title: Candidate-gene analysis of white matter hyperintensities on neuroimaging.
abstract: BACKGROUND
  White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR).
  
  
  METHODS
  Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR.
  
  
  RESULTS
  We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixed-effects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(-344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90-3.41; observed OR=1.68; 95% CI, 0.97-2.94). Neither CYP11B2 T(-344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH.
  
  
  CONCLUSIONS
  There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest.
authors.affiliation: Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL) and Ashford & St Peters NHS Foundation Trust, London, UK Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.
authors.forename: Theresa
authors.initials: T
authors.lastname: Tran
authors.affiliation: Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL) and Ashford & St Peters NHS Foundation Trust, London, UK.
authors.forename: Ioana
authors.initials: I
authors.lastname: Cotlarciuc
authors.affiliation: Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.
authors.forename: Sunaina
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.
authors.forename: Nazeeha
authors.initials: N
authors.lastname: Hasan
authors.affiliation: Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Bentley
authors.affiliation: Department of Neurology, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Levi
authors.affiliation: Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rost
authors.affiliation: Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL) and Ashford & St Peters NHS Foundation Trust, London, UK Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D030541:Databases, Genetic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D059906:Neuroimaging; D011110:Polymorphism, Genetic / Q000235:genetics; D065840:Protective Factors; D011859:Radiography; D012307:Risk Factors; D066127:White Matter / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*
chemical_list: D019405:Cytochrome P-450 CYP11B2; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: GENETICS; STROKE
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