Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.
Dobril Ivanov, Wolfgang Maier, Reinhard Heun, Frank Jessen, Oliver Peters, Martin Dichgans, Alfredo Ramirez, Lesley Jones, John Hardy, Carlos Cruchaga, Matthew Hill, Peter Holmans, Nicholas D Allen, B Paul Morgan, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, Valentina Escott-Price, Peter Passmore, Lutz Frölich, Emily Baker, Rebecca Sims, Ganna Leonenko, Aura Frizzati, Janet C Harwood, Detelina Grozeva, Kevin Morgan, Sudha Seshadri, Clive Holmes, John Powell, Carol Brayne, Michael Gill, Simon Mead, Paola Bossù, Gianfranco Spalletta, Alison M Goate
Journal: PloS one
2020;14(7):e0218111
PMID: 31283791
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.
Address:
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.; UK Dementia Research Institute at Cardiff University, Cardiff, United Kingdom.; Human Genetics, School of Life Sciences, Life Sciences Building A27, University Park, University of Nottingham, Nottingham, NG7 2RD, United Kingdom.; Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queens University, Belfast, United Kingdom.; Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom.; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom.; Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.; Mercer's Institute for Research on Ageing, St. James' Hospital, Dublin, Ireland.; James Hospital and Trinity College, Dublin, Ireland.; MRC Prion Unit at UCL, Institute of Prion Diseases, London, United Kingdom.; Experimental Neuropsychobiology Laboratory, IRCCS Santa Lucia Foundation, Department of Clinical and Behavioral Neurology, Rome, Italy.; Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.; Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, Missouri, United States of America.; Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America.; German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.; Department of Psychiatry and Psychotherapy, University of Bonn, 53127, Bonn, Germany.; Department of Psychiatry and Psychotherapy, University of Cologne, 50937 Cologne, Germany.; Department of Psychiatry and Psychotherapy, Charité Berlin, Berlin, Germany.; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.; Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, 80336, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.; Department of Molecular Neuroscience, UCL, Institute of Neurology, London, United Kingdom.; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.; Univ. Lille, Inserm, CHU Lille University Hospital, Institut Pasteur de Lille, LabEx DISTALZ-UMR1167 - RID-AGE - Risk factors and molecular determinants of aging-related, F-59000 Lille, France.
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MeSH Terms:
Alzheimer Disease,
Amyloid beta-Peptides,
Centrosome,
Cholesterol,
Circadian Rhythm,
DNA Damage,
DNA Repair,
Energy Metabolism,
Female,
Genome, Human,
Genome-Wide Association Study,
Humans,
Inflammation,
Male,
Nuclear Receptor Subfamily 1, Group F, Member 1,
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha,
Polymorphism, Single Nucleotide,
Proteins
