{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:24:14Z","timestamp":1791815054551,"version":"4.3.4"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T00:00:00Z","timestamp":1668211200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015569","name":"Canadian Consortium on Neurodegeneration in Aging","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015569","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010785","name":"Canada First Research Excellence Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010785","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013301","name":"Parkinson\u2019s Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013301","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K02NS080915"],"award-info":[{"award-number":["K02NS080915"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UL1 TR000040"],"award-info":[{"award-number":["UL1 TR000040"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001405","name":"Brookdale Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001405","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The association between glucocerebrosidase, encoded by GBA, and Parkinson\u2019s disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism.<\/jats:p>\n               <jats:p>We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson\u2019s Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity.<\/jats:p>\n               <jats:p>The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 \u00d7 10\u221295). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR\u2013Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity.<\/jats:p>\n               <jats:p>Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied.<\/jats:p>","DOI":"10.1093\/brain\/awac413","type":"journal-article","created":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T10:19:07Z","timestamp":1668248347000},"page":"1859-1872","source":"Crossref","is-referenced-by-count":42,"title":["<i>GALC<\/i> variants affect galactosylceramidase enzymatic activity and risk of Parkinson\u2019s disease"],"prefix":"10.1093","volume":"146","author":[{"given":"Konstantin","family":"Senkevich","sequence":"first","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia E","family":"Zorca","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , Canada"},{"name":"Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University , Montreal H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliza","family":"Dworkind","sequence":"additional","affiliation":[{"name":"Department of Physiology, McGill University , Montr\u00e9al H3A 1A1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uladzislau","family":"Rudakou","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , Canada"},{"name":"Department of Human Genetics, McGill University , Montr\u00e9al H3A 1A1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Somerville","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Human Genetics, McGill University , Montr\u00e9al H3A 1A1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Yu","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Human Genetics, McGill University , Montr\u00e9al H3A 1A1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Ermolaev","sequence":"additional","affiliation":[{"name":"Center of Molecular Biotechnology, Russian State Agrarian University-Moscow Timiryazev Agricultural Academy , Moscow 127550 , Russia"},{"name":"\u0203Research Department, Bioinformatics Institute , Saint-Petersburg 194100 , Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Nikanorova","sequence":"additional","affiliation":[{"name":"\u0203Research Department, Bioinformatics Institute , Saint-Petersburg 194100 , Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamil","family":"Ahmad","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A","family":"Ruskey","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , 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Neurology, College of Physicians and Surgeons, Columbia University Medical Center , New York, NY 10032-3784 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oury","family":"Monchi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , Canada"},{"name":"Department of Clinical Neurosciences and Department of Radiology, University of Calgary , Calgary T2N 1N4 , Canada"},{"name":"Hotchkiss Brain Institute, Cumming School of Medicine , Calgary T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0683-6506","authenticated-orcid":false,"given":"Yves","family":"Dauvilliers","sequence":"additional","affiliation":[{"name":"\u0203National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061 , 34090 Montpellier , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Dupr\u00e9","sequence":"additional","affiliation":[{"name":"Neuroscience Axis, CHU de Qu\u00e9bec\u2014Universit\u00e9 Laval , Quebec City G1V 4G2 , Canada"},{"name":"Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval , Qu\u00e9bec G1V 0A6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior","family":"Greenbaum","sequence":"additional","affiliation":[{"name":"\u0203The Danek Gertner Institute of Human Genetics, Sheba Medical Center , Tel Hashomer 52621 , Israel"},{"name":"The Joseph Sagol Neuroscience Center, Sheba Medical Center , Tel Hashomer 52621 , Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Hassin-Baer","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 , Israel"},{"name":"Department of Neurology, The Movement Disorders Institute, Sheba Medical Center , Tel Hashomer 52621 , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis P","family":"Grenn","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, MD 20814 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1484-5405","authenticated-orcid":false,"given":"Ming Sum Ruby","family":"Chiang","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Therapeutic Area, Sanofi , Framingham, MA 01701 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S Pablo","family":"Sardi","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Therapeutic Area, Sanofi , Framingham, MA 01701 , 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Columbia University Medical Center , New York, NY 10032-3784 , USA"},{"name":"Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Medical Center , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0332-234X","authenticated-orcid":false,"given":"Ziv","family":"Gan-Or","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University , Montreal H3A 2B4 , Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University , Montr\u00e9al H3A 2B4 , Canada"},{"name":"Department of Human Genetics, McGill University , Montr\u00e9al H3A 1A1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"2023050200151110200_awac413-B1","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S1474-4422(19)30320-5","article-title":"Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: A meta-analysis of genome-wide association studies","volume":"18","author":"Nalls","year":"2019","journal-title":"Lancet Neurol"},{"key":"2023050200151110200_awac413-B2","doi-asserted-by":"crossref","first-page":"R102","DOI":"10.1093\/hmg\/ddv259","article-title":"Non-coding genetic variants in human disease","volume":"24","author":"Zhang","year":"2015","journal-title":"Human Mol Genet"},{"key":"2023050200151110200_awac413-B3","doi-asserted-by":"crossref","first-page":"190221","DOI":"10.1098\/rsob.190221","article-title":"A practical view of fine-mapping and gene prioritization in the post-genome-wide 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