Objective: To determine whether there is a relationship between genetic risk for Parkinson’s disease (PD) and brain structure in healthy adults.

Background: PD pathology begins many years before clinical diagnosis. Improved characterisation of the earliest phases of PD will be critical for the development of interventions that delay or prevent clinical disease. Established PD is associated with reduced brain volume in a range of cortical and subcortical brain regions; however, structural neuroanatomical change in ‘at-risk’ groups at the population level has not been clearly defined.

Method: We derived polygenic risk scores for PD using external weights from the largest PD case-control GWAS summary statistics (excluding UK Biobank participants). We applied these scores to individual-level genotype data in 488,377 UK Biobank (UKB) participants. We selected the optimal score based on discriminative performance in a large subset of UKB participants without brain imaging data.  We then examined the structural brain correlates of these optimised PD-PRS scores in 27,496 healthy UKB participants (median age 64 years at time of scan, IQR 12; 52% male) who did not have a diagnosis of PD or other neurodegenerative disease at the date of brain scan or 3 subsequent years. We performed voxel-based morphometry (VBM) of segmented grey and white matter T1-weighted magnetic resonance images (MRI) to examine the association between PD-PRS and brain volume after family-wise error (FWE) correction (α = 0.05) for multiple voxelwise comparisons over the whole brain. Age at the time of MRI scan, genetic sex, and total intracranial volume were used as covariates in a multiple regression model.

Results: Higher genetic risk of PD (as quantified by the PD-PRS) was associated with reduced grey matter volume in bilateral substantia nigra and regions of the cerebellum and left thalamus (p_FWE<0.05). A higher PD-PRS was also associated with a more extensive pattern of decreased white matter volume in bilateral midbrain, pons, medulla, and the deep white matter of both cerebral hemispheres (p_FWE<0.001).

Conclusion: In healthy adults without PD or other neurodegenerative disorders, genetic liability to PD was associated with reduced brain volume in an extensive network of subcortical brain regions. Structural brain markers warrant further evaluation as potential outcome measures in PD prevention trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuroanatomical-signatures-of-genetic-risk-for-parkinsons-disease-in-healthy-adults/