Hippocampal transcriptome-wide association study and neurobiological pathway analysis for Alzheimer's disease.
Nana LiuJiayuan XuHuaigui LiuShijie ZhangMiao-Xin LiYao ZhouWen QinMulin Jun LiChunshui Yunull nullPublished in: PLoS genetics (2021)
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.
Keyphrases
- gene expression
- cerebral ischemia
- genome wide
- poor prognosis
- temporal lobe epilepsy
- dna methylation
- subarachnoid hemorrhage
- genome wide association
- blood brain barrier
- systematic review
- oxidative stress
- electronic health record
- type diabetes
- multiple sclerosis
- randomized controlled trial
- single cell
- high resolution
- rna seq
- binding protein
- prognostic factors
- long non coding rna
- mild cognitive impairment
- signaling pathway
- dna damage
- artificial intelligence
- newly diagnosed
- endoplasmic reticulum stress
- air pollution
- data analysis
- skeletal muscle
- cell death
- bioinformatics analysis
- middle aged
- cognitive impairment
- community dwelling
- cell cycle arrest