Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ genetics
Centrosome
/ metabolism
Cholesterol
/ genetics
Circadian Rhythm
/ genetics
DNA Damage
/ genetics
DNA Repair
/ genetics
Energy Metabolism
/ genetics
Female
Genome, Human
Genome-Wide Association Study
Humans
Inflammation
/ genetics
Male
Nuclear Receptor Subfamily 1, Group F, Member 1
/ genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ genetics
Polymorphism, Single Nucleotide
Proteins
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
16
01
2019
accepted:
27
05
2019
entrez:
9
7
2019
pubmed:
10
7
2019
medline:
19
2
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31283791
doi: 10.1371/journal.pone.0218111
pii: PONE-D-19-01465
pmc: PMC6613773
doi:
Substances chimiques
Amyloid beta-Peptides
0
Nuclear Receptor Subfamily 1, Group F, Member 1
0
PPARGC1A protein, human
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Proteins
0
RORA protein, human
0
ornithine decarboxylase antizyme
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0218111Subventions
Organisme : Medical Research Council
ID : MC_PC_17112
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U123160651
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U24 AG021886
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U24 AG056270
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00024/8
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100540
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600237
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J004758/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG052409
Pays : United States
Organisme : Medical Research Council
ID : G0901254
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG049505
Pays : United States
Organisme : Medical Research Council
ID : MR/K01417X/1
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS017950
Pays : United States
Organisme : Medical Research Council
ID : G0902227
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG054076
Pays : United States
Organisme : Medical Research Council
ID : MR/L023784/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001253
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG032984
Pays : United States
Organisme : Medical Research Council
ID : MR/L501542/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M009076/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1604/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1307
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K013041/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300429
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900652
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400074
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : P30 AG010129
Pays : United States
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0701075
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L501517/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0502157
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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