Genome sequencing unveils a regulatory landscape of platelet reactivity
Journal
Nature Communications
Journal Volume
12
Journal Issue
1
Pages
3626
Date Issued
2021
Author(s)
Chen M.-H.
Rodriguez B.A.T.
Yanek L.R.
Bhan A.
Gaynor B.J.
Ryan K.
Brody J.A.
Zhong X.
Wei Q.
Abe N.
Abecasis G.
Aguet F.
Albert C.
Almasy L.
Alonso A.
Ament S.
Anderson P.
Anugu P.
Applebaum-Bowden D.
Ardlie K.
Arking D.
Arnett D.K.
Ashley-Koch A.
Aslibekyan S.
Assimes T.
Auer P.
Avramopoulos D.
Ayas N.
Balasubramanian A.
Barnard J.
Barnes K.
Barr R.G.
Barron-Casella E.
Barwick L.
Beaty T.
Beck G.
Becker D.
Becker L.
Beer R.
Beitelshees A.
Benjamin E.
Benos T.
Bezerra M.
Bielak L.
Bis J.
Blackwell T.
Blangero J.
Boerwinkle E.
Bowden D.W.
Bowler R.
Brody J.
Broeckel U.
Broome J.
Brown D.
Bunting K.
Burchard E.
Bustamante C.
Buth E.
Cade B.
Cardwell J.
Carey V.
Carrier J.
Carty C.
Casaburi R.
Romero J.P.C.
Casella J.
Castaldi P.
Chaffin M.
Chang C.
Chasman D.
Chavan S.
Chen B.-J.
Chen W.-M.
Chen Y.-D.I.
Cho M.
Choi S.H.
Chung M.
Chung R.-H.
Clish C.
Comhair S.
Conomos M.
Cornell E.
Correa A.
Crandall C.
Crapo J.
Cupples L.A.
Curran J.
Curtis J.
Custer B.
Damcott C.
Darbar D.
David S.
Davis C.
Daya M.
de Andrade M.
Fuentes L.
de Vries P.
DeBaun M.
Deka R.
DeMeo D.
Devine S.
Dinh H.
Doddapaneni H.
Duan Q.
Dugan-Perez S.
Duggirala R.
Durda J.P.
Dutcher S.K.
Eaton C.
Ekunwe L.
Boueiz A.E.
Ellinor P.
Emery L.
Erzurum S.
Farber C.
Farek J.
Fingerlin T.
Flickinger M.
Fornage M.
Franceschini N.
Frazar C.
Fu M.
Fullerton S.M.
Fulton L.
Gabriel S.
Gan W.
Gao S.
Gao Y.
Gass M.
Geiger H.
Gelb B.
Geraci M.
Germer S.
Gerszten R.
Ghosh A.
Gibbs R.
Gignoux C.
Gladwin M.
Glahn D.
Gogarten S.
Gong D.-W.
Goring H.
Graw S.
Gray K.J.
Grine D.
Gross C.
Gu C.C.
Guan Y.
Guo X.
Gupta N.
Haas D.M.
Haessler J.
Hall M.
Han Y.
Hanly P.
Harris D.
Hawley N.L.
He J.
Heavner B.
Heckbert S.
Hernandez R.
Herrington D.
Hersh C.
Hidalgo B.
Hixson J.
Hobbs B.
Hokanson J.
Hong E.
Hoth K.
Hsiung C.A.
Hu J.
Hung Y.-J.
Huston H.
Hwu C.M.
Irvin M.R.
Jackson R.
Jain D.
Jaquish C.
Johnsen J.
Johnson A.
Johnson C.
Johnston R.
Jones K.
Kang H.M.
Kaplan R.
Kardia S.
Kelly S.
Kenny E.
Kessler M.
Khan A.
Khan Z.
Kim W.
Kimoff J.
Kinney G.
Konkle B.
Kooperberg C.
Kramer H.
Lange C.
Lange E.
Lange L.
Laurie C.
Laurie C.
LeBoff M.
Lee J.
Lee S.
Lee W.-J.
LeFaive J.
Levine D.
Levy D.
Lewis J.
Li X.
Li Y.
Lin H.
Lin H.
Lin X.
Liu S.
Liu Y.
Liu Y.
Loos R.J.F.
Lubitz S.
Lunetta K.
Luo J.
Magalang U.
Mahaney M.
Make B.
Manichaikul A.
Manning A.
Manson J.A.
Martin L.
Marton M.
Mathai S.
Mathias R.
May S.
McArdle P.
McDonald M.-L.
McFarland S.
McGarvey S.
McGoldrick D.
McHugh C.
McNeil B.
Mei H.
Meigs J.
Menon V.
Mestroni L.
Metcalf G.
Meyers D.A.
Mignot E.
Mikulla J.
Min N.
Minear M.
Minster R.L.
Mitchell B.D.
Moll M.
Momin Z.
Montasser M.E.
Montgomery C.
Muzny D.
Mychaleckyj J.C.
Nadkarni G.
Naik R.
Naseri T.
Natarajan P.
Nekhai S.
Nelson S.C.
Neltner B.
Nessner C.
Nickerson D.
Nkechinyere O.
North K.
O’Connell J.
O’Connor T.
Ochs-Balcom H.
Okwuonu G.
Pack A.
Paik D.T.
Palmer N.
Pankow J.
Papanicolaou G.
Parker C.
Peloso G.
Peralta J.M.
Perez M.
Perry J.
Peters U.
Peyser P.
Phillips L.S.
Pleiness J.
Pollin T.
Post W.
Becker J.P.
Boorgula M.P.
Preuss M.
Psaty B.
Qasba P.
Qiao D.
Qin Z.
Rafaels N.
Raffield L.
Rajendran M.
Ramachandran V.S.
Rao D.C.
Rasmussen-Torvik L.
Ratan A.
Redline S.
Reed R.
Reeves C.
Regan E.
Reiner A.
Sefuiva Reupena M.
Rice K.
Rich S.
Robillard R.
Robine N.
Roden D.
Roselli C.
Rotter J.
Ruczinski I.
Runnels A.
Russell P.
Ruuska S.
Ryan K.
Sabino E.C.
Saleheen D.
Salimi S.
Salvi S.
Salzberg S.
Sandow K.
Sankaran V.G.
Santibanez J.
Schwander K.
Schwartz D.
Sciurba F.
Seidman C.
Seidman J.
Series F.
Sheehan V.
Sherman S.L.
Shetty A.
Shetty A.
Sheu W.H.-H.
Shoemaker M.B.
Silver B.
Silverman E.
Skomro R.
Smith A.V.
Smith J.
Smith J.
Smith N.
Smith T.
Smoller S.
Snively B.
Snyder M.
Sofer T.
Sotoodehnia N.
Stilp A.M.
Storm G.
Streeten E.
Su J.L.
Sung Y.J.
Sylvia J.
Szpiro A.
Taliun D.
Tang H.
Taub M.
Taylor K.D.
Taylor M.
Taylor S.
Telen M.
Thornton T.A.
Threlkeld M.
Tinker L.
Tirschwell D.
Tishkoff S.
Tiwari H.
Tong C.
Tracy R.
Tsai M.
Vaidya D.
Berg D.V.D.
VandeHaar P.
Vrieze S.
Walker T.
Wallace R.
Walts A.
Wang F.F.
Wang H.
Wang J.
Watson K.
Watt J.
Weeks D.E.
Weir B.
Weiss S.T.
Weng L.-C.
Wessel J.
Willer C.
Williams K.
Williams L.K.
Wilson C.
Wilson J.
Winterkorn L.
Wong Q.
Wu J.
Xu H.
Yanek L.
Yang I.
Yu K.
Zekavat S.M.
Zhang Y.
Zhao S.X.
Zhao W.
Zhu X.
Zody M.
Zoellner S.
Kammers K.
Kanchan K.
Iyer K.
Kowalski M.H.
Pitsillides A.N.
Cupples L.A.
Li B.
Schlaeger T.M.
Shuldiner A.R.
O’Connell J.R.
Ruczinski I.
Mitchell B.D.
Faraday N.
Taub M.A.
Becker L.C.
Lewis J.P.
Mathias R.A.
Johnson A.D.
NHLBI Trans-Omics for Precision (TOPMed) Consortium
Abstract
Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
SDGs
Type
journal article