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

Emily Baker, Rebecca Sims, Ganna Leonenko, Aura Frizzati, Janet C. Harwood, Detelina Grozeva, 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 JessenOliver 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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish
Article numbere0218111
JournalPloS one
Issue number7
StatePublished - Jul 1 2019


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