Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.
Journal: Neurology
Volume: 99
Issue: 7
Year of Publication: 2022
Affiliated Institutions: From the Centre for Genetic Epidemiology (S.G., A.A.K.S., M.S.), Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany; Department of Neurology (L. Pihlstrom, M.T.), Oslo University Hospital, Norway; Université Paris-Saclay (C.D., P.E.S., O.M., B.P., A.E.), UVSQ, Univ. Paris-Sud, Inserm, Team "Exposome, heredity, cancer and health," CESP, Villejuif, France; Department for Neurodegenerative Diseases (C.S., K.B., T.G., M.S.), Hertie Institute for Clinical Brain Research, University of Tubingen; German Center for Neurodegenerative Diseases (DZNE) (C.S., L.F.B., T.G.), Tübingen; Institute of Human Genetics (M.R.B., P.L.), Helmholtz Zentrum München, Neuherberg, Germany; Luxembourg Centre for Systems Biomedicine (LCSB) (Z.L., P.M., D.B., R.K.), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Molecular Genetics Section (C.E., D.G.H., C.B., A.B.S.,), Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD; Group of Applied Bioinformatics (F.B., M.H., J.K.), University of Tübingen; High Performance and Cloud Computing Group ZDV (F.B., M.H.), University of Tübingen, Germany; Griffith Institute for Drug Discovery (G.D.M.), Griffith University, Don Young Road, Nathan, Queensland, Australia; Department of Neurology (A.Z.), Medical University of Vienna; Department of Neurology (W.P.), Wilhelminenspital, Austria; Department of Clinical and Movement Neurosciences (M.T.), UCL Queen Square Institute of Neurology, University College London, London, UK; Tanz Centre for Research in Neurodegenerative Diseases (E.R, A.L.), University of Toronto; Edmond J. Safra Program in Parkinson's Disease (A.L.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN; Division of Neurology (A.L.), University of Toronto; Krembil Brain Institute (A.L.), Toronto, Ontario, Canada; Centre for Molecular Medicine and Innovative Therapeutics (S.K.), Murdoch University, Murdoch, Australia; Perron Institute for Neurological and Translational Science (S.K.), Nedlands, Western Australia, Australia; Department of Neurology and Neurosurgery (P.T.), University of Tartu; Neurology Clinic, Tartu University Hospital (P.T.), Estonia; Sorbonne Université (SU) Unité Mixte de Recherche (UMR) (S.L., A.B., J.C.C.), Institut du Cerveau et de la Moelle épinière, ICM; Assistance Publique Hôpitaux de Paris (J.C.C.), Department of Neurology, CIC Neurosciences, Paris, France; Univ. Lille (M.C.C.H., E.M.), Inserm, CHU Lille, UMR-S -JPArc-Centre de Recherche Lille Neurosciences & Cognition, Lille, France; Department of Neurology (A.B.D.), Ludwig Maximilians University of Munich; Department of Neurology (A.B.D.), Max Planck Institute of Psychiatry, Munich, Germany; Department of Neurology and Department of Clinical Genomics (A.B.D.), Mayo Clinic Florida, Jacksonville, FL; Department of Neurology (G.M.H.), Medical School, University of Cyprus, Nicosia, Cyprus; Department of Neurology (G.M.H., E.D.), Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece; Center of Clinical Research (L.S.), Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens; st Department of Neurology (L.S, A.M.S.), Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Department of Molecular Medicine (E.M.V.), University of Pavia; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Mondino Foundation (E.M.V.), Pavia; UOC Medical Genetics and Advanced Cell Diagnostics (S.P.), S. Andrea University Hospital; Department of Clinical and Molecular Medicine (S.P.), University of Rome, Italy; Department of Biomedical Sciences-Humanitas University (L.S.); Humanitas Clinical and Research Center (L.S.), IRCCS, Via Manzoni , Milan, Italy; Parkinson Institute (A.Z., G.P.), Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO, Milano, Italia; Department of Neurology (L.B., C.F.), San Gerardo Hospital, Milan; Center for Neuroscience (L.B., C.F.), University of Milano Bicocca, Monza; Institute for Biomedical Research and Innovation (G.A., M.G.), National Research Council, Mangone, Cosenza; Institute of Neurology (A.Q.), Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Department of Neurology (L.F.B., D.K.), Northwestern University Feinberg School of Medicine, Chicago, IL; Metabolic Biochemistry (L.F.B.), Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University; Munich Cluster for Systems Neurology (SyNergy) (L.F.B.), Munich, Germany; Department of Integrative Physiology and Bio-Nano Medicine (H.M., Y.K.), National Defense Medical College, Saitama; Department of Neurology (N.H., K.N.), Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Department of Neurology (S.J.C.), Asan Medical Center, University of Ulsan College of Medicine; Department of Neurology (Y.J.K.), Yonsei University College of Medicine, Seoul, South Korea; Luxembourg Centre for Systems Biomedicine (L. Pavelka), University of Luxembourg, Belval, Luxembourg; Radboud University Medical Centre (B.P.C.v.d.W., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The Netherlands; Department of Neurology (J.A.), St Olav's Hospital and Norwegian University of Science and Technology, Trondheim, Norway; Instituto de Medicina Molecular João Lobo Antunes (L.C.G., J.J.F.), Faculdade de Medicina, Universidade de Lisboa; Department of Neurosciences and Mental Health (L.C.G.), Neurology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN); Laboratory of Clinical Pharmacology and Therapeutics (J.J.F.), Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Division of Molecular Biology and Human Genetics (S.B.), Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University; Division of Neurology (J.C.), Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa; Parkinson's disease & Movement Disorders Unit, Neurology Service (E.T.), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB//-ISCIII) Barcelona (E.T.), Spain; Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders (M.E.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Catalonia; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (P.P., M.D.F.); Movement Disorders Unit (P.P., M.D.F.), Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain; Department of Clinical Neuroscience (K.W.), Karolinska Institutet; Department of Medical Epidemiology and Biostatistics (K.W., N.L.P.), Karolinska Institutet; Department of Neuroscience, Karolinska Institutet (C.R., A.C.B.), Stockholm; Lund University (A.P., C.H.), Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden; University of Birmingham and Sandwell and West Birmingham Hospitals NHS Trust (C.E.C.); Faculty of Medicine, Health and Life Sciences (K.E.M.), Queens University, Belfast, United Kingdom; Department of Neurology (M.J.F.), McKnight Brain Institute, University of Florida, Gainesville, FL; Parkinson Research Clinic (R.K.), Centre Hospitalier de Luxembourg; Transversal Translational Medicine, Luxembourg Institute of Health (LIH) (R.K.), Strassen; and Neurology (R.K.), Centre Hospitalier de Luxembourg, Luxembourg. From the Centre for Genetic Epidemiology (S.G., A.A.K.S., M.S.), Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany; Department of Neurology (L. Pihlstrom, M.T.), Oslo University Hospital, Norway; Université Paris-Saclay (C.D., P.E.S., O.M., B.P., A.E.), UVSQ, Univ. Paris-Sud, Inserm, Team "Exposome, heredity, cancer and health," CESP, Villejuif, France; Department for Neurodegenerative Diseases (C.S., K.B., T.G., M.S.), Hertie Institute for Clinical Brain Research, University of Tubingen; German Center for Neurodegenerative Diseases (DZNE) (C.S., L.F.B., T.G.), Tübingen; Institute of Human Genetics (M.R.B., P.L.), Helmholtz Zentrum München, Neuherberg, Germany; Luxembourg Centre for Systems Biomedicine (LCSB) (Z.L., P.M., D.B., R.K.), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Molecular Genetics Section (C.E., D.G.H., C.B., A.B.S.,), Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD; Group of Applied Bioinformatics (F.B., M.H., J.K.), University of Tübingen; High Performance and Cloud Computing Group ZDV (F.B., M.H.), University of Tübingen, Germany; Griffith Institute for Drug Discovery (G.D.M.), Griffith University, Don Young Road, Nathan, Queensland, Australia; Department of Neurology (A.Z.), Medical University of Vienna; Department of Neurology (W.P.), Wilhelminenspital, Austria; Department of Clinical and Movement Neurosciences (M.T.), UCL Queen Square Institute of Neurology, University College London, London, UK; Tanz Centre for Research in Neurodegenerative Diseases (E.R, A.L.), University of Toronto; Edmond J. Safra Program in Parkinson's Disease (A.L.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN; Division of Neurology (A.L.), University of Toronto; Krembil Brain Institute (A.L.), Toronto, Ontario, Canada; Centre for Molecular Medicine and Innovative Therapeutics (S.K.), Murdoch University, Murdoch, Australia; Perron Institute for Neurological and Translational Science (S.K.), Nedlands, Western Australia, Australia; Department of Neurology and Neurosurgery (P.T.), University of Tartu; Neurology Clinic, Tartu University Hospital (P.T.), Estonia; Sorbonne Université (SU) Unité Mixte de Recherche (UMR) (S.L., A.B., J.C.C.), Institut du Cerveau et de la Moelle épinière, ICM; Assistance Publique Hôpitaux de Paris (J.C.C.), Department of Neurology, CIC Neurosciences, Paris, France; Univ. Lille (M.C.C.H., E.M.), Inserm, CHU Lille, UMR-S -JPArc-Centre de Recherche Lille Neurosciences & Cognition, Lille, France; Department of Neurology (A.B.D.), Ludwig Maximilians University of Munich; Department of Neurology (A.B.D.), Max Planck Institute of Psychiatry, Munich, Germany; Department of Neurology and Department of Clinical Genomics (A.B.D.), Mayo Clinic Florida, Jacksonville, FL; Department of Neurology (G.M.H.), Medical School, University of Cyprus, Nicosia, Cyprus; Department of Neurology (G.M.H., E.D.), Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece; Center of Clinical Research (L.S.), Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens; st Department of Neurology (L.S, A.M.S.), Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Department of Molecular Medicine (E.M.V.), University of Pavia; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Mondino Foundation (E.M.V.), Pavia; UOC Medical Genetics and Advanced Cell Diagnostics (S.P.), S. Andrea University Hospital; Department of Clinical and Molecular Medicine (S.P.), University of Rome, Italy; Department of Biomedical Sciences-Humanitas University (L.S.); Humanitas Clinical and Research Center (L.S.), IRCCS, Via Manzoni , Milan, Italy; Parkinson Institute (A.Z., G.P.), Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO, Milano, Italia; Department of Neurology (L.B., C.F.), San Gerardo Hospital, Milan; Center for Neuroscience (L.B., C.F.), University of Milano Bicocca, Monza; Institute for Biomedical Research and Innovation (G.A., M.G.), National Research Council, Mangone, Cosenza; Institute of Neurology (A.Q.), Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Department of Neurology (L.F.B., D.K.), Northwestern University Feinberg School of Medicine, Chicago, IL; Metabolic Biochemistry (L.F.B.), Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University; Munich Cluster for Systems Neurology (SyNergy) (L.F.B.), Munich, Germany; Department of Integrative Physiology and Bio-Nano Medicine (H.M., Y.K.), National Defense Medical College, Saitama; Department of Neurology (N.H., K.N.), Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Department of Neurology (S.J.C.), Asan Medical Center, University of Ulsan College of Medicine; Department of Neurology (Y.J.K.), Yonsei University College of Medicine, Seoul, South Korea; Luxembourg Centre for Systems Biomedicine (L. Pavelka), University of Luxembourg, Belval, Luxembourg; Radboud University Medical Centre (B.P.C.v.d.W., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The Netherlands; Department of Neurology (J.A.), St Olav's Hospital and Norwegian University of Science and Technology, Trondheim, Norway; Instituto de Medicina Molecular João Lobo Antunes (L.C.G., J.J.F.), Faculdade de Medicina, Universidade de Lisboa; Department of Neurosciences and Mental Health (L.C.G.), Neurology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN); Laboratory of Clinical Pharmacology and Therapeutics (J.J.F.), Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Division of Molecular Biology and Human Genetics (S.B.), Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University; Division of Neurology (J.C.), Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa; Parkinson's disease & Movement Disorders Unit, Neurology Service (E.T.), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB//-ISCIII) Barcelona (E.T.), Spain; Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders (M.E.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Catalonia; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (P.P., M.D.F.); Movement Disorders Unit (P.P., M.D.F.), Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain; Department of Clinical Neuroscience (K.W.), Karolinska Institutet; Department of Medical Epidemiology and Biostatistics (K.W., N.L.P.), Karolinska Institutet; Department of Neuroscience, Karolinska Institutet (C.R., A.C.B.), Stockholm; Lund University (A.P., C.H.), Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden; University of Birmingham and Sandwell and West Birmingham Hospitals NHS Trust (C.E.C.); Faculty of Medicine, Health and Life Sciences (K.E.M.), Queens University, Belfast, United Kingdom; Department of Neurology (M.J.F.), McKnight Brain Institute, University of Florida, Gainesville, FL; Parkinson Research Clinic (R.K.), Centre Hospitalier de Luxembourg; Transversal Translational Medicine, Luxembourg Institute of Health (LIH) (R.K.), Strassen; and Neurology (R.K.), Centre Hospitalier de Luxembourg, Luxembourg. manu.sharma@uni-tuebingen.de.
Abstract summary
Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified and loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC).The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance ( < 5 × 10). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance ( < 0.025): (rs34311866: β(SE) = 0.477(0.203), = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported locus (rs983361: β(SE) = 0.720(0.122), = 3.13 × 10) and a novel locus (rs4698412: β(SE) = -0.526(0.096), = 4.41 × 10).Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.Authors & Co-authors: Grover Sandeep S Kumar Sreelatha Ashwin Ashok AA Pihlstrom Lasse L Domenighetti Cloé C Schulte Claudia C Sugier Pierre-Emmanuel PE Radivojkov-Blagojevic Milena M Lichtner Peter P Mohamed Océane O Portugal Berta B Landoulsi Zied Z May Patrick P Bobbili Dheeraj D Edsall Connor C Bartusch Felix F Hanussek Maximilian M Krüger Jens J Hernandez Dena G DG Blauwendraat Cornelis C Mellick George D GD Zimprich Alexander A Pirker Walter W Tan Manuela M Rogaeva Ekaterina E Lang Anthony A Koks Sulev S Taba Pille P Lesage Suzanne S Brice Alexis A Corvol Jean-Christophe JC Chartier-Harlin Marie-Christine MC Mutez Eugenie E Brockmann Kathrin K Deutschländer Angela B AB Hadjigeorgiou Georges M GM Dardiotis Efthimos E Stefanis Leonidas L Simitsi Athina Maria AM Valente Enza Maria EM Petrucci Simona S Straniero Letizia L Zecchinelli Anna A Pezzoli Gianni G Brighina Laura L Ferrarese Carlo C Annesi Grazia G Quattrone Andrea A Gagliardi Monica M Burbulla Lena F LF Matsuo Hirotaka H Kawamura Yusuke Y Hattori Nobutaka N Nishioka Kenya K Chung Sun Ju SJ Kim Yun Joong YJ Pavelka Lukas L van de Warrenburg Bart P C BPC Bloem Bastiaan R BR Singleton Andrew B AB Aasly Jan J Toft Mathias M Guedes Leonor Correia LC Ferreira Joaquim J JJ Bardien Soraya S Carr Jonathan J Tolosa Eduardo E Ezquerra Mario M Pastor Pau P Diez-Fairen Monica M Wirdefeldt Karin K Pedersen Nancy L NL Ran Caroline C Belin Andrea C AC Puschmann Andreas A Hellberg Clara C Clarke Carl E CE Morrison Karen E KE Krainc Dimitri D Farrer Matt J MJ Kruger Rejko R Elbaz Alexis A Gasser Thomas T Sharma Manu M
Study Outcome
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Citations : Soldner F, Stelzer Y, Shivalila CS, et al. . Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature. 2016;533(7601):95-99.Authors : 84
Identifiers
Doi : 10.1212/WNL.0000000000200699SSN : 1526-632X