title: Genetic variation at 16q24.2 is associated with small vessel stroke.
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 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
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authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany.
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authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
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authors.affiliation: Institute of Cardiovascular Research Royal Holloway University of London (ICR2UL), London, United Kingdom.
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authors.affiliation: Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Boston, MA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.
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authors.affiliation: deCODE genetics/AMGEN, Reykjavik, Iceland.
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authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
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authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
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authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
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authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
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authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
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authors.initials: PI
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authors.affiliation: Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Boston, MA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.|University of Cincinnati College of Medicine, Cincinnati, OH.
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059345:Cerebral Small Vessel Diseases / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke / Q000235:genetics*; D059409:Stroke, Lacunar / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*