Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease
Year: 2019
Type: article
Study design: Observational Study
Abstract: Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
Source: PLoS ONE
Authors: Emily Baker, Rebecca Sims, Ganna Leonenko, Aura Frizzati, Janet C. Harwood, Detelina Grozeva, GERAD/PERADES, CHARGE, ADGC, EADI, IGAP consortia, Kevin Morgan, Peter Passmore, Clive Holmes, John Powell, Carol Brayne, Michael Gill, Simon Mead, Paola Bossù, Gianfranco Spalletta, Alison M. Goate, Carlos Cruchaga, Wolfgang Maier, Reinhard Heun, Frank Jessen, Oliver Peters, Martin Dichgans, Lutz FröLich, Alfredo Ramirez, Lesley Jones, John Hardy, Dobril Ivanov, Matthew Hill, Peter Holmans, Nicholas D. Allen, B. Paul Morgan, Sudha Seshadri, Gerard D. Schellenberg, Philippe Amouyel, Julie Williams, Valentina Escott-Price
Institutions: Cardiff University, Medical Research Council, University of Nottingham, Queen's University Belfast, University of Southampton, King's College London, QIMR Berghofer Medical Research Institute, University of Cambridge, Trinity College Dublin, St. James's Hospital, MRC Prion Unit, University College London, Fondazione Santa Lucia, Washington University in St. Louis, Icahn School of Medicine at Mount Sinai, German Center for Neurodegenerative Diseases, University of Bonn, University of Cologne, Stiftung Charité, Charité – Universitätsmedizin Berlin, Munich Cluster for Systems Neurology, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Heidelberg University, Central Institute of Mental Health, University Hospital Bonn, UCL Queen Square Institute of Neurology, Boston University, University of Pennsylvania, Inserm, Université de Lille, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement, LabEx DISTALZ
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,595
Funders: University of Miami, University of Pennsylvania, Northwestern University, School of Medicine, Boston University, University of Washington, Johns Hopkins University, University of Pittsburgh, Rush University, Wellcome Trust, National Institute for Health and Care Research, Parkinson's UK, Rosetrees Trust, Agence Nationale de la Recherche, UK Dementia Research Institute, Dementias Platform UK, University of California, Los Angeles, Perelman School of Medicine, University of Pennsylvania, Geriatric Research Education and Clinical Center, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke, NIH Clinical Center
Awards: G1072871761, UK Dementias Platform, UC Davis Alzheimer's Disease Core Center, G1492513106, CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample, NIHR Senior Investigator Award, G2621534636, G2725042310, Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime, ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems, G3942183342, G4627509756, G4684299935, Temporal Trends, Novel Imaging and Molecular Characterization of Preclinical and Clinical Alzheimer's Disease in the Framingham Cohorts, Alzheimer's Disease Genetics Consortium, NIHR Senior Investigator Award, G5737115378, MRC Centre for Neuropsychiatric Genetics and Genomics, G5953459058, G6680420078, NIHR Senior Investigator Award, G6891509549, G7880223742, G7890220928, G7979393549, G8900867631, National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS), Precursors of Stroke Incidence and Prognosis, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W2958689915