Neuroanatomical correlates of polygenic risk for Parkinson’s Disease

Abstract

AbstractParkinson ‘s Disease (PD) is heritable, however how genetic risk confers vulnerability remains mostly unknown. Here we use genetic and neuroimaging measures from 20,000 healthy adults from the UK Biobank to show that PD polygenic risk score (PRS) is associated with cortical thinning in a pattern that resembles cortical atrophy seen in PD. Conversely, PD PRS is associated with a global increase in cortical surface area. We also show that the genetically determined cortical thinning profile overlaps with the expression of genes associated with synaptic signaling, is dependent on anatomical connectivity and on regional expression of the most significant PD risk genes. Despite identical PRS distributions in males and females, only males show the associated brain features, possibly explaining the sex disparity in PD. We discuss potential mechanisms linking genetic risk to cortical thickness and surface area, and suggest that the divergent effects may reflect separate routes of genetic vulnerability.