Abstract
High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium.GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3. kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants.The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I2 estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest.This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
| Original language | English |
|---|---|
| Journal | Neurobiology of Aging |
| Volume | 32 |
| Issue number | 3 |
| ISSN | 0197-4580 |
| DOIs | |
| Publication status | Published - 01.03.2011 |
Funding
Australia : G.T. Sutherland (Eskitis Institute for Cell and Molecular Therapies, School of Biomolecular & Physical Sciences, Griffith University, Nathan, QLD), G.A. Siebert (Eskitis Institute for Cell and Molecular Therapies, School of Biomolecular & Physical Sciences, Griffith University, Nathan, QLD). Belgium : Christine Van Broeckhoven PhD DSc (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurogenetics, Institute Born-Bunge; and University of Antwerp, Antwerpen), Jessie Theuns, PhD (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurogenetics, Institute Born-Bunge, and University of Antwerp, Antwerpen), David Crosiers MD (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurobiology, Institute Born-Bunge; and University of Antwerp; and Department of Neurology, University Hospital of Antwerp, Antwerpen), Barbara Pickut, MD (Memory Clinic and Division of Neurology, ZNA Middelheim, Antwerpen), Philippe Pals, MD, PhD (Laboratory of Neurobiology, Institute Born-Bunge; and Department of Neurology, University Hospital Antwerp; Antwerpen), Sebastiaan Engelborghs, MD, PhD (Laboratory of Neurochemistry and Behavior, Institute Born-Bunge; and University of Antwerp; and Memory Clinic and Division of Neurology, ZNA Middelheim, Antwerpen), Karen Nuytemans (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; and Laboratory of Neurogenetics, Institute Born-Bunge; and University of Antwerp, Antwerpen), Peter P. De Deyn, MD, PhD (Laboratory of Neurochemistry and Behavior, Institute Born-Bunge; and University of Antwerp; and Memory Clinic and Division of Neurology, ZNA Middelheim, Antwerpen), Patrick Cras, MD, PhD (Laboratory of Neurobiology, Institute Born-Bunge; and University of Antwerp; and Department of Neurology, University Hospital of Antwerp, Antwerpen). Canada : Ekaterina Rogaeve, MD (Centre for Research in Neurodegenerative Diseases, Department of Medicine, Division of Neurology, University of Toronto, ON, Canada). France : From the French Parkinson's Disease Genetics Study Group: Y. Agid, A-M. Bonnet, M. Borg, A. Brice, E. Broussolle, P. Damier, A. Destée, A. Dürr, F. Durif, S. Lesage, E. Lohmann, P. Pollak, O. Rascol, F. Tison, C. Tranchant, F. Viallet, M. Vidailhet. Also, Dr Marie-Christine Chartier-Harlin (Inserm U837), Christophe Tzourio (Inserm U708, Paris), Philippe Amouyel (Inserm U744, Lille), Marie-Anne Loriot (Inserm UMRS775, Paris). Germany : Rejko Krüger (Department of Neurology, University Hospital Tuebingen), Manu Sharma (Department of Neurology, University Hospital Tuebingen), Thomas Gasser, Prof (Medical Genetics, Unversity of Tübingen) Olaf Riess, PhD (Department of Neurology, University Hospital Tuebingen) Daniela Berg MD (Department of Neurology, University Hospital Tuebingen), Claudia Schulte, MSc (Department of Neurology, University Hospital Tuebingen) and Christine Klein, MD (Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck), Ana Djarmati, PhD (Department of Neurology, University of Lübeck), Johann Hagenah, MD (Department of Neurology, University of Lübeck), Katja Lohmann, PhD (Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck). Greece : Efthimios Dardiotis, MD (Department of Neurology, Faculty of Medicine, University of Thessaly and Institute of Biomedical Research & Technology, CERETETH, Larissa), Vaia Tsimourtou (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa), Styliani Ralli (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa), Persa Kountra, MD (Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa), Konstantinos Aggelakis (Institute of Biomedical Research & Technology, CERETETH, Larissa). Japan : Nobutaka Hattori, MD, PhD (Department of Neurology, Juntendo University School of Medicine, Tokyo), Hiroyuki Tomiyama, MD, PhD (Department of Neurology, Juntendo University School of Medicine, Tokyo), Manabu Funayama, PhD (Department of Neurology, Juntendo University School of Medicine, Tokyo), Hiroyo Yoshino, BS (Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo) Yuanzhe Li, MD, PhD (Department of Neurology, Juntendo University School of Medicine, Tokyo), Yoko Imamichi (Department of Neurology, Juntendo University School of Medicine, Tokyo), Tatsushi Toda, MD (Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan), Wataru Satake (Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan). Ireland : Prof Tim Lynch FRCPI, FRCP (The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Clinical Investigator at the Conway Institute, University College Dublin, Ireland) and Dr J. Mark Gibson, MD (Department of Neurology, Royal Victoria Hospital, Belfast, Ireland). Italy : Enza Maria Valente, MD, PhD (Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome), Alessandro Ferraris, MD (Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome), Bruno Dallapiccola (Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome), Anna Rita Bentivoglio, MD, PhD (Institute of Neurology, Catholic University, Rome), Tamara Ialongo, MD, PhD (Institute of Neurology, Catholic University, Rome), Chiara Riva, PhD (Department of Neuroscience, University of Milano-Bicocca, Monza), Barbara Corradi, PhD (Department of Paediatrics, University of Milano-Bicocca, Monza), Patrizia Tarantino, PhD (Institute of Neurological Sciences, National Research Council) and Ferdinanda Annesi, PhD (Institute of Neurological Sciences, National Research Council). Norway : J Aasly MD (Department of Neurology, University of Trondheim, Norway). Poland : Grzegorz Opala, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice), Barbara Jasinska-Myga, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice), Gabriela Klodowska-Duda, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice), Magdalena Boczarska-Jedynak, MD, PhD (Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice). Singapore : Dr. Eng King Tan, MD, PhD (National Medical and Biomedical Research Councils, and the Duke-NUS Graduate Medical School, Singapore Millenium Foundation). Sweden : Andrea Carmine Belin, PhD (Department of Neuroscience, Karolinska Institutet, Stockholm), Lars Olson, Professor (Department of Neuroscience, Karolinska Institutet, Stockholm), Dagmar Galter, PhD (Department of Neuroscience, Karolinska Institutet, Stockholm), Marie Westerlund, PhD (Department of Neuroscience, Karolinska Institutet, Stockholm), Olof Sydow, PhD (Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm), Nancy Pedersen, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Nancy Pedersen, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm. Also Christer Nilsson, MD, PhD (Department of Geriatric Psychiatry, Lund University), Andreas Puschmann, MD (Department of Neurology, Lund University Hospital, Department of Geriatric Psychiatry, Lund University). Taiwan : JJ Lin, MD, Department of Neurology, Cushang Show-Chwan Hospital, Taiwan. USA : Demetrius M. Maraganore, MD (Department of Neurology, Mayo Clinic, Rochester, MN) J, Eric Ahlskog PhD, MD (Department of Neurology, Mayo Clinic, Rochester, MN, USA), Mariza de Andrade, PhD (Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA), Timothy G. Lesnick, MS (Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA) and Walter A. Rocca, MD, MPH (Departments of Neurology and Health Sciences Research, Mayo Clinic, Rochester, MN, USA). Also, Harvey Checkoway, PhD (Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA), M Farrer PhD, OA Ross PhD (Division of Neurogenetics, Mayo Clinic, Jacksonville, USA). Disclosure statement : All authors have reported no actual or potential conflict of interest and have certified that all data contained in this manuscript have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under the consideration of Neurobiology of Aging. Appropriate approval and procedures were used concerning human subjects. All authors have reviewed the contents of the manuscript being submitted, approve of its content and validate the accuracy of the data. Should a significant conflict of interest be present, the Editors reserve the right to reject the article on that basis. Funding to investigators was provided by the German Federal Ministry for Education and Research (BMBF, NGFNplus ; 01GS08134 ) to T.G.O.R and R.K. and the German Research Council (DFG , KR2119/3-1 ) to R.K.; “High-Tech Research Center” Project, Grant-in-Aid for Scientific Research (to N.H., 17390256 , and to H.T., 21591098 ) from the Japanese Ministry of Education, Culture, Sports, Science and Technology ; Italian Ministry of Health , Ricerca Finalizzata ex. art. 56, grant nr. ART56-OGR-704795 to E.M.V., the Volkswagen Foundation and the Hermann and Lilly Schilling Foundation to C.K. and a Rapid Response Innovation Award from the Michael J. Fox Foundation to O.A.R.; The Morris K. Udall Center, NIH/NINDS P50NS40256, and by P01AG17216, R01NS057567, R01AG15866, R01NS042859, R01NS039422, CIHR121849, and PARF to Z.W.; the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-V), the Institute for Science and Technology – Flanders (IWT-V), the Interuniversity Attraction Poles program P6/43 of the Belgian Science Policy Office, the Medical Research Foundation Antwerp and Neurosearch Antwerp and a Methusalem Excellence Grant of the Flemish Government, Flanders, Belgium to the Antwerp site.
