Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Nat Genet
Authors
Rainer Malik
Ganesh Chauhan
Matthew Traylor
Muralidharan Sargurupremraj
Yukinori Okada
Aniket Mishra
Loes Rutten-Jacobs
Anne-Katrin Giese
Sander van der Laan
Solveig Gretarsdottir
Christopher Anderson
Michael Chong
Hieab Adams
Tetsuro Ago
Peter Almgren
Philippe Amouyel
Hakan Ay
Traci Bartz
Oscar Benavente
Steve Bevan
Giorgio Boncoraglio
Robert Brown
Adam Butterworth
Caty Carrera
Cara Carty
Daniel Chasman
Wei-Min Chen
John Cole
Adolfo Correa
Ioana Cotlarciuc
Carlos Cruchaga
John Danesh
Paul de Bakker
Anita DeStefano
Marcel Hoed
Qing Duan
Stefan Engelter
Guido Falcone
Rebecca Gottesman
Raji Grewal
Vilmundur Gudnason
Stefan Gustafsson
Jeffrey Haessler
Tamara Harris
Ahamad Hassan
Aki Havulinna
Susan Heckbert
Elizabeth Holliday
George Howard
Fang-Chi Hsu
Hyacinth Hyacinth
M Arfan Ikram
Erik Ingelsson
Marguerite Irvin
Xueqiu Jian
Jordi Jimenez-Conde
Julie Johnson
J Wouter Jukema
Masahiro Kanai
Keith Keene
Brett Kissela
Dawn Kleindorfer
Charles Kooperberg
Michiaki Kubo
Leslie Lange
Carl Langefeld
Claudia Langenberg
Lenore Launer
Jin-Moo Lee
Robin Lemmens
Didier Leys
Cathryn Lewis
Wei-Yu Lin
Arne Lindgren
Erik Lorentzen
Patrik Magnusson
Jane Maguire
Ani Manichaikul
Patrick McArdle
James Meschia
Braxton Mitchell
Thomas Mosley
Michael Nalls
Toshiharu Ninomiya
Martin O'Donnell
Bruce Psaty
Sara Pulit
Kristiina Rannikmae
Alexander Reiner
Kathryn Rexrode
Kenneth Rice
Stephen Rich
Paul Ridker
Natalia Rost
Peter Rothwell
Jerome Rotter
Tatjana Rundek
Ralph Sacco
Saori Sakaue
Michèle Sale
Veikko Salomaa
Bishwa Sapkota
Reinhold Schmidt
Carsten Schmidt
Ulf Schminke
Pankaj Sharma
Agnieszka Slowik
Cathie Sudlow
Christian Tanislav
Turgut Tatlisumak
Kent Taylor
Vincent Thijs
Gudmar Thorleifsson
Unnur Thorsteinsdottir
Steffen Tiedt
Stella Trompet
Christophe Tzourio
Cornelia van Duijn
Matthew Walters
Nicholas Wareham
Sylvia Wassertheil-Smoller
James Wilson
Kerri Wiggins
Qiong Yang
Salim Yusuf
AFGen Consortium
Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
International Genomics of Blood Pressure (iGEN-BP) Consortium
INVENT Consortium
STARNET
Joshua Bis
Tomi Pastinen
Arno Ruusalepp
Eric Schadt
Simon Koplev
Johan Björkegren
Veronica Codoni
Mete Civelek
Nicholas Smith
David Trégouët
Ingrid Christophersen
Carolina Roselli
Steven Lubitz
Patrick Ellinor
E Shyong Tai
Jaspal Kooner
Norihiro Kato
Jiang He
Pim van der Harst
Paul Elliott
John Chambers
Fumihiko Takeuchi
Andrew Johnson
BioBank Japan Cooperative Hospital Group
COMPASS Consortium
EPIC-CVD Consortium
EPIC-InterAct Consortium
International Stroke Genetics Consortium (ISGC)
METASTROKE Consortium
Neurology Working Group of the CHARGE Consortium
NINDS Stroke Genetics Network (SiGN)
UK Young Lacunar DNA Study
MEGASTROKE Consortium
Dharambir Sanghera
Olle Melander
Christina Jern
Daniel Strbian
Israel Fernandez-Cadenas
W Longstreth
Arndt Rolfs
Jun Hata
Daniel Woo
Jonathan Rosand
Guillaume Pare
Jemma Hopewell
Danish Saleheen
Kari Stefansson
Bradford Worrall
Steven Kittner
Sudha Seshadri
Myriam Fornage
Hugh Markus
Joanna Howson
Yoichiro Kamatani
Stéphanie Debette
Martin Dichgans
Keywords
Female
Humans
Male
Genetic Predisposition to Disease
Computational Biology
Risk Factors
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Linkage Disequilibrium
Epigenesis, Genetic
Genetic Loci
Gene Regulatory Networks
Models, Genetic
Databases, Genetic
INDEL Mutation
Stroke
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
4
Pages
524-537
Date Published
2018 04
ISSN
1546-1718
DOI
10.1038/s41588-018-0058-3
PubMed ID
29531354
PubMed Central ID
PMC5968830
Links
Grant list
R01 NS017950 / NS / NINDS NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
MR/P013880/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS087541 / NS / NINDS NIH HHS / United States
Z99 AG999999 / ImNIH / Intramural NIH HHS / United States
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
RG/16/4/32218 / BHF_ / British Heart Foundation / United Kingdom
MR/P02811X/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL138423 / HL / NHLBI NIH HHS / United States
FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom
UL1 TR001881 / TR / NCATS NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 HL088521 / HL / NHLBI NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States

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