{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T20:20:58Z","timestamp":1771618858970,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,18]]},"group-title":"Neurology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Lysosomal dysfunction is central to Parkinson\u2019s disease pathogenesis, with\n                  <jats:italic>GBA1<\/jats:italic>\n                  as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinson\u2019s disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency &lt; 0.01) across 36 lysosomal genes (excluding\n                  <jats:italic>GBA1<\/jats:italic>\n                  ) in 8,267 individuals with Parkinson\u2019s disease and 68,208 controls, including a subset of 793 early-onset Parkinson\u2019s disease (\u226450 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3,456 Parkinson\u2019s disease patients and 2,664 controls) and results were combined with whole-genome sequencing data from the UK Biobank (2,848 cases, 62,451 controls), and from the Accelerating Medicines Partnership - Parkinson\u2019s Disease (1,963 cases, 3,093 controls). We analysed the association of rare variants in these genes with Parkinson\u2019s disease using Sequence Kernel Association Test-Optimal (SKAT-O) across variant classes (all rare variants, nonsynonymous, loss-of-function and predicted damaging variants with a Combined Annotation Dependent Depletion (CADD) score &gt;20), with meta-analysis across cohorts. We additionally performed per-domain analyses for variants in gene segments encoding functional domains. False discovery rate correction was applied. Meta-analysis identified a significant association between rare variants in\n                  <jats:italic>ST3GAL3<\/jats:italic>\n                  and Parkinson\u2019s disease (Pfdr=0.04). Several additional lysosomal genes showed nominal associations (P&lt;0.05), including\n                  <jats:italic>HGSNAT, ASAH1, CTSD, HEXA, ST3GAL4<\/jats:italic>\n                  and\n                  <jats:italic>SGPP1<\/jats:italic>\n                  . Domain-based analyses identified a strong enrichment of nonsynonymous variants within the beta-acetyl-hexosaminidase\u2013like domain of HEXA (P = 8.0 \u00d7 10), although this signal did not survive correction for multiple testing (Pfdr=0.154). In early-onset Parkinson\u2019s disease, domain-based analyses revealed significant associations in\n                  <jats:italic>NAGLU<\/jats:italic>\n                  (Pfdr=7.3\u00d710) and\n                  <jats:italic>ST3GAL5<\/jats:italic>\n                  (Pfdr=0.03). Together, these results provide genetic evidence that rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to Parkinson\u2019s disease susceptibility beyond\n                  <jats:italic>GBA1<\/jats:italic>\n                  , highlighting biologically coherent pathways for future replication and functional investigation.\n                <\/jats:p>","DOI":"10.64898\/2026.02.18.26346391","type":"posted-content","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:20:19Z","timestamp":1771460419000},"source":"Crossref","is-referenced-by-count":0,"title":["Rare-variant burden across lysosomal genes implicates sialylation and ganglioside metabolism in Parkinson\u2019s disease"],"prefix":"10.64898","author":[{"given":"Konstantin","family":"Senkevich","sequence":"first","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sitki Cem","family":"Parlar","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cloe","family":"Chantereault","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lang","family":"Liu","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Yu","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uladzislau","family":"Rudakou","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, 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Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Spiegelman","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheryl","family":"Waters","sequence":"additional","affiliation":[{"name":"Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oury","family":"Monchi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Clinical Neurosciences and Department of Radiology, University of Calgary, Calgary, Alberta, Canada"},{"name":"Hotchkiss Brain Institute, Cumming School of Medicine, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves","family":"Dauvilliers","sequence":"additional","affiliation":[{"name":"National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Dupr\u00e9","sequence":"additional","affiliation":[{"name":"Neuroscience Research Program, CHU de Qu\u00e9bec-Universit\u00e9 Laval Research Center, Quebec City, Quebec, Canada"},{"name":"Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval, Qu\u00e9bec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lior","family":"Greenbaum","sequence":"additional","affiliation":[{"name":"The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel"},{"name":"Gray Faculty of Medical & Health Sciences, 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