Biomarkers.

Area of Science:

• Neurogenetics
• Neuroimaging
• Computational Biology

Background:

• Parkinson's disease (PD) involves genetic risk factors and brain structural changes.
• The precise influence of genetic factors on brain anatomy and PD risk is not fully understood.

Purpose of the Study:

• To investigate the relationship between PD genetic risk and brain structure.
• To differentiate genetic factors influencing neurodevelopment from those contributing to later-life PD vulnerability.

Main Methods:

• Utilized polygenic risk scores (PD-PRS) for PD and linear regression to assess associations with brain structure.
• Employed Mendelian randomization to explore causal links between brain structure and PD.
• Stratified PD risk genes by function (lysosomal, autophagy, mitochondrial) and analyzed pathway-specific neuroanatomical associations.
• Examined developmental gene expression trajectories using RNA-sequencing data.

Main Results:

• PD-PRS showed positive associations with cortical surface area, subcortical volumes, and white matter fractional anisotropy.
• Mendelian randomization suggested a potential causal effect of increased cortical surface area and larger subcortical volumes on PD development.
• No significant associations were found between pathway-specific PD-PRSs (lysosomal, autophagy, mitochondrial) and brain structure.
• Mitochondrial and autophagy pathway genes exhibited lower expression during fetal stages compared to other PD risk genes.

Conclusions:

• PD genetic risk correlates with larger gray matter volume and higher white matter integrity, potentially increasing PD susceptibility.
• Mitochondrial and autophagy pathways may contribute to PD risk via mechanisms independent of early neurodevelopment.
• Findings highlight the complex interplay of developmental and pathway-specific genetic mechanisms in PD pathogenesis.