INVESTIGATING THE GENETICS OF MICROSTRUCTURE OF THE CORPUS CALLOSUM IN THE AGEING BRAIN

Abstract

Abstract:

Age-related atrophy of the corpus callosum (CC) has been associated with cognitive impairment and neurodegenerative disease. To date, there is limited knowledge about the role genetics plays in age-related microstructural changes of CC. The current study sought to examine the role of genetic factors on the microstructure of CC in older individuals. Heritability, genetic correlation analyses and a genome-wide search for SNPs associated with the microstructural integrity of CC were undertaken. Brain imaging scans were collected from two studies of community-dwelling older adults the Older Australian Twins Study (OATS) and the Sydney Memory and Ageing Study (MAS). Diffusion tensor imaging (DTI) measures were estimated for the whole CC as well as for five subregions. Parcellation of the CC was performed using Analyze® software. Heritability analyses for CC DTI measures were undertaken in 284 healthy older twins (66% female; 79 MZ and 63 DZ pairs) from OATS (mean age = 69.82, SD=4.76 years). Heritability and genetic correlation analyses were undertaken using the SOLAR software package. Genome-wide association studies (GWAS) for CC DTI measures were undertaken in MAS and replication performed in OATS. Heritability (h2) analysis for the whole CC, indicated significant h2 for fractional anisotropy (FA) (h2=0.56), mean diffusivity (MD) (h2=0.52), radial diffusivity (RD) (h2=0.49) and axial diffusivity (AD) (h2=0.37). Bivariate genetic correlation analyses were also performed between whole CC DTI measures. Across the DTI measures for the whole CC, MD and RD shared 84% of the common genetic variance, followed by MD- AD (77%), FA - RD (52%), RD- AD (37%) and FA MD (11%). The GWAS did not identify any significant SNPs nor were any of the suggestive SNPs replicated in OATS. In addition, candidate CC DTI SNPs were not associated with CC DTI measures. These findings suggest that the CC white matter microstructure in older adults is generally under moderate genetic control. There was also evidence of shared genetic factors between all four CC DTI measures. This study did not identify any significant SNPs associated with CC DTI measures in the GWAS analysis. This work suggests larger genetic association studies may be required to find CC-DTI associated SNPs.