Hippocampal transcriptome-wide association study and neurobiological pathway analysis for Alzheimer's disease.
PLoS Genet
; 17(2): e1009363, 2021 02.
Article
in En
| MEDLINE
| ID: mdl-33630843
ABSTRACT
Genome-wide association studies (GWASs) have identified multiple susceptibility loci for Alzheimer's disease (AD), which is characterized by early and progressive damage to the hippocampus. However, the association of hippocampal gene expression with AD and the underlying neurobiological pathways remain largely unknown. Based on the genomic and transcriptomic data of 111 hippocampal samples and the summary data of two large-scale meta-analyses of GWASs, a transcriptome-wide association study (TWAS) was performed to identify genes with significant associations between hippocampal expression and AD. We identified 54 significantly associated genes using an AD-GWAS meta-analysis of 455,258 individuals; 36 of the genes were confirmed in another AD-GWAS meta-analysis of 63,926 individuals. Fine-mapping models further prioritized 24 AD-related genes whose effects on AD were mediated by hippocampal expression, including APOE and two novel genes (PTPN9 and PCDHA4). These genes are functionally related to amyloid-beta formation, phosphorylation/dephosphorylation, neuronal apoptosis, neurogenesis and telomerase-related processes. By integrating the predicted hippocampal expression and neuroimaging data, we found that the hippocampal expression of QPCTL and ERCC2 showed significant difference between AD patients and cognitively normal elderly individuals as well as correlated with hippocampal volume. Mediation analysis further demonstrated that hippocampal volume mediated the effect of hippocampal gene expression (QPCTL and ERCC2) on AD. This study identifies two novel genes associated with AD by integrating hippocampal gene expression and genome-wide association data and reveals candidate hippocampus-mediated neurobiological pathways from gene expression to AD.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Predisposition to Disease
/
Polymorphism, Single Nucleotide
/
Genome-Wide Association Study
/
Alzheimer Disease
/
Transcriptome
/
Hippocampus
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Aged
/
Aged80
/
Female
/
Humans
/
Male
Language:
En
Journal:
PLoS Genet
Journal subject:
GENETICA
Year:
2021
Document type:
Article
Affiliation country:
China