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Research paper
Candidate-gene analysis of white matter hyperintensities on neuroimaging
  1. Theresa Tran1,2,
  2. Ioana Cotlarciuc1,
  3. Sunaina Yadav2,
  4. Nazeeha Hasan2,
  5. Paul Bentley2,
  6. Christopher Levi3,
  7. Bradford B Worrall4,
  8. James F Meschia5,
  9. Natalia Rost6,
  10. Pankaj Sharma1,2
  1. 1Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL) and Ashford & St Peters NHS Foundation Trust, London, UK
  2. 2Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK
  3. 3Department of Neurology, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
  4. 4Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia, USA
  5. 5Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA
  6. 6Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Professor Pankaj Sharma, Institute of Cardiovascular Research, Royal Holloway University of London, Egham, TW20 OEX, UK; pankaj.sharma{at}


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.


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