Journal article

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Guenter U Hoeglinger, Nadine M Melhem, Dennis W Dickson, Patrick MA Sleiman, Li-San Wang, Lambertus Klei, Rosa Rademakers, Rohan de Silva, Irene Litvan, David E Riley, John C van Swieten, Peter Heutink, Zbigniew K Wszolek, Ryan J Uitti, Jana Vandrovcova, Howard I Hurtig, Rachel G Gross, Walter Maetzler, Stefano Goldwurm, Eduardo Tolosa Show all

Nature Genetics | NATURE PUBLISHING GROUP | Published : 2011

Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associate..

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Grants

Awarded by US National Institutes of Health (NIH) (National Institute on Aging (NIA)/NIH)


Awarded by US National Institutes of Health (NIH) (National Institute of Mental Health (NIMH)


Awarded by German National Genome Research Network


Awarded by Deutsche Forschungsgemeinschaft


Awarded by Prinses Beatrix Fonds


Awarded by UK Medical Research Council


Awarded by TELETHON Italy


Awarded by Federal Ministry of Education and Research (BMBF)


Awarded by NIH/NINDS


Awarded by Mayo Clinic Florida (MCF) Research Committee


Awarded by National Human Genome Research Institute (NHGRI)


Awarded by Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy


Awarded by Wisconsin Department of Commerce


Awarded by NIH


Awarded by NATIONAL HUMAN GENOME RESEARCH INSTITUTE


Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Awarded by NATIONAL INSTITUTE ON AGING


Awarded by Alzheimers Research UK


Awarded by Medical Research Council


Funding Acknowledgements

We thank the subjects and their families that participated in this study. This work was funded by grants from the CurePSP Foundation, the Peebler PSP Research Foundation and US National Institutes of Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 (National Institute on Aging (NIA)/NIH), MH057881 and MH077930 (National Institute of Mental Health (NIMH)). Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01-0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust and by a grant from the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Research Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and Parkinsonism' (http://www.parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project no. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute and the Canadian Institute of Health Research. Brain-Net-Germany is supported by the Federal Ministry of Education and Research (BMBF) (01GI0505). R.d.S., A.J.L. and J.A.H. are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. R.d.S. is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. Z.K.W. is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030) and the gift from C. E. Bolch Jr. and S. B. Bolch (MCF #90052031/PAU # 90052). The Mayo Clinic College of Medicine would like to acknowledge M. Baker, R. Crook, M. DeJesus-Hernandez and N. Rutherford for their preparation of samples. P. P. was supported by a grant from the Government of Navarra ('Ayudas para la Realizacion de Proyectos de Investigacion' 2006-2007) and acknowledges the 'Iberian Atypical Parkinsonism Study Group Researchers': M. A. Pastor, M. R. Luquin, M. Riverol, J.A. Obeso and M. C. Rodriguez-Oroz (Department of Neurology, Clinica Universitaria de Navarra, University of Navarra, Pamplona, Spain), M. Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), A. Lopez de Munain, B. Indakoetxea, J. Olaskoaga, J. Ruiz, J. Felix Marti Masso (Servicio de Neurologia, Hospital Donostia, San Sebastian, Spain), V. Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), T. Tu on (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), F. Moreno (Servicio de Neurologia, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), A. Alzualde (Neurogenetics Department, Hospital Donostia, San Sebastian, Spain). E. T. wishes to acknowledge the Banco de Tejidos Neurologicos de la Universidad de Barcelona-Hospital Clinic, which provided many tissue samples for the project. We also acknowledge E.Loomis for providng technical support.The datasets used for older controls were obtained from Database for Genotypes and Phenotypes (dbGap) at http://www.ncbi.nlm.nih.gov/gap/. Funding support for the 'Genetic Consortium for Late Onset Alzheimer's Disease' was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer's Disease (study accession number: phs000168.v1.p1) includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer's Disease. Funding support for the 'CIDR Visceral Adiposity Study' (study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genome-wide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. Funding support for the Personalized Medicine Research Project (PMRP) was provided through a cooperative agreement (U01HG004608) with the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute for General Medical Sciences (NIGMS). The samples used for PMRP analyses were obtained with funding from Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy grant number D1A RH00025 and Wisconsin Department of Commerce Technology Development Fund contract number TDF FYO10718. Funding support for genotyping, which was performed at Johns Hopkins University, was provided by the NIH (U01HG004438). Assistance with phenotype harmonization and genotype cleaning was provided by the eMERGE Administrative Coordinating Center (U01HG004603) and the National Center for Biotechnology Information (NCBI). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000170.v1.p1.