Objective: To explore the genetic overlap and identify shared genomic regions between brain morphometry and Parkinson’s disease (PD) risk.

Background: PD is a genetically complex neurodegenerative disorder that is most common among individuals aged 60 and over. Previous studies have identified genetic variants and differences in brain morphometry associated with increased PD risk. Nonetheless, the relationship between PD and brain structure has not been investigated on a genetic level, and the genetic pathways and molecular mechanisms underpinning these associations remain unknown.

Method: We examined the genetic overlap between PD susceptibility and ten brain structures, including total intracranial volume and regional volumes of nine subcortical structures using genome-wide association studies (GWAS) summary statistics. We applied the Pairwise GWAS method to identify specific regions of the genome that are involved in both PD and brain structure aetiology, and further explored the biological pathways and identified genes in these genomic regions of interest using MAGMA.

Results: We observed significant genetic overlap between PD and intracranial volume, and the volumes of the brainstem, pallidum, putamen, caudate, nucleus accumbens, ventral diencephalon, and the thalamus at a whole-genome level. These results indicate that genetic variants increasing PD risk are also associated with larger brain volume in these regions. We identified 148 genomic regions shared between PD and at least one brain region. Gene enrichment analysis in these regions suggests potential links with verbal numerical reasoning, cognitive resilience, production of α-synuclein-specific T-cells, alpha-synuclein phosphorylation and intracytoplasmic aggregation, and higher levels of the glycoprotein nonmetastatic melanoma protein B in the substantia nigra. The regulation of biological pathways such as calcium-dependent processes, the hypothalamic-pituitary-adrenal pathway, cellular membrane dynamics, and autophagic dysfunction, was also linked to a higher PD risk and brain morphometry.

Conclusion: We provide evidence of shared molecular pathways involved in the aetiology of PD risk and brain morphometry. These findings improve our understanding of the aetiology of PD and provide new research avenues to explore the development of new interventions to prevent or slow down disease onset and progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/shared-molecular-genetic-factors-influence-brain-morphometry-and-parkinsons-disease-risk/