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However, the reason why individuals with the same\n                      <jats:italic>GBA<\/jats:italic>\n                      variant may or may not develop neurodegeneration and PD is still unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      Therefore, we evaluated the contribution of rare variants in genes responsible for lysosomal storage disorders (LSDs) to\n                      <jats:italic>GBA<\/jats:italic>\n                      \u2010PD risk, comparing the burden of deleterious variants in LSD genes in PD patients versus asymptomatic subjects, all carriers of deleterious variants in\n                      <jats:italic>GBA<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used a custom next\u2010generation sequencing panel, including 50 LSD genes, to screen 305 patients and 207 controls (discovery cohort). Replication and meta\u2010analysis were performed in two replication cohorts of\n                      <jats:italic>GBA<\/jats:italic>\n                      \u2010variant carriers, of 250 patients and 287 controls, for whom exome or genome data were available.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Statistical analysis in the discovery cohort revealed a significantly increased burden of deleterious variants in LSD genes in patients (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0029). Moreover, our analyses evidenced that the two strongest modifiers of\n                      <jats:italic>GBA<\/jats:italic>\n                      penetrance are a second variation in\n                      <jats:italic>GBA<\/jats:italic>\n                      (5.6% vs. 1.4%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.023) and variants in genes causing mucopolysaccharidoses (6.9% vs. 1%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0020). These results were confirmed in the meta\u2010analysis, where we observed pooled odds ratios of 1.42 (95% confidence interval [CI]\u00a0=\u00a01.10\u20131.83,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0063), 4.36 (95% CI\u00a0=\u00a02.02\u20139.45,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.00019), and 1.83 (95% CI\u00a0=\u00a01.04\u20133.22,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.038) for variants in LSD genes,\n                      <jats:italic>GBA<\/jats:italic>\n                      , and mucopolysaccharidosis genes, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The identification of genetic lesions in lysosomal genes increasing PD risk may have important implications in terms of patient stratification for future therapeutic trials. \u00a9 2022 The Authors.\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.28987","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T05:42:30Z","timestamp":1646804550000},"page":"1202-1210","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Role of Lysosomal Gene Variants in Modulating\n                    <scp>\n                      <i>GBA<\/i>\n                    <\/scp>\n                    \u2010Associated Parkinson's Disease Risk"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-7561","authenticated-orcid":false,"given":"Letizia","family":"Straniero","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences Humanitas University  Milan Italy"},{"name":"Humanitas Clinical and Research Center IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-3986","authenticated-orcid":false,"given":"Valeria","family":"Rimoldi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Humanitas University  Milan Italy"},{"name":"Humanitas Clinical and Research Center IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4720-9234","authenticated-orcid":false,"given":"Edoardo","family":"Monfrini","sequence":"additional","affiliation":[{"name":"IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico Neurology Unit  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