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Title | Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Baker E, Sims R, Leonenko G, Frizzati A, Harwood JC, Grozeva D, Morgan K, Passmore P, Holmes C, Powell J, Brayne C, Gill M, Mead S, Bossù P, Spalletta G, Goate AM, Cruchaga C, Maier W, Heun R, Jessen F, Peters O, Dichgans M, Frölich L, Ramirez A, Jones L, Hardy J, Ivanov D, Hill M, Holmans P, Allen ND, B Morgan P, Seshadri S, Schellenberg GD, Amouyel P, Williams J, Escott-Price V |
Corporate Authors | GERAD/PERADES, CHARGE, ADGC, EADI, IGAP consortia |
Journal | PLoS One |
Volume | 14 |
Issue | 7 |
Pagination | e0218111 |
Date Published | 07/2019 |
ISSN | 1932-6203 |
Keywords | 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 |
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. |
DOI | 10.1371/journal.pone.0218111 |
Alternate Journal | PLoS ONE |
PubMed ID | 31283791 |
PubMed Central ID | PMC6613773 |
Grant List | MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom R01 AG054076 / AG / NIA NIH HHS / United States MC_U123160651 / MRC_ / Medical Research Council / United Kingdom G0701075 / MRC_ / Medical Research Council / United Kingdom G0902227 / MRC_ / Medical Research Council / United Kingdom MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom U01 AG052409 / AG / NIA NIH HHS / United States / WT_ / Wellcome Trust / United Kingdom MR/M009076/1 / MRC_ / Medical Research Council / United Kingdom G0600237 / MRC_ / Medical Research Council / United Kingdom G0901254 / MRC_ / Medical Research Council / United Kingdom R01 NS017950 / NS / NINDS NIH HHS / United States MR/L501542/1 / MRC_ / Medical Research Council / United Kingdom U24 AG021886 / AG / NIA NIH HHS / United States MR/K01417X/1 / MRC_ / Medical Research Council / United Kingdom MC_UU_00024/1 / MRC_ / Medical Research Council / United Kingdom G1001253 / MRC_ / Medical Research Council / United Kingdom G0300429 / MRC_ / Medical Research Council / United Kingdom G-1307 / PUK_ / Parkinson's UK / United Kingdom MC_PC_17112 / MRC_ / Medical Research Council / United Kingdom MR/J004758/1 / MRC_ / Medical Research Council / United Kingdom MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom |