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

Baker, E; Sims, R; Leonenko, G; Frizzati, A; Harwood, JC; Grozeva, D; GERAD/PERADES, .; ... Escott-Price, V; + view all (2019) Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease. PLoS One , 14 (7) , Article e0218111. 10.1371/journal.pone.0218111. Green open access

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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.

Type: Article
Title: Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0218111
Publisher version: https://doi.org/10.1371/journal.pone.0218111
Language: English
Additional information: © 2019 Baker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Alzheimer's disease, Apolipoprotein genes, Gene expression, Gene regulation, Circadian rhythms, Consortia, Molecular genetics
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10078044
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