Transcriptome-wide Associations Between Hippocampal Transcription And Alzheimer’s Disease

Objective: Genome-wide association studies(GWAS)identify multiple susceptibility loci for Alzheimer’s disease(AD),which is characterized by early and progressive damage of the hippocampus;however,associations between hippocampal transcription and AD remain elusive.Here,we attempted to provide new insights into associations between hippocampal transcription and AD by transcriptome-wide association study(TWAS)and explain its underlying mechanisms.Subjects and Methods: 1.AD TWAS and Fine-mapping of causal gene sets(FOCUS)analysis This study used whole genome sequencing(WGS)and RNA-seq data of 111 hippocampal samples from the GTEx to build prediction models for gene expression in hippocampal tissue.GWAS summary data included 71,880 AD or AD-by-proxy cases and 383,378 controls.TWAS was used to integrate the hippocampal expression prediction models and the GWAS data to identify AD-related hippocampal-expressed genes.In the validation stage,we replicated our findings in a GWAS meta-analysis of diagnosed AD(21,982 cases,41,944 controls).FOCUS was further used to identify causal genes for AD by estimate the posterior inclusion probabilities for causality of TWAS associations.2.Functional annotation of AD related genes Hippocampal tissue-specific gene network analysis was used to test whether the identified AD-related genes were involved in certain cohesive gene clusters in hippocampal tissue.Functional enrichment was performed for resulting functional modules using Gene Ontology(GO)biological process terms.3.ADNI data validating analysis First,for the AD related genes,we used binary logistic regression to compare the difference in the hippocampal tissue predicted expression of each gene between the AD(N = 599)and cognitively normal(CN,N = 317)groups.Second,we performed linear regression between the predicted expression of each validated AD related gene and mean hippocampal volume.Third,we performed a mediation analysis to test whether the hippocampal volume mediates the association between the hippocampal tissue predicted expression and AD.Results: 1.TWAS and FOCUS identified AD-related genes In the discovery stage,TWAS identified 54 genes whose expression in hippocampal tissue was significantly associated with AD.In the validation stage,we were able to replicate 36 of the 54 TWAS associations.FOCUS found that 24 out of the 36 TWAS identified genes were included in credible set at nominal confidence level(90%).APOE expression in hippocampus was confirmed to affect AD,and 2 novel genes of AD were identified(PTPN9 and PCDHA4).2.Hippocampal tissue-specific functional modules and GO processes related to AD Using the 24 AD-related genes,two cohesive functional modules were identified in hippocampal tissue-specific network-based functional interpretation,further functional enrichment revealed the association of dephosphorylation,neurogenesis and neuron differentiation processes with AD.3.Hippocampal gene expression-hippocampal volume-AD pathway QPCTL and ERCC2 showed significant difference in the predicted hippocampal expression between the AD and CN groups and demonstrated significant correlations between the predicted hippocampal expression and hippocampal volume.Mediation analysis showed that the hippocampal volume mediated the effect of the predicted hippocampal gene expression(QPCTL and ERCC2)on the development of ADConclusion: This study provides a set of candidate genes linking to AD via affecting gene expression in hippocampal tissue and explains the biological mechanism of these genes,additionally,provides neural mechanisms for the association of hippocampal expression of QPCTL and ERCC2 with AD.