Analytical Strategy to Prioritize Alzheimer’s Disease Candidate Genes in Gene Regulatory Networks Using Public Expression Data

Kawalia, Shweta Bagewadi; Raschka, Tamara; Naz, Mufassra; Simoes, Ricardo de Matos; Senger, Philipp; Hofmann-Apitius, Martin

doi:10.3233/jad-170011

Cited by 18 publications

(10 citation statements)

References 97 publications

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“…Another important gene, ATP2A3, encodes one of the SERCA Ca(2+)-ATPases, which are involved in maintenance of low intraneural Ca2+ concentration. The malfunction of this pump was recently found in brains of AD subjects (42,43). On the protein-protein interaction network, the RHBDF2 gene is connected to ADAM17, which is an alpha-secretase candidate processing amyloid precursor protein (APP) (44).…”

Section: Resultsmentioning

confidence: 85%

coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes

Gomez

Odom

Young

et al. 2019

Nucleic Acids Research

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Recent technology has made it possible to measure DNA methylation profiles in a cost-effective and comprehensive genome-wide manner using array-based technology for epigenome-wide association studies. However, identifying differentially methylated regions (DMRs) remains a challenging task because of the complexities in DNA methylation data. Supervised methods typically focus on the regions that contain consecutive highly significantly differentially methylated CpGs in the genome, but may lack power for detecting small but consistent changes when few CpGs pass stringent significance threshold after multiple comparison. Unsupervised methods group CpGs based on genomic annotations first and then test them against phenotype, but may lack specificity because the regional boundaries of methylation are often not well defined. We present coMethDMR, a flexible, powerful, and accurate tool for identifying DMRs. Instead of testing all CpGs within a genomic region, coMethDMR carries out an additional step that selects co-methylated sub-regions first. Next, coMethDMR tests association between methylation levels within the sub-region and phenotype via a random coefficient mixed effects model that models both variations between CpG sites within the region and differential methylation simultaneously. coMethDMR offers well-controlled Type I error rate, improved specificity, focused testing of targeted genomic regions, and is available as an open-source R package.

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Section: Resultsmentioning

confidence: 85%

coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes

Gomez

Odom

Young

et al. 2019

Nucleic Acids Research

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“…Besides, SNPs near YDJC are suggested to be a pleiotropic locus between AD and Crohn disease . Lately, UBE2L3 has been identified as a hub gene in the gene regulatory networks of AD …”

Section: Discussionmentioning

confidence: 99%

Shared genes between Alzheimer’s disease and ischemic stroke

Wei

Cui

et al. 2019

CNS Neurosci Ther

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Summary Aims Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. Methods Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. Results 16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2 , two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes ( EPHA1 , MS4A4A , UBE2L3 and TREM2 ), implicating crucial roles of the immune system in the pathogenesis of AD and IS. Conclusions The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

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“…These genes encode not only transcription factors but also proteins involved in neuron differentiation, synaptic plasticity and intracellular signaling. Stx2 was reported to play a role in CNS damage [33][34][35]. Stx2 interacts with neurons and promotes structural changes in the cell membrane that may indicate the synaptic vesicle cycle [36].…”

Section: Discussionmentioning

confidence: 99%

Behavioral Sensitization Induced by Methamphetamine Causes Differential Alterations in Gene Expression and Histone Acetylation of the Prefrontal Cortex in Rats

Chen

Ding

et al. 2020

Preprint

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Background: Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats.Methods: We conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays.Results: In the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure.Conclusions: The present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.

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Analytical Strategy to Prioritize Alzheimer’s Disease Candidate Genes in Gene Regulatory Networks Using Public Expression Data

Cited by 18 publications

References 97 publications

coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes

coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes

Shared genes between Alzheimer’s disease and ischemic stroke

Behavioral Sensitization Induced by Methamphetamine Causes Differential Alterations in Gene Expression and Histone Acetylation of the Prefrontal Cortex in Rats

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