Genome-wide Network-assisted Association and Enrichment Study of Amyloid Imaging Phenotype in Alzheimer’s Disease

Author(s): Jin Li, Feng Chen, Qiushi Zhang, Xianglian Meng, Xiaohui Yao, Shannon L. Risacher, Jingwen Yan, Andrew J. Saykin, Hong Liang*, Li Shen*, for the Alzheimer’s Disease Neuroimaging Initiative

Journal Name: Current Alzheimer Research

Volume 16 , Issue 13 , 2019

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Abstract:

Background: 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.

Keywords: Alzheimer’s disease, amyloid imaging phenotype, genome-wide association, network analysis, pathway enrichment, consensus modules, neurodegenerative disease.

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Article Details

VOLUME: 16
ISSUE: 13
Year: 2019
Page: [1163 - 1174]
Pages: 12
DOI: 10.2174/1567205016666191121142558
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