Li, JinChen, FengZhang, QiushiMeng, XianglianYao, XiaohuiRisacher, Shannon L.Yan, JingwenSaykin, Andrew J.Liang, HongShen, Li2023-02-282023-02-282019Li J, Chen F, Zhang Q, et al. Genome-wide Network-assisted Association and Enrichment Study of Amyloid Imaging Phenotype in Alzheimer's Disease. Curr Alzheimer Res. 2019;16(13):1163-1174. doi:10.2174/1567205016666191121142558https://hdl.handle.net/1805/31515Background: The etiology of Alzheimer's disease remains poorly understood at the mechanistic level, and genome-wide network-based genetics have the potential to provide new insights into the disease mechanisms. Objective: The study aimed to explore the collective effects of multiple genetic association signals on an AV-45 PET measure, which is a well-known Alzheimer's disease biomarker, by employing a network assisted strategy. Methods: First, we took advantage of a dense module search algorithm to identify modules enriched by genetic association signals in a protein-protein interaction network. Next, we performed statistical evaluation to the modules identified by dense module search, including a normalization process to adjust the topological bias in the network, a replication test to ensure the modules were not found randomly , and a permutation test to evaluate unbiased associations between the modules and amyloid imaging phenotype. Finally, topological analysis, module similarity tests and functional enrichment analysis were performed for the identified modules. Results: We identified 24 consensus modules enriched by robust genetic signals in a genome-wide association analysis. The results not only validated several previously reported AD genes (APOE, APP, TOMM40, DDAH1, PARK2, ATP5C1, PVRL2, ELAVL1, ACTN1 and NRF1), but also nominated a few novel genes (ABL1, ABLIM2) that have not been studied in Alzheimer's disease but have shown associations with other neurodegenerative diseases. Conclusion: The identified genes, consensus modules and enriched pathways may provide important clues to future research on the neurobiology of Alzheimer's disease and suggest potential therapeutic targets.en-USPublisher PolicyAlzheimer’s diseaseAmyloid imaging phenotypeGenome-wide associationNetwork analysisPathway enrichmentConsensus modulesNeurodegenerative diseaseArticle