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

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, Wt Longstreth, M. Arfan IkramLenore 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, Catherine 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

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Objective: 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.
Methods: 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.
Results: 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).
Interpretation: 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.
Original languageEnglish
JournalAnnals of Neurology
Early online date20 Dec 2016
Publication statusE-pub ahead of print - 20 Dec 2016


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