Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study |
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| Authors: | Ross Owen A Soto-Ortolaza Alexandra I Heckman Michael G Aasly Jan O Abahuni Nadine Annesi Grazia Bacon Justin A Bardien Soraya Bozi Maria Brice Alexis Brighina Laura Van Broeckhoven Christine Carr Jonathan Chartier-Harlin Marie-Christine Dardiotis Efthimios Dickson Dennis W Diehl Nancy N Elbaz Alexis Ferrarese Carlo Ferraris Alessandro Fiske Brian Gibson J Mark Gibson Rachel Hadjigeorgiou Georgios M Hattori Nobutaka Ioannidis John P A Jasinska-Myga Barbara Jeon Beom S Kim Yun Joong Klein Christine Kruger Rejko Kyratzi Elli Lesage Suzanne Lin Chin-Hsien Lynch Timothy Maraganore Demetrius M |
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| Affiliation: | aDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA;bDivision of Biostatistics, Mayo Clinic, Jacksonville, FL, USA;cDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA;dDepartment of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway;eDepartment of Neurology, Goethe University Frankfurt am Main, Frankfurt am Main, Germany;fInstitute of Neurological Sciences, National Research Council, Cosenza, Italy;gDivision of Molecular Biology and Human Genetics, University of Stellenbosch, Cape Town, South Africa;hDivision of Neurology, University of Stellenbosch, Cape Town, South Africa;iGeneral Hospital of Syros, Syros, Greece;jUniversité Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR-S975, Paris, France;kInstitut National de la Santé et de la Recherche Médicale (INSERM), U975, Paris, France;lCentre National de la Recherche Scientifique (CNRS), UMR 7225, Paris, France;mAssistance Publique–Hôpitaux de Paris (AP-HP), Hôpital de la Salpêtrière, Department of Genetics and Cytogenetics, Paris, France;nDepartment of Neuroscience-Section of Neurology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy;oNeurodegenerative Brain Diseases group, Department of Molecular Genetics, Vlaams Instituut voor Biotechnologie, Antwerp, Belgium;pLaboratory of Neurogenetics, Institute Born-Bunge and University of Antwerp, Antwerp, Belgium;qUniversity Lille Nord de France, Centre de Recherche Jean-Pierre Aubert, Lille, France;rINSERM, U837, Lille, France;sDepartment of Neurology, Laboratory of Neurogenetics, Faculty of Medicine, University of Thessaly, Larissa, Greece;tInstitute of Biomedical Research and Technology, Centre for Research and Technology Thessaly (CERETETH), Larissa, Greece;uINSERM, U708, Neuroepidemiology, Paris, France;vUniversité Pierre et Marie Curie-Paris 6, UMR S708, Neuroepidemiology, Paris, France;wIRCCS Casa Sollievo della Sofferenza Hospital, Mendel Laboratory, San Giovanni Rotondo, Italy;xMichael J Fox Foundation for Parkinson's Research, New York, NY, USA;yDepartment of Neurology, Royal Victoria Hospital, Belfast, UK;zResearch and Development, GlaxoSmithKline Pharmaceuticals, Harlow, UK;aaDepartment of Neurology, Juntendo University School of Medicine, Tokyo, Japan;abClinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece;acStanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA;adDepartment of Neurology, Medical University of Silesia, Katowice, Poland;aeDepartment of Neurology, Seoul National University Hospital, Seoul, South Korea;afDepartment of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea;agIlsong Institute of Life Science and Department of Neurology, Hallym University, Anyang, South Korea;ahSection of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Lübeck, Germany;aiDepartment for Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and German Centre for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany;ajDivisions of Basic Neurosciences and Cell Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece;akDepartment of Neurology, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan;alDublin Neurological Institute at the Mater Misericordiae University Hospital, and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, UK;amDepartment of Neurology, Mayo Clinic, Rochester, MN, USA;anEskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, QLD, Australia;aoCentre Hospitalier Regional Universitaire de Lille, Lille, France;apDepartment of Clinical Science, Section of Geriatric Psychiatry, Lund University, Lund, Sweden;aqDepartment of Neurology, Skåne University Hospital, Lund, Sweden;arDepartment of Medical Sciences, Institute of Neurology, University Magna Graecia, and Neuroimaging Research Unit, National Research Council, Catanzaro, Italy;asUniversity of Queensland, Centre for Clinical Research, Royal Brisbane Hospital, Brisbane, QLD, Australia;atDepartment of Neurology, Yonsei University College of Medicine, Seoul, South Korea;auDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada;avUniversity Hospital and Norges Teknisk-Naturvitenskapelige Universitet, Trondheim, Norway;awDepartment of Clinical Neuroscience and Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;axDepartment of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan |
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| Abstract: | BackgroundBackground The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.MethodsLRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab–Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.Findings121 exonic LRRK2 variants were assessed in 15?540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab–Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15–1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35–3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab–Berber series (combined odds ratio 0·82, 0·72–0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20–2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36–1·07; p=0·087). In the Arab–Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33–15·09; p=0·012).InterpretationThe results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.FundingMichael J Fox Foundation and National Institutes of Health. |
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