Genetic variation at 16q24.2 is associated with small vessel stroke.
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Authors
Malik, Rainer
Nalls, Mike A
Cotlarciuc, Ioana
Radmanesh, Farid
Thorleifsson, Gudmar
Hanscombe, Ken B
Langefeld, Carl
Saleheen, Danish
Rost, Natalia S
Yet, Idil
Spector, Tim D
Bell, Jordana T
Hannon, Eilis
Mill, Jonathan
Chauhan, Ganesh
Debette, Stephanie
Bis, Joshua C
Longstreth, WT
Ikram, M Arfan
Launer, Lenore J
Seshadri, Sudha
METASTROKE, UK Young Lacunar DNA Study NINDS Stroke Genetics Network Neurology Working Group of the CHARGE Consortium
Hamilton-Bruce, Monica Anne
Jimenez-Conde, Jordi
Cole, John W
Schmidt, Reinhold
Słowik, Agnieszka
Lemmens, Robin
Lindgren, Arne
Melander, Olle
Grewal, Raji P
Sacco, Ralph L
Rundek, Tatjana
Rexrode, Kathryn
Arnett, Donna K
Johnson, Julie A
Benavente, Oscar R
Wasssertheil-Smoller, Sylvia
Lee, Jin-Moo
Pulit, Sara L
Wong, Quenna
Rich, Stephen S
de, Bakker Paul IW
McArdle, Patrick F
Woo, Daniel
Anderson, Christopher D
Xu, Huichun
Heitsch, Laura
Fornage, Myriam
Jern, Christina
Stefansson, Kari
Thorsteinsdottir, Unnur
Gretarsdottir, Solveig
Lewis, Cathryn M
Sharma, Pankaj
Sudlow, Cathie LM
Rothwell, Peter M
Boncoraglio, Giorgio B
Thijs, Vincent
Levi, Chris
Meschia, James F
Rosand, Jonathan
Kittner, Steven J
Mitchell, Braxton D
Dichgans, Martin
Worrall, Bradford B
International, Stroke Genetics Consortium
Publication Date
2017-03Journal Title
Annals of neurology
ISSN
0364-5134
Publisher
Wiley
Volume
81
Pages
383-394
Language
English
Type
Article
This Version
AM
Physical Medium
Print
Metadata
Show full item recordCitation
Traylor, M., Malik, R., Nalls, M. A., Cotlarciuc, I., Radmanesh, F., Thorleifsson, G., Hanscombe, K. B., et al. (2017). Genetic variation at 16q24.2 is associated with small vessel stroke.. Annals of neurology, 81 383-394. https://doi.org/10.1002/ana.24840
Abstract
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 $\textit{ZCCHC14}$ 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 $\textit{ZCCHC14}$ and DNA methylation suggest the locus acts through changes to regulatory elements.
Keywords
METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium, International Stroke Genetics Consortium, Chromosomes, Human, Pair 16, Humans, Zinc Fingers, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Stroke, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Cerebral Small Vessel Diseases, Stroke, Lacunar
Sponsorship
Matthew Traylor is funded by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by NIHR Comprehensive Biomedical Research Unit funding awarded to Cambridge University Hospitals Trust. Cathryn Lewis receives salary support from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Collection of the UK Young Lacunar Stroke DNA Study (DNA Lacunar) was primarily supported by the Wellcome Trust (WT072952) with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA Lacunar samples was supported by a Stroke Association Grant (TSA 2013/01). Robin Lemmens is a senior clinical investigator of FWO Flanders. Martin Dichgans received funding from the DFG (CRC 1123, B3) and a EU Horizon 2020 grant (agreement No 666881 SVDs@target). The TwinsUK study was funded in part by the European Research Council (ERC 250157), and from the TwinsUK resource, which receives support from the Wellcome Trust and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The SiGN study was funded by a cooperative agreement grant from the US National Institute of Neurological Disorders and Stroke, National Institutes of Health (U01 NS069208).
Funder references
Stroke Association (TSA 2013/01)
Identifiers
External DOI: https://doi.org/10.1002/ana.24840
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262766
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International