Genetic variation in white matter hyperintensity volume in the Framingham study

Background and Purpose - In a previous study of normal elderly male twins, the heritability of quantitative white matter hyperintensity (WMH) volume has been estimated to be high (0.73). We investigated heritability of WMH in a family-based sample of the Framingham Heart Study for sex differences and the impact of age. Methods - Brain magnetic resonance scans were performed on 2012 individuals in the cohort and offspring of the Framingham study. This report was limited to 1330 stroke-free and dementia-free members ( mean age 61.0 years) of the Framingham offspring. Individuals with a history of multiple sclerosis, stroke, dementia, or other neurological condition including traumatic brain injury were excluded from this analysis. WMH volume and total cranial volume (TCV) were quantified using a previously published algorithm. Because of extreme skewing, measures of WMH were log-transformed before analysis. Variance components methods were used to estimate heritability of WMH after adjusting for sex, age, age(2), and TCV. Results - In the full dataset, WMH heritability was 0.55 ( P < 0.0001). Heritability among women was 0.78 ( P < 0.0001) whereas heritability among men was 0.52 ( P < 0.0003). Heritability varied as average age increased, with a peak of 0.68 ( P < 0.0001) in individuals aged 55 or older. Conclusion - Using a family-based study design comprising generally healthy individuals, this study found high heritability of WMH overall and similar heritability for both men and women. In addition, the heritability of WMH remained high among individuals in whom the prevalence of cerebrovascular brain injury was generally low, suggesting that WMH is also likely to be an excellent genetic marker of brain aging.