{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:48:48Z","timestamp":1791791328017,"version":"4.3.4"},"reference-count":46,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. 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Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid, and ceramide metabolism have been proposed as contributors to PD, highlighting the need for genetic analyses across these pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The aim was to evaluate the contribution of rare variants across lysosomal genes to PD risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed rare variants (minor allele frequency\u2009\u22640.01) across 36 lysosomal genes in 8267 individuals with PD and 68,208 controls, including 793 early\u2010onset PD (\u226450\u2009years) cases. Targeted sequencing was performed in four cohorts at McGill University (3456 cases and 2664 controls) and combined with whole\u2010genome sequencing data from the United Kingdom (UK) Biobank (2848 cases, 62,451 controls) and the Accelerating Medicines Partnership\u2010PD cohort (1963 cases, 3093 controls). Associations were tested using Sequence Kernel Association Test\u2010Optimal across variant classes (rare variants, nonsynonymous, loss\u2010of\u2010function, and predicted damaging variants with combined annotation\u2010dependent depletion score &gt;20), followed by meta\u2010analysis across cohorts. Domain\u2010level analyses were performed for variants located within protein domains. False discovery rate (FDR) correction was applied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Meta\u2010analysis identified a significant association between rare variants in\n                      <jats:italic>ST3GAL3<\/jats:italic>\n                      and Parkinson's disease (Pfdr\u2009=\u20090.04). Domain\u2010based analyses showed enrichment of nonsynonymous variants within the \u03b2\u2010acetyl\u2010hexosaminidase\u2013like domain of\n                      <jats:italic>HEXA<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20098.0\u2009\u00d7\u200910\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), although this signal did not survive correction (Pfdr\u2009= 0.154). In early\u2010onset PD, domain\u2010based analyses identified significant associations in\n                      <jats:italic>NAGLU<\/jats:italic>\n                      (Pfdr\u2009= 7.3\u2009\u00d7\u200910\n                      <jats:sup>\u22126<\/jats:sup>\n                      ) and\n                      <jats:italic>ST3GAL5<\/jats:italic>\n                      (Pfdr\u2009=\u20090.03).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to PD susceptibility beyond\n                      <jats:italic>GBA1<\/jats:italic>\n                      , highlighting pathways for future replication and investigation. \u00a9 2026 The Author(s).\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70391","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:04:41Z","timestamp":1781154281000},"page":"2349-2356","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rare\u2010Variant Burden across Lysosomal Genes Implicates Sialylation and Ganglioside Metabolism in Parkinson's Disease"],"prefix":"10.1002","volume":"41","author":[{"given":"Konstantin","family":"Senkevich","sequence":"first","affiliation":[{"name":"The Neuro (Montreal Neurological Institute\u2010Hospital), McGill University  Montreal Quebec Canada"},{"name":"Department of Neurology and Neurosurgery McGill University  Montr\u00e9al Quebec 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