Abstract
BACKGROUND: Contralateral brain structures represent a unique, within-patient reference element for disease, and asymmetries can provide a personalized measure of the accumulation of past disease processes. Neuroanatomical shape asymmetries have recently been associated with the progression of Alzheimer's disease (AD), but the biological basis of asymmetric brain changes in AD remains unknown. METHODS: We investigated genetic influences on brain asymmetry by identifying associations between magnetic resonance imaging-derived measures of asymmetry and candidate single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for AD diagnosis and for brain subcortical volumes. For analyzing longitudinal neuroimaging data (1241 individuals, 6395 scans), we used a mixed effects model with interaction between genotype and diagnosis. RESULTS: Significant associations between asymmetry of the amygdala, hippocampus, and putamen and SNPs in the genes BIN1, CD2AP, ZCWPW1, ABCA7, TNKS, and DLG2 were found. CONCLUSIONS: The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with AD pathology. For AD candidate SNPs, we extend previous work to show that their effects on subcortical brain structures are asymmetric. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker.