HMGCR genetic variability in Parkinson's disease in a Spanish cohort: associations with lipid metabolism and early onset.

Lipid metabolism has emerged as a key factor in the pathophysiology of Parkinson's disease (PD). While 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis, has been implicated in neurodegenerative disorders, such as Alzheimer disease, its role in PD remains unexplored. Given the shared pathological features between these neurodegenerative disorders (such as lysosomal dysfunction and lipid dysregulation) we hypothesized that HMGCR genetic variability could influence PD susceptibility and/or phenotypic expression, particularly in early-onset cases (EOPD). Therefore, we performed targeted sequencing of HMGCR in 1162 Spanish PD patients and analyzed associations with PD risk or age at onset. Replication was attempted in 436 PD cases from Parkinson's Progression Markers Initiative (PPMI). We identified 21 HMGCR variants, including a likely pathogenic variant affecting the splice site of exon 4 (c.278-1G > A) in a patient with early-onset PD (EOPD), rapid progression, and severe dyslipidemia. The rs5908 variant was significantly associated with EOPD in our cohort (OR = 2.22, p = 0.025). Further analysis revealed rs5908 is in linkage disequilibrium with rs115169875, an intronic variant with putative regulatory impact. Our findings nominate HMGCR as a candidate gene for PD development, particularly in early-onset cases. The metabolic profile of the c.278-1G > A carrier parallels GBA-associated PD, suggesting convergent lipid-lysosomal pathways in neurodegeneration. While cohort differences highlight population-specific genetic effects, these findings underscore the importance of lipid pathways in PD and the need to explore HMGCR's role in PD subtypes with metabolic comorbidity.