We analyzed the degree of genetic control over intersubject variability in the microstructure of cerebral white matter (WM) using diffusion tensor imaging (DTI). We performed heritability, genetic correlation and quantitative trait loci (QTL) analyses for the whole-brain and 10 major cerebral WM tracts. Average measurements for fractional anisotropy (FA), radial (L( perpendicular)) and axial (L( vertical line)) diffusivities served as quantitative traits. These analyses were done in 467 healthy individuals (182 males/285 females; average age 47.9+/-13.5 years; age range: 19-85 years), recruited from randomly-ascertained pedigrees of extended families. Significant heritability was observed for FA (h(2)=0.52+/-0.11; p=10(-7)) and L( perpendicular) (h(2)=0.37+/-0.14; p=0.001), while L( vertical line) measurements were not significantly heritable (h(2)=0.09+/-0.12; p=0.20). Genetic correlation analysis indicated that the FA and L( perpendicular) shared 46% of the genetic variance. Tract-wise analysis revealed a regionally diverse pattern of genetic control, which was unrelated to ontogenic factors, such as tract-wise age-of-peak FA values and rates of age-related change in FA. QTL analysis indicated linkages for whole-brain average FA (LOD=2.36) at the marker D15S816 on chromosome 15q25, and for L( perpendicular) (LOD=2.24) near the marker D3S1754 on the chromosome 3q27. These sites have been reported to have significant co-inheritance with two psychiatric disorders (major depression and obsessive-compulsive disorder) in which patients show characteristic alterations in cerebral WM. Our findings suggest that the microstructure of cerebral white matter is under a strong genetic control and further studies in healthy as well as patients with brain-related illnesses are imperative to identify the genes that may influence cerebral white matter.
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