Brain size links neurodevelopment to neurodegeneration in Parkinson's disease

Genetic studies have advanced our understanding of Parkinson's disease (PD) pathogenesis, establishing a role for autophagy and lysosomal and mitochondrial dysfunction. However, how genetic risk translates into neuronal vulnerability remains mostly unknown. Using recent genome-wide association studies and neuroimaging data from 25,000 participants (age 44 to 85) in UK Biobank, we show that higher polygenic risk score (PRS) of PD correlates with greater cortical surface area, white matter fractional anisotropy and subcortical volumes. Mendelian randomization supports a causal relation from increased brain size to PD, and cortical regions showing the greatest polygenic expansion in surface area show the greatest atrophy in PD. Consistent with a genetically mediated increase in cortical surface area, we also find that PD polygenic risk score correlates with greater educational attainment, socioeconomic status, and other cognitive traits. Lifespan gene expression and pathway-specific analyses identify mitochondrial, autophagy, lysosomal, and neurodevelopmental pathways as separate mechanisms of genetic vulnerability. We show that a portion of PD susceptibility originates from neurodevelopmental processes that regulate neuronal proliferation. In further support of a neurodevelopmental mechanism of genetic risk, we also observed an association between PD PRS and increased cortical and subcortical size in 9-11 year olds from the ABCD cohort. Genetically-determined increases in brain size confer vulnerability to PD in later life, supporting the existence of shared neurobiological pathways between brain development and neurodegeneration.