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Genetic Variation at 16q24.2 is associated with small vessel stroke.

Journal article
Authors Matthew Traylor
Rainer Malik
Mike A Nalls
Ioana Cotlarciuc
Farid Radmanesh
Gudmar Thorleifsson
Ken B Hanscombe
Carl Langefeld
Danish Saleheen
Natalia S Rost
Idil Yet
Tim D Spector
Jordana T Bell
Eilis Hannon
Jonathan Mill
Ganesh Chauhan
Stephanie Debette
Joshua C Bis
W T Longstreth
M Arfan Ikram
Lenore J Launer
Sudha Seshadri
Jordi Jimenez-Conde
John W Cole
Reinhold Schmidt
Agnieszka Słowik
Robin Lemmens
Arne Lindgren
Olle Melander
Raji P Grewal
Ralph L Sacco
Tatjana Rundek
Kathryn Rexrode
Donna K Arnett
Julie A Johnson
Oscar R Benavente
Sylvia Wasssertheil-Smoller
Jin-Moo Lee
Sara L Pulit
Quenna Wong
Stephen S Rich
Paul I W de Bakker
Patrick F McArdle
Daniel Woo
Christopher D Anderson
Huichun Xu
Laura Heitsch
Myriam Fornage
Christina Jern
Kari Stefansson
Unnur Thorsteinsdottir
Solveig Gretarsdottir
Cathryn M Lewis
Pankaj Sharma
Cathie L M Sudlow
Peter M Rothwell
Giorgio B Boncoraglio
Vincent Thijs
Chris Levi
James F Meschia
Jonathan Rosand
Steven J Kittner
Braxton D Mitchell
Martin Dichgans
Bradford B Worrall
Hugh S Markus
Published in Annals of neurology
Volume 81
Issue 3
Pages 383–394
ISSN 1531-8249
Publication year 2017
Published at Institute of Biomedicine, Department of Pathology
Pages 383–394
Language en
Subject categories Basic Medicine


Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises a quarter of all ischaemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown younger onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger onset SVS population, to identify novel associations with stroke.We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on mRNA expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (OR(95% CI)=1.16(1.10-1.22); p=3.2x10(-9) ). The lead SNP (rs12445022) was also associated with cerebral white matter hyperintensities (OR(95% CI)=1.10(1.05-1.16); p=5.3x10(-5) ; N=3,670), but not intracerebral haemorrhage (OR(95% CI)=0.97(0.84-1.12); p=0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p=9.4x10(-7) ), and DNA methylation at probe cg16596957 in whole blood (p=5.3x10(-6) ).16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. This article is protected by copyright. All rights reserved.

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