A genome-wide search for genetic influences and biological pathways related to the brain’s white matter integrity

A genome-wide search for genetic variants influencing the brain’s white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At approximately 73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 x 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 x 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 x 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA).