Genome-Wide Association Study of Brain Connectivity Changes for Alzheimer’s Disease

Elsheikh, Samar S. M.; Chimusa, Emile R.; Mulder, Nicola; Crimi, Alessandro

doi:10.1101/342436

Cited by 4 publications

(10 citation statements)

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“…In brief, GO summarizes our current knowledge on biological domains regarding three main aspects: (i) biological process, (ii) molecular function, and (iii) cellular component-all attributes of genes, gene products or gene-product groups. In this context, to explore the molecular aspects underlying the complex changes observed in AD, a number of genome-wide expression profiling experiments were performed in hippocampal tissues from AD patients (Elsheikh et al, 2019;Andrews et al, 2020), including functional pathway enrichment analyses with gene ontology terms of expression profiling. The most relevant GO categories in molecular function are those primarily involved in synaptic function, notably "synaptic signaling, transmission and processing, " and "synaptic vesicle metabolism" (Wu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Neuronal–Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer’s Disease: Gene Ontology and Lithium Pathways

et al. 2020

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Neuronal-glial interactions are critical for brain homeostasis, and disruption of this process may lead to excessive glial activation and inadequate pro-inflammatory responses. Abnormalities in neuronal-glial interactions have been reported in the pathophysiology of Alzheimer’s disease (AD), where lithium has been shown to exert neuroprotective effects, including the up-regulation of cytoprotective proteins. In the present study, we characterize by Gene Ontology (GO) the signaling pathways related to neuronal-glial interactions in response to lithium in a triple-transgenic mouse model of AD (3×-TgAD). Mice were treated for 8 months with lithium carbonate (Li) supplemented to chow, using two dose ranges to yield subtherapeutic working concentrations (Li1, 1.0 g/kg; and Li2, 2.0 g/kg of chow), or with standard chow (Li0). The hippocampi were removed and analyzed by proteomics. A neuronal-glial interaction network was created by a systematic literature search, and the selected genes were submitted to STRING, a functional network to analyze protein interactions. Proteomics data and neuronal-glial interactomes were compared by GO using ClueGo (Cytoscape plugin) with p ≤ 0.05. The proportional effects of neuron-glia interactions were determined on three GO domains: (i) biological process; (ii) cellular component; and (iii) molecular function. The gene ontology of this enriched network of genes was further stratified according to lithium treatments, with statistically significant effects observed in the Li2 group (as compared to controls) for the GO domains biological process and cellular component. In the former, there was an even distribution of the interactions occurring at the following functions: “positive regulation of protein localization to membrane,” “regulation of protein localization to cell periphery,” “oligodendrocyte differentiation,” and “regulation of protein localization to plasma membrane.” In cellular component, interactions were also balanced for “myelin sheath” and “rough endoplasmic reticulum.” We conclude that neuronal-glial interactions are implicated in the neuroprotective response mediated by lithium in the hippocampus of AD-transgenic mice. The effect of lithium on homeostatic pathways mediated by the interaction between neurons and glial cells are implicated in membrane permeability, protein synthesis and DNA repair, which may be relevant for the survival of nerve cells amidst AD pathology.

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Section: Introductionmentioning

confidence: 99%

Neuronal–Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer’s Disease: Gene Ontology and Lithium Pathways

et al. 2020

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“…Of note, previous studies have mostly found that the ApoE genotypeodulates brain network properties, especially in AD patients (Zhao et al, 2012;Wang et al, 2015). Another study also found that significant associations between the change in structural brain connectivity defined by tractography and genes (Elsheikh et al, 2020). However, the genetic variants associated with the topology of the functional brain network on the basis of whole genome-wide analysis and its pathological alterations in AD are largely unknown.…”

Section: Introductionmentioning

confidence: 98%

“…Rapid progress in deciphering the biological mechanism of AD has arisen from the application of genotype-to-phenotype relationships (Selkoe, 2001). Recent genome-wide association studies (GWAS) on neuroimaging phenotypes have identified several genes and their variants associated with AD, such as APOE, TAU, TOMM40, ABCA7, CLU, CR1, CD33, CD2AP, EPHA1, BIN1, PICALM, MS4A (Bertram et al, 2008;Denise et al, 2009;Jean-Charles et al, 2009;Potkin et al, 2009;Hollingworth et al, 2011;Naj et al, 2011;Bettens et al, 2013;Lambert et al, 2013), and other novel genes, such as ANTXR2, OR5L1, IGF1, ZDHHC12, ENDOG and JAK1 (Elsheikh et al, 2020). In these genes, single nucleotide polymorphism (SNP) variants affect AD risk (Braskie et al, 2011;Hibar et al, 2015;Farfel et al, 2016;Gaiteri et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase 4D Gene Modifies the Functional Network of Patients With Mild Cognitive Impairment and Alzheimer’s Disease

et al. 2020

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is affected by several genetic variants. It has been demonstrated that genetic variants affect brain organization and function. In this study, using whole genome-wide association studies (GWAS), we analyzed the functional magnetic resonance imaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative dataset (ADNI) dataset and identified genetic variants associated with the topology of the functional brain network http://www. adni-info.org. We found three novel loci (rs2409627, rs9647533, and rs11955845) in an intron of the phosphodiesterase 4D (PDE4D) gene that contribute to abnormalities in the topological organization of the functional network. In particular, compared to the wildtype genotype, the subjects carrying the PDE4D variants had altered network properties, including a significantly reduced clustering coefficient, small-worldness, global and local efficiency, a significantly enhanced path length and a normalized path length. In addition, we found that all global brain network attributes were affected by PDE4D variants to different extents as the disease progressed. Additionally, brain regions with alterations in nodal efficiency due to the variations in PDE4D were predominant in the limbic lobe, temporal lobe and frontal lobes. PDE4D has a great effect on memory consolidation and cognition through long-term potentiation (LTP) effects and/or the promotion of inflammatory effects. PDE4D variants might be a main reasons underlyling for the abnormal topological properties and cognitive impairment. Furthermore, we speculated that PDE4D is a risk factor for neural degenerative diseases and provided important clues for the earlier detection and therapeutic intervention for AD.

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“…Moreover, the connectome can also be used to quantify local properties of the brain (i.e., properties at specific nodes/areas). These measures (i.e., global and local connectivity metrics) can reflect neurodegeneration in the sense that neuronal apoptosis (i.e., programmed cell death) can be represented as a reduction in structural connectivity (Douaud et al, 2007;Elsheikh et al, 2020b).…”

Section: Introductionmentioning

confidence: 99%

“…Genetic variants located in about 20 genes have been reported to affect the disease through many cell-type specific biological functions (Gaiteri et al, 2016). Genome-Wide Associations Studies (GWAS), also highlighted dozens of multi-scale genetic variations associated with AD risk (Lambert et al, 2013;Escott-Price et al, 2014;Elsheikh et al, 2020b). From the early stages of studying the disease, the well known genetic risk factors of AD were found to lie within the coding genes of proteins involved in amyloidβ(Aβ) processing.…”

Section: Introductionmentioning

confidence: 99%

Relating Global and Local Connectome Changes to Dementia and Targeted Gene Expression in Alzheimer's Disease

Elsheikh

Chimusa

Initiative³

et al. 2021

Front. Hum. Neurosci.

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Networks are present in many aspects of our lives, and networks in neuroscience have recently gained much attention leading to novel representations of brain connectivity. The integration of neuroimaging characteristics and genetics data allows a better understanding of the effects of the gene expression on brain structural and functional connections. The current work uses whole-brain tractography in a longitudinal setting, and by measuring the brain structural connectivity changes studies the neurodegeneration of Alzheimer's disease. This is accomplished by examining the effect of targeted genetic risk factors on the most common local and global brain connectivity measures. Furthermore, we examined the extent to which Clinical Dementia Rating relates to brain connections longitudinally, as well as to gene expression. For instance, here we show that the expression of PLAU gene increases the change over time in betweenness centrality related to the fusiform gyrus. We also show that the betweenness centrality metric impact dementia-related changes in distinct brain regions. Our findings provide insights into the complex longitudinal interplay between genetics and brain characteristics and highlight the role of Alzheimer's genetic risk factors in the estimation of regional brain connectivity alterations.

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Genome-Wide Association Study of Brain Connectivity Changes for Alzheimer’s Disease

Cited by 4 publications

References 64 publications

Neuronal–Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer’s Disease: Gene Ontology and Lithium Pathways

Neuronal–Glial Interaction in a Triple-Transgenic Mouse Model of Alzheimer’s Disease: Gene Ontology and Lithium Pathways

Phosphodiesterase 4D Gene Modifies the Functional Network of Patients With Mild Cognitive Impairment and Alzheimer’s Disease

Relating Global and Local Connectome Changes to Dementia and Targeted Gene Expression in Alzheimer's Disease

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