Jhun M.A.
Johnsen J.
Johnson A.
Johnston R.
Jones K.
Kang H.M.
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 S.S.
Lee W.-J.
Lefaive J.
Levine D.
Levy D.
Lewis J.
Li Y.
Lin H.
Lin K.H.
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 M.-L.
McFarland S.
McGarvey S.
Mei H.
Meyers D.A.
Mikulla J.
Min N.
Minear M.
Minster R.L.
Montasser M.E.
Musani S.
Mwasongwe S.
Mychaleckyj J.C.
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 J.M.
Perez M.
Perry J.
Peters U.
Peyser P.
Phillips L.
Phillips S.
Pollin T.
Becker J.P.
Boorgula M.P.
Preuss M.
Prokopenko D.
Psaty B.
Qasba P.
Qiao D.
Qin Z.
Rafaels N.
Raffield L.
Rao D.C.
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 W.H.-H.
Shoemaker M.B.
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 Y.J.
Sylvia J.
Szpiro A.
Sztalryd C.
Taliun D.
Tang H.
Taub M.
Taylor K.
Taylor S.
Telen M.
Thornton T.A.
Tinker L.
Tirschwell D.
Tiwari H.
Tracy R.
Vaidya D.
Vandehaar P.
Vrieze S.
Walker T.
Wallace R.
Walts A.
Wan E.
Wang F.F.
Watson K.
Weeks D.E.
Weir B.
Weiss S.
Weng L.-C.
Willer C.
Williams K.
Williams L.K.
Wilson C.
Wong Q.
Xu H.
Yanek L.
Yang I.
Yang R.
Zaghloul N.
Zhang Y.
Zhao S.X.
Zhao W.
Zheng X.
Zhi D.
Zhou X.
Zody M.
Zoellner S.
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. ? 2018 The Author(s).
SDGs
Other Subjects
apolipoprotein B; cholesterol; cholesterol ester transfer protein; high density lipoprotein cholesterol; kringle IV 2 protien; lipoprotein A; low density lipoprotein cholesterol; protein; sortilin; unclassified drug; lipoprotein A; low density lipoprotein cholesterol; sortilin; vesicular transport adaptor protein; ancestry; cardiovascular disease; concentration (composition); genetic analysis; genome; plasma; protein; risk factor; African; African American; ancestry group; Article; cohort analysis; copy number variation; coronary artery atherosclerosis; European; expression quantitative trait locus; genetic association; genetic difference; genetic risk; genetic variation; genome analysis; genotype; human; lipoprotein blood level; major clinical study; Mendelian randomization analysis; risk assessment; risk factor; single nucleotide polymorphism; whole genome sequencing; Black person; blood; cardiovascular disease; Caucasian; copy number variation; ethnology; gene expression; genetics; genome-wide association study; human genome; quantitative trait locus; single nucleotide polymorphism; whole genome sequencing; Adaptor Proteins, Vesicular Transport; African Continental Ancestry Group; Cardiovascular Diseases; Cholesterol, LDL; DNA Copy Number Variations; European Continental Ancestry Group; Gene Expression; Genome, Human; Genome-Wide Association Study; Humans; Lipoprotein(a); Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Whole Genome Sequencing
Publisher
Nature Publishing Group
Type
journal article