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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\n                    <jats:italic>HMGCR<\/jats:italic>\n                    genetic variability could influence PD susceptibility and\/or phenotypic expression, particularly in early-onset cases (EOPD)\n                    <jats:bold>.<\/jats:bold>\n                    Therefore, we performed targeted sequencing of\n                    <jats:italic>HMGCR<\/jats:italic>\n                    in 1162 Spanish PD patients and analyzed associations with PD risk or age at onset. Replication was attempted in 436 PD cases from Parkinson\u2019s Progression Markers Initiative (PPMI). We identified 21\n                    <jats:italic>HMGCR<\/jats:italic>\n                    variants, including a likely pathogenic variant affecting the splice site of exon 4 (c.278-1G\u2009&gt;\u2009A) 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\u2009=\u20092.22, p\u2009=\u20090.025). Further analysis revealed rs5908 is in linkage disequilibrium with rs115169875, an intronic variant with putative regulatory impact. Our findings nominate\n                    <jats:italic>HMGCR<\/jats:italic>\n                    as a candidate gene for PD development, particularly in early-onset cases. The metabolic profile of the c.278-1G\u2009&gt;\u2009A carrier parallels\u00a0\n                    <jats:italic>GBA<\/jats:italic>\n                    -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\u00a0\n                    <jats:italic>HMGCR<\/jats:italic>\n                    \u2019s role in PD subtypes with metabolic comorbidity.\n                  <\/jats:p>","DOI":"10.1007\/s00415-025-13404-6","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T14:14:07Z","timestamp":1759414447000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HMGCR genetic variability in Parkinson\u2019s disease in a Spanish cohort: associations with lipid metabolism and early onset"],"prefix":"10.1007","volume":"272","author":[{"given":"Rafael","family":"D\u00edaz-Belloso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Mart\u00edn-Bornez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Mac\u00edas-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Garc\u00eda-D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bonilla-Toribio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Buiza-Rueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo Pineda","family":"S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mu\u00f1oz-Delgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Ojeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Jes\u00fas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Adarmes-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e1tima","family":"Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Mir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0437-6182","authenticated-orcid":false,"given":"Pilar","family":"G\u00f3mez-Garre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"13404_CR1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12859-020-3340-1","volume":"21","author":"TA Alexander","year":"2020","unstructured":"Alexander TA, Machiela MJ (2020) Ldpop: an interactive online tool to calculate and visualize geographic ld patterns. 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