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Genetic variation at 16q24.2 is associated with small vessel stroke
Author(s) -
Traylor Matthew,
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.,
Han Eilis,
Mill Jonathan,
Chauhan Ganesh,
Debette Stephanie,
Bis Joshua C.,
Longstreth W.T.,
Ikram M. Arfan,
Launer Lenore J.,
Seshadri Sudha,
HamiltonBruce Monica Anne,
JimenezConde 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.,
WasssertheilSmoller Sylvia,
Lee JinMoo,
Pulit Sara L.,
Wong Quenna,
Rich Stephen S.,
Bakker Paul I.W.,
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 L.M.,
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.,
Markus Hugh S.
Publication year - 2017
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24840
Subject(s) - genome wide association study , odds ratio , stroke (engine) , medicine , single nucleotide polymorphism , intracerebral hemorrhage , population , confidence interval , genetic association , biology , genetics , genotype , subarachnoid hemorrhage , gene , engineering , mechanical engineering , environmental health
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 one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that 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 messenger RNA (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 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10 −9 ). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10 −5 ; N = 3,670), but not intracerebral hemorrhage (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 = 9.4 × 10 −7 ) and DNA methylation at probe cg16596957 in whole blood ( p = 5.3 × 10 −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. Ann Neurol 2017;81:383–394