Stroke genetics informs drug discovery and risk prediction across ancestries

Aniket Mishra; Rainer Malik; Tsuyoshi Hachiya; Tuuli Jurgenson; Shinichi Namba; Daniel C. Posner; Frederick K. Kamanu; Masaru Koido; Quentin Le Grand; Mingyang Shi; Yunye He; Marios K. Georgakis; Ilana Caro; Kristi Krebs; Yi-Ching Liaw; Felix C. Vaura; Kuang Lin; Bendik Slagsvold Winsvold; Vinodh Srinivasasainagendra; Livia Parodi; Hee-Joon Bae; Ganesh Chauhan; Michael R Chong; Liisa Tomppo; Gennady V. Roshchupkin; Naomi Habib; Yon Ho Jee; Jesper Qvist Thomassen; Vida Abedi; Jara Carcel-Marquez; Marianne Nygaard; Hampton L. Leonard; Chaojie Yang; Ekaterina Yonova-Doing; Maria J. Knol; Adam J.. Lewis; Renae L Judy; Tetsuro Ago; Philippe Amouyel; Nicole D. Armstrong; Mark K. Bakker; Traci M. Bartz; David A. Bennett; Joshua C. Bis; Constance Bordes; Sigrid Borte; Anael Cain; Paul M. Ridker; Kelly Cho; Zhengming Chen; Carlos Cruchaga; John W. Cole; Phil L. de Jager; Rafael de Cid; Matthias Endres; Leslie E. Ferreira; Mirjam I. Geerlings; Natalie C. Gasca; Vilmundur Gudnason; Jun Hata; Jing He; Alicia K. Heath; Yuk-Lam Ho; Aki S. Havulinna; Jemma .C Hopewell; Hyacinth I. Hyacinth; Michael Inouye; Mina A. Jacob; Christina E. Jeon; Christina Jern; Masahiro Kamouchi; Keith L. Keene; Takanari Kitazono; Steven J. Kittner; Takahiro Konuma; Amit Kumar; Paul Lacaze; Lenore J. Launer; Keon-Joo Lee; Kaido Lepik; Jiang Li; Liming Li; Ani Manichaikul; Hugh S. Markus; Nicholas A. Marston; Thomas Meitinger; Braxton D. Mitchell; Felipe A. Montellano; Takayuki Morisaki; Thomas H. Mosley; Mike A. Nalls; Borge G. Nordestgaard; Martin J. O'Donnell; Yukinori Okada; N. Charlotte Onland-Moret; Bruce Ovbiagele; Annette Peters; Bruce M Psaty; Stephen S.. Rich; Jonathan Rosand; CHARGE Consortium; Manal Ibrahim

doi:10.1038/s41586-022-05165-3

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Stroke genetics informs drug discovery and risk prediction across ancestries

Journal article

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Peer reviewed

Stroke genetics informs drug discovery and risk prediction across ancestries

Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jurgenson, Shinichi Namba, Daniel C. Posner, Frederick K. Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, …

Nature (London), Vol.611(7934), pp.1-15

2022

DOI: https://doi.org/10.1038/s41586-022-05165-3

PMID: 36180795

Abstract

Life Sciences

Santé publique et épidémiologie

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). 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 analysis(3), 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 approach(4), 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 ancestry(5). 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.

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Title: Stroke genetics informs drug discovery and risk prediction across ancestries
Creators - without role: Aniket Mishra - University of Bordeaux
Rainer Malik - LMU Klinikum
Tsuyoshi Hachiya - Iwate Medical University
Tuuli Jurgenson - University of Tartu
Shinichi Namba - Osaka University
Daniel C. Posner - VA Boston Healthcare System
Frederick K. Kamanu - Thrombolysis in Myocardial Infarction Study Group
Masaru Koido - Tokyo Medical University
Quentin Le Grand - Bordeaux Population Health
Mingyang Shi - The University of Tokyo
Yunye He - The University of Tokyo
Marios K. Georgakis - LMU Klinikum
Ilana Caro - Bordeaux Population Health
Kristi Krebs - University of Tartu
Yi-Ching Liaw - The University of Tokyo
Felix C. Vaura - University of Turku
Kuang Lin - University of Oxford
Bendik Slagsvold Winsvold - Oslo University Hospital
Vinodh Srinivasasainagendra - University of Alabama at Birmingham
Livia Parodi - Massachusetts General Hospital
Hee-Joon Bae - Seoul National University Bundang Hospital
Ganesh Chauhan - Rajendra Institute of Medical Sciences
Michael R Chong - Thrombosis and Atherosclerosis Research Institute
Liisa Tomppo - University of Helsinki
Gennady V. Roshchupkin - Erasmus MC
Naomi Habib - Hebrew University of Jerusalem
Yon Ho Jee - Harvard University
Jesper Qvist Thomassen - Copenhagen University Hospital
Vida Abedi - Geisinger Health System
Jara Carcel-Marquez - Hospital de Sant Pau
Marianne Nygaard - University of Southern Denmark
Hampton L. Leonard - National Institute on Aging
Chaojie Yang - University of Virginia
Ekaterina Yonova-Doing - University of Cambridge
Maria J. Knol - Erasmus MC
Adam J.. Lewis - Vanderbilt University Medical Center
Renae L Judy - University of Pennsylvania
Tetsuro Ago - Kyushu University
Philippe Amouyel - University of Lille
Nicole D. Armstrong - University of Alabama at Birmingham
Mark K. Bakker - University Medical Center Utrecht
Traci M. Bartz - University of Washington
David A. Bennett - Rush University Medical Center
Joshua C. Bis - University of Washington
Constance Bordes - Bordeaux Population Health
Sigrid Borte
Anael Cain - Hebrew University of Jerusalem
Paul M. Ridker - Brigham and Women's Hospital
Kelly Cho - VA Boston Healthcare System
Zhengming Chen - University of Oxford
Carlos Cruchaga - Washington University in St. Louis
John W. Cole - VA Maryland Health Care System
Phil L. de Jager
Rafael de Cid - Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
Matthias Endres - Charité - Universitätsmedizin Berlin
Leslie E. Ferreira - Universidade da Região de Joinville
Mirjam I. Geerlings - University Medical Center Utrecht
Natalie C. Gasca - University of Washington
Vilmundur Gudnason - Icelandic Heart Association
Jun Hata - Kyushu University
Jing He - Vanderbilt University Medical Center
Alicia K. Heath - Imperial College London
Yuk-Lam Ho - VA Boston Healthcare System
Aki S. Havulinna - Finnish Institute for Health and Welfare
Jemma .C Hopewell - University of Oxford
Hyacinth I. Hyacinth - University of Cincinnati Medical Center
Michael Inouye - University of Cambridge
Mina A. Jacob - Radboud University Nijmegen
Christina E. Jeon - Los Angeles County Department of Public Health
Christina Jern - University of Gothenburg
Masahiro Kamouchi - Kyushu University
Keith L. Keene - East Carolina University
Takanari Kitazono - Kyushu University
Steven J. Kittner - University of Maryland, Baltimore
Takahiro Konuma - Osaka University
Amit Kumar - Rajendra Institute of Medical Sciences
Paul Lacaze - Monash University
Lenore J. Launer - Institute on Aging
Keon-Joo Lee - Korea University Medical Center
Kaido Lepik - University of Tartu
Jiang Li - Geisinger Health System
Liming Li - Peking University
Ani Manichaikul - University of Virginia
Hugh S. Markus - University of Cambridge
Nicholas A. Marston - Thrombolysis in Myocardial Infarction Study Group
Thomas Meitinger - Technical University of Munich
Braxton D. Mitchell - University of Maryland, Baltimore
Felipe A. Montellano - University of Würzburg
Takayuki Morisaki - Tokyo Medical University
Thomas H. Mosley - University of Mississippi Medical Center
Mike A. Nalls - National Institute on Aging
Borge G. Nordestgaard
Martin J. O'Donnell - Ollscoil na Gaillimhe – University of Galway
Yukinori Okada - The University of Tokyo
N. Charlotte Onland-Moret - University Medical Center Utrecht
Bruce Ovbiagele - University of California, San Francisco
Annette Peters - German Centre for Cardiovascular Research
Bruce M Psaty - University of Washington
Stephen S.. Rich - University of Virginia
Jonathan Rosand
CHARGE Consortium
Manal Ibrahim - King Abdulaziz University
Publication Details: Nature (London), Vol.611(7934), pp.1-15
Publisher: Nature Publishing Group
Identifiers: 9940481808331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article