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.
Highlights
This study identifies genes whose expression in hippocampal tissue is associated with Alzheimer’s disease (AD) and establishes the pathways from hippocampal gene expression to hippocampal volume to AD
We demonstrate that 24 genes are associated with AD in hippocampal tissue, and these genes are enriched for AD-related biological processes of amyloid-beta formation, phosphorylation/dephosphorylation, neuronal apoptosis, neurogenesis and telomerase-related processes
We further show that hippocampal volume mediates the effects of the hippocampal gene expression of QPCTL and ERCC2 on AD
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder clinically characterized by progressive dementia and pathologically featured by senile plaques composed of amyloid beta peptide (Aβ) and intracellular neurofibrillary tangles (NFTs), which themselves are composed of hyperphosphorylated tau [1,2]. By integrating the large-scale gene expression data of a given tissue and disease-related GWAS data, transcriptome-wide association study (TWAS) has been proposed as a powerful approach to identify genes with significant associations between gene expression in certain tissues and the disease of interest [14,15,16]. By incorporating transcriptomic data of available human tissues and GWAS data of AD, several TWAS studies have confirmed multiple AD-related genes identified by GWASs and found novel genes that have not been previously reported [17,18,19,20,21]. The inclusion of all available tissues in these TWAS studies could improve the power, they provide little tissue-specific information, which is important for exploring pathogenic mechanisms of AD because tissues show different eQTLs [22] and TWAS is more reliable for trait-related tissues than for trait-unrelated tissues [23]
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