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Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

Baker, Emily; Sims, Rebecca; Leonenko, Ganna; Maier, Wolfgang; Heun, Reinhard; Harwood, Janet C.; Frizzati, Aura; Gill, Michael; Mead, Simon; Morgan, Kevin; Grozeva, Detelina; Passmore, Peter; Holmes, Clive; Powell, John; Brayne, Carol; Bossù, Paola; Spalletta, Gianfranco; Goate, Alison M.; Cruchaga, Carlos; Jessen, Frank; Peters, Oliver; Dichgans, Martin; FröLich, Lutz; Ramirez, Alfredo; Jones, Lesley; Hardy, John; Ivanov, Dobril; Hill, Matthew; Holmans, Peter; Allen, Nicholas D.; Morgan, B. Paul; Seshadri, Sudha; Schellenberg, Gerard D.; Amouyel, Philippe; Williams, Julie; Escott-Price, Valentina

Authors

Emily Baker

Rebecca Sims

Ganna Leonenko

Wolfgang Maier

Reinhard Heun

Janet C. Harwood

Aura Frizzati

Michael Gill

Simon Mead

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics

Detelina Grozeva

Peter Passmore

Clive Holmes

John Powell

Carol Brayne

Paola Bossù

Gianfranco Spalletta

Alison M. Goate

Carlos Cruchaga

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



Contributors

Evangelos Evangelou
Editor

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.

Journal Article Type Article
Publication Date Jul 8, 2019
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 14
Issue 7
Article Number e0218111
Pages 1-11
APA6 Citation Baker, E., Sims, R., Leonenko, G., Maier, W., Heun, R., Harwood, J. C., …Escott-Price, V. (2019). Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease. PLoS ONE, 14(7), 1-11. https://doi.org/10.1371/journal.pone.0218111
DOI https://doi.org/10.1371/journal.pone.0218111
Keywords General Biochemistry, Genetics and Molecular Biology; General Agricultural and Biological Sciences; General Medicine
Publisher URL https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218111

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