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However, its risk genes remain incompletely identified. We developed an Alzheimer\u2019s brain gene network-based approach to predict AD-associated genes by leveraging the functional pattern of known AD-associated genes. Our constructed network outperformed existing networks in predicting AD genes. We then systematically validated the predictions using independent genetic, transcriptomic, proteomic data, neuropathological and clinical data. First, top-ranked genes were enriched in AD-associated pathways. Second, using external gene expression data from the Mount Sinai Brain Bank study, we found that the top-ranked genes were significantly associated with neuropathological and clinical traits, including the Consortium to Establish a Registry for Alzheimer\u2019s Disease score, Braak stage score and clinical dementia rating. The analysis of Alzheimer\u2019s brain single-cell RNA-seq data revealed cell-type-specific association of predicted genes with early pathology of AD. Third, by interrogating proteomic data in the Religious Orders Study and Memory and Aging Project and Baltimore Longitudinal Study of Aging studies, we observed a significant association of protein expression level with cognitive function and AD clinical severity. The network, method and predictions could become a valuable resource to advance the identification of risk genes for AD.<\/jats:p>","DOI":"10.1093\/bib\/bbab522","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T13:43:45Z","timestamp":1636983825000},"source":"Crossref","is-referenced-by-count":6,"title":["An integrated brain-specific network identifies genes associated with neuropathologic and clinical traits of Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"23","author":[{"given":"Cui-Xiang","family":"Lin","sequence":"first","affiliation":[{"name":"School of Computer Science and Engineering, Central South University, Changsha, Hunan 410083, P. R. 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Erhardt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang-Xiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, SKS7N5A9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing-Ming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanfang","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daifeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics and Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Engineering Medicine, Beijing Institute of Technology, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Central South University, Changsha, Hunan 410083, P. 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