Candidate-gene analysis of white matter hyperintensities on neuroimaging The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters

Background White matter hyperintensities (WMH) are a common radiographic fi nding 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 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. interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixed-effects meta-analysis 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, signi fi cance (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 signi fi cantly 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.