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. 2019 Jul 8;14(7):e0218111.
doi: 10.1371/journal.pone.0218111. eCollection 2019.

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

Emily Baker  1   2 , Rebecca Sims  1 , Ganna Leonenko  1 , Aura Frizzati  1 , Janet C Harwood  1 , Detelina Grozeva  1 ; GERAD/PERADES; CHARGE; ADGC; EADI; IGAP consortia; Kevin Morgan  3 , Peter Passmore  4 , Clive Holmes  5 , John Powell  6   7 , Carol Brayne  8 , Michael Gill  9   10 , Simon Mead  11 , Paola Bossù  12 , Gianfranco Spalletta  13 , Alison M Goate  14   15 , Carlos Cruchaga  16   15 , Wolfgang Maier  17 , Reinhard Heun  18 , Frank Jessen  17   19 , Oliver Peters  20   21 , Martin Dichgans  22   23   24 , Lutz FröLich  25 , Alfredo Ramirez  19   26 , Lesley Jones  1 , John Hardy  27 , Dobril Ivanov  2 , Matthew Hill  2 , Peter Holmans  1 , Nicholas D Allen  2 , B Paul Morgan  2 , Sudha Seshadri  28 , Gerard D Schellenberg  29 , Philippe Amouyel  30 , Julie Williams  1   2 , Valentina Escott-Price  1   2
Affiliations

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

Emily Baker et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Manhattan Plot for the POLARIS Gene-Based Analysis in Imputed GERAD Data Using a Gene Window 35kb Upstream and 10kb Downstream.
See this image and copyright information in PMC

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