Unraveling the Genetic Overlap Between Parkinson's Disease and Schizophrenia Through Genome-wide Association and Cell-Type Specific Transcriptomic Analysis

BackgroundParkinsons disease (PD) and schizophrenia (SZ), while clinically distinct, exhibit overlapping symptoms and neurobiological features. Emerging genetic evidence suggests a shared heritable component between the two disorders. In this study, we aim to identify novel genetic loci common to both PD and SZ and to further investigate the convergent molecular mechanisms that may underlie their shared pathophysiology. MethodsWe analyzed large-scale genome-wide association studies (GWAS) on SZ (55,193 cases, 74,132 controls, 7,659,767 SNPs) and PD (56,306 cases, 1,417,791 controls, 7,200,892 SNPs) using a proxy-phenotype method combined with a Bayesian statistical approach to evaluate overlap in common genetic variants and enhance statistical power for genetic discovery. To elucidate the biological mechanisms underlying newly identified shared genetic loci associated with PD, we leveraged single-cell RNA sequencing (scRNA-seq) data from induced pluripotent stem cell (iPSC)-derived dopaminergic neurons generated by the FOUNDIN-PD consortium (416,216 high-quality single-cells from PD patients). We performed differential gene expression analysis, and gene ontology (GO) enrichment analysis to systematically investigate the functional relevance of these loci in a disease-relevant cellular context. ResultsWe identified thirteen SNPs with concordant effect directions and one SNP with a discordant direction shared between PD and SZ. Of these fourteen SNPs, eleven SNPs were in linkage disequilibrium with previous PD GWAS hits. Further, we identified another three shared novel SNPs (rs2240921, rs11649804, and rs9607782) associated with PD and SZ. In addition, a missense variant in RAI1 (rs11649804) was identified as a shared genetic signal associated with both PD and SZ. Notably, differential expression analysis of RAI1 demonstrated distinct genotype-dependent expression patterns (CC/CA/AA) in both idiopathic PD (iPD) and PD patients carrying GBA1 mutation (GBA1-PD) cohorts. Gene ontology (GO) enrichment analysis further implicated RAI1 in mitochondrial dysfunction-related biological processes, highlighting its potential role in PD pathogenesis. ConclusionIn summary, our study provides novel insights into the shared genetic architecture of PD and SZ, highlighting previously unrecognized loci with potential cross-disorder relevance. The functional characterization of these loci suggests that inflammation and mitochondrial dysfunction may represent convergent biological mechanisms underlying both neurodegenerative and psychiatric pathologies. These findings advance our understanding of the molecular interplay between PD and SZ and open new avenues for exploring shared therapeutic targets.