| Literature DB >> 36180795 |
Aniket Mishra1, Rainer Malik2, Tsuyoshi Hachiya3, Tuuli Jürgenson4,5, Shinichi Namba6, Daniel C Posner7, Frederick K Kamanu8,9, Masaru Koido10,11, Quentin Le Grand1, Mingyang Shi11, Yunye He11, Marios K Georgakis2,12,13, Ilana Caro1, Kristi Krebs4, Yi-Ching Liaw14,15, Felix C Vaura16,17, Kuang Lin18, Bendik Slagsvold Winsvold19,20,21, Vinodh Srinivasasainagendra22, Livia Parodi12,13, Hee-Joon Bae23, Ganesh Chauhan24, Michael R Chong25,26, Liisa Tomppo27, Rufus Akinyemi28,29, Gennady V Roshchupkin30,31, Naomi Habib32, Yon Ho Jee33, Jesper Qvist Thomassen34, Vida Abedi35,36, Jara Cárcel-Márquez37,38, Marianne Nygaard39,40, Hampton L Leonard41,42,43, Chaojie Yang44,45, Ekaterina Yonova-Doing46,47, Maria J Knol30, Adam J Lewis48, Renae L Judy49, Tetsuro Ago50, Philippe Amouyel51,52,53, Nicole D Armstrong54, Mark K Bakker55, Traci M Bartz56,57, David A Bennett58, Joshua C Bis56, Constance Bordes1, Sigrid Børte20,59,60, Anael Cain32, Paul M Ridker61,62, Kelly Cho7, Zhengming Chen18,63, Carlos Cruchaga64,65, John W Cole66,67, Phil L de Jager13,68, Rafael de Cid69, Matthias Endres70,71,72,73, Leslie E Ferreira74, Mirjam I Geerlings75, Natalie C Gasca57, Vilmundur Gudnason76,77, Jun Hata78, Jing He48, Alicia K Heath79, Yuk-Lam Ho7, Aki S Havulinna80,81, Jemma C Hopewell82, Hyacinth I Hyacinth83, Michael Inouye46,84,85,86,87, Mina A Jacob88, Christina E Jeon89, Christina Jern90,91, Masahiro Kamouchi92, Keith L Keene93, Takanari Kitazono50, Steven J Kittner67,94, Takahiro Konuma6, Amit Kumar24, Paul Lacaze95, Lenore J Launer96, Keon-Joo Lee97, Kaido Lepik4,98,99,100, Jiang Li35, Liming Li101, Ani Manichaikul44, Hugh S Markus102, Nicholas A Marston8,9, Thomas Meitinger103,104, Braxton D Mitchell105,106, Felipe A Montellano107,108, Takayuki Morisaki10, Thomas H Mosley109, Mike A Nalls41,42,43, Børge G Nordestgaard110,111, Martin J O'Donnell112, Yukinori Okada6,113,114,115,116,117, N Charlotte Onland-Moret75, Bruce Ovbiagele118, Annette Peters119,120,121, Bruce M Psaty56,122,123, Stephen S Rich44, Jonathan Rosand12,13,124, Marc S Sabatine8,9, Ralph L Sacco125,126, Danish Saleheen127, Else Charlotte Sandset128,129, Veikko Salomaa80, Muralidharan Sargurupremraj130, Makoto Sasaki3, Claudia L Satizabal130,131, Carsten O Schmidt132, Atsushi Shimizu3, Nicholas L Smith122,133,134, Kelly L Sloane135, Yoichi Sutoh3, Yan V Sun136,137, Kozo Tanno3, Steffen Tiedt2, Turgut Tatlisumak138, Nuria P Torres-Aguila37, Hemant K Tiwari22, David-Alexandre Trégouët1, Stella Trompet139,140, Anil Man Tuladhar88, Anne Tybjærg-Hansen34,111, Marion van Vugt141, Riina Vibo142, Shefali S Verma143, Kerri L Wiggins56, Patrik Wennberg144, Daniel Woo83, Peter W F Wilson136,145, Huichun Xu105, Qiong Yang131,146, Kyungheon Yoon147, Iona Y Millwood18,63, Christian Gieger148, Toshiharu Ninomiya78, Hans J Grabe149,150, J Wouter Jukema140,151,152, Ina L Rissanen75, Daniel Strbian27, Young Jin Kim147, Pei-Hsin Chen15, Ernst Mayerhofer12,13, Joanna M M Howson46,47, Marguerite R Irvin54, Hieab Adams153,154, Sylvia Wassertheil-Smoller155, Kaare Christensen39,40,156, Mohammad A Ikram30, Tatjana Rundek125,126, Bradford B Worrall157,158, G Mark Lathrop159, Moeen Riaz95, Eleanor M Simonsick160, Janika Kõrv142, Paulo H C França74, Ramin Zand161,162, Kameshwar Prasad24, Ruth Frikke-Schmidt34,111, Frank-Erik de Leeuw88, Thomas Liman71,75,163, Karl Georg Haeusler108, Ynte M Ruigrok55, Peter Ulrich Heuschmann107,164,165, W T Longstreth122,166, Keum Ji Jung18,167, Lisa Bastarache48, Guillaume Paré25,26,168,169, Scott M Damrauer170,171, Daniel I Chasman61,62, Jerome I Rotter172, Christopher D Anderson12,13,124,173, John-Anker Zwart19,20,59, Teemu J Niiranen16,17,174, Myriam Fornage175,176, Yung-Po Liaw15,177, Sudha Seshadri130,131,178, Israel Fernández-Cadenas37, Robin G Walters18,63, Christian T Ruff8,9, Mayowa O Owolabi28,179, Jennifer E Huffman7, Lili Milani4, Yoichiro Kamatani11, Martin Dichgans180,181,182, Stephanie Debette183,184.
Abstract
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.Entities:
Year: 2022 PMID： 36180795 PMCID： PMC9524349 DOI： 10.1038/s41586-022-05165-3
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504