title: Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden.
abstract: Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ran
authors.affiliation: Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Brodin
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Forsgren
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Westerlund
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Mehrafarin
authors.initials: M
authors.lastname: Ramezani
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gellhaar
authors.affiliation: Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Fengqing
authors.initials: F
authors.lastname: Xiang
authors.affiliation: Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fardell
authors.affiliation: Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Nissbrandt
authors.affiliation: Faculty of Health Sciences, Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.affiliation: Department of Neurology, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences Lund, Neurology, Skane University Hospital, Lund University, Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Puschmann
authors.affiliation: Department of Clinical Sciences Lund, Neurology, Skane University Hospital, Lund University, Lund, Sweden.
authors.forename: Emil
authors.initials: E
authors.lastname: Ygland
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.affiliation: Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Willows
authors.affiliation: Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Johansson
authors.affiliation: Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Sydow
authors.affiliation: Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Wirdefeldt
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.affiliation: Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Solna, Sweden. Electronic address: andrea.carmine.belin@ki.se.
authors.forename: Andrea Carmine
authors.initials: AC
authors.lastname: Belin
mesh_terms: D000368:Aged; D005260:Female; D056726:Genetic Association Studies; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D013548:Sweden
chemical_list: D005962:Glucosylceramidase
keywords: GBA; Gaucher's disease; Genetics; Lysosome; α-Synuclein