Analysis of brain region-specific co-expression networks reveals clustering of established and novel genes associated wi
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(2020) 12:103
RESEARCH
Open Access
Analysis of brain region-specific coexpression networks reveals clustering of established and novel genes associated with Alzheimer disease Daniel Lancour1,2, Josée Dupuis3, Richard Mayeux4, Jonathan L. Haines5, Margaret A. Pericak-Vance6, Gerard C. Schellenberg7, Mark Crovella1,8†, Lindsay A. Farrer1,2,3,9,10,11*† and Simon Kasif1,12†
Abstract Background: Identifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with agerelated neurodegeneration. Methods: A gene co-expression network was constructed using data obtained from the Allen Brain Atlas for multiple brain regions (cerebral cortex, cerebellum, and brain stem) in six individuals. Gene network analyses were seeded with 52 reproducible (i.e., established) AD (RAD) genes. Genome-wide association study summary data were integrated with the gene co-expression results and phenotypic information (i.e., memory and aging-related outcomes) from gene knockout studies in Drosophila to generate rankings for other genes that may have a role in AD. Results: We found that co-expression of the RAD genes is strongest in the cortical regions where neurodegeneration due to AD is most severe. There was significant evidence for two novel AD-related genes including EPS8 (FDR p = 8.77 × 10−3) and HSPA2 (FDR p = 0.245). Conclusions: Our findings indicate that AD-related risk factors are potentially associated with brain region-specific effects on gene expression that can be detected using a gene network approach. Keywords: Alzheimer disease, Gene network analysis, Brain regions, Genome-wide association study, EPS8, HSPA2
Background Neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis, impair or damage neurons. Although many sub-cellular similarities between neurodegenerative diseases have been identified [1], the * Correspondence: [email protected] † Mark Crovella, Lindsay A. Farrer and Simon Kasif contributed equally to this work. 1 Bioinformatics Graduate Program, Boston University, Boston, MA, USA 2 Department of Medicine (Biomedical Genetics E200), Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA Full list of author information is available at the end of the article
regional differences between them are quite profound [2–5]. For example, neuronal cell death from HD is primarily localized to the basal ganglia, whereas both AD and PD result in cell death throughout the brain [5]. Furthermore, PD causes the most severe cell death in the substantia nigra [2] whereas AD most heavily affects the hippocampus, the frontal cortex, and the temporal lobe [4]. These studies highlight the importance of studying gene expression signatures and relationships of AD-associated genes in different brain regions. For instance, an increased correlation in gene expression among two AD-associated genes in
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