Genome-Wide Meta-Analysis of Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Parkinson's Disease Cohorts.
Alzheimer's disease
Parkinson's disease
genome-wide association study
longitudinal GWAS
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
14
04
2023
received:
28
02
2023
accepted:
30
05
2023
medline:
19
9
2023
pubmed:
4
8
2023
entrez:
4
8
2023
Statut:
ppublish
Résumé
Amyloid-β, phosphorylated tau (p-tau), and total tau (t-tau) in cerebrospinal fluid are established biomarkers for Alzheimer's disease (AD). In other neurodegenerative diseases, such as Parkinson's disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated. To investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status. We conducted genome-wide association studies (GWASs) for the AD biomarkers on subjects from the Parkinson's Progression Markers Initiative, the Fox Investigation for New Discovery of Biomarkers, and the Alzheimer's Disease Neuroimaging Initiative, and meta-analyzed with the largest AD GWAS. We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control). We observed three GWAS signals: the APOE locus for amyloid-β, the 3q28 locus between GEMC1 and OSTN for p-tau and t-tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p-tau. The 7p22 locus is novel and colocalized with the brain DNAAF5 expression. Although no heterogeneity from underlying disease status was observed for the earlier GWAS signals, some disease risk loci suggested disease-specific associations with these biomarkers. Our study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p-tau across all diseases. We also observed some disease-specific genetic associations with these biomarkers. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
Sections du résumé
BACKGROUND
Amyloid-β, phosphorylated tau (p-tau), and total tau (t-tau) in cerebrospinal fluid are established biomarkers for Alzheimer's disease (AD). In other neurodegenerative diseases, such as Parkinson's disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated.
OBJECTIVE
To investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status.
METHODS
We conducted genome-wide association studies (GWASs) for the AD biomarkers on subjects from the Parkinson's Progression Markers Initiative, the Fox Investigation for New Discovery of Biomarkers, and the Alzheimer's Disease Neuroimaging Initiative, and meta-analyzed with the largest AD GWAS. We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control).
RESULTS
We observed three GWAS signals: the APOE locus for amyloid-β, the 3q28 locus between GEMC1 and OSTN for p-tau and t-tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p-tau. The 7p22 locus is novel and colocalized with the brain DNAAF5 expression. Although no heterogeneity from underlying disease status was observed for the earlier GWAS signals, some disease risk loci suggested disease-specific associations with these biomarkers.
CONCLUSIONS
Our study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p-tau across all diseases. We also observed some disease-specific genetic associations with these biomarkers. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
Substances chimiques
tau Proteins
0
Amyloid beta-Peptides
0
Biomarkers
0
Peptide Fragments
0
OSTN protein, human
0
Muscle Proteins
0
Transcription Factors
0
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1697-1705Subventions
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AG000534
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AG000957
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
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