Speaker
Description
Objectives
Genetic risk factors of Parkinson's disease (PD) may influence disease susceptibility through various mechanisms throughout the lifespan. However, how different mechanisms contribute to PD development remains unclear. Here we aimed to investigate relationships between brain structure and PD and distinguish between neurodevelopmental and later-life mechanisms underlying genetic PD risk.
Methods
We performed two-sample Mendelian randomization (MR) to assess potentially causal relationships between brain morphometry and PD in the UK Biobank. We then divided PD risk genes into those involved in mitochondrial, lysosomal, and autophagy functions and compared their developmental expression trajectories to all other PD risk genes using the BrainSpan dataset and performed gene-set analyses using multimarker analysis of genomic annotation (MAGMA) to characterize the underlying biological processes of remaining PD risk variants.
Results
MR revealed potentially causal positive associations between larger cortical surface area and subcortical volumes and increased PD risk. Additionally, mitochondrial, lysosomal, and autophagy pathway genes showed lower fetal expression which increased after birth, while other genes maintained stable expression throughout development. Gene-set analysis further revealed that while pathway-specific variants were enriched for mechanisms such as oxidative stress responses, the remaining variants were enriched for neurodevelopmental processes including neural progenitor cell division, microtubule organization, and synaptic development.
Conclusions
Our findings demonstrate that genetic predisposition toward larger brain structures may causally increase susceptibility to PD. Expression patterns suggest PD genetic risk operates through distinct mechanisms whereby some genetic variants increase PD risk by influencing early neurodevelopmental processes determining brain structure, while others contribute through later-life cellular dysfunctions. These results provide novel insights into how genetic risk factors shape PD vulnerability across the lifespan, implicating both developmental brain architecture and adult cellular maintenance in disease susceptibility.
