Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

Naz, Mufassra; Younesi, Erfan; Hofmann‐Apitius, Martin

doi:10.4172/2161-0460.1000368

Cited by 2 publications

(2 citation statements)

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“…Therefore, chances are higher that literature aided inferences could represent biased knowledge. Taking this into consideration, Naz et al (2017) have analyzed genomic data and performed functional assessment of prioritized SNPs using literature to depict stress-induced comorbid association in AD and PD [ 14 ]. This approach not only eliminates biasedness of over-representation of well-known biological entities and processes, but also identifies new genes and associated events which can serve as putative drug targets and drugable mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Data-Driven Modeling of Knowledge Assemblies in Understanding Comorbidity Between Type 2 Diabetes Mellitus and Alzheimer’s Disease

Karki

Madan

Gadiya

et al. 2020

JAD

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Background: Recent studies have suggested comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) through identification of shared molecular mechanisms. However, the inference is pre-dominantly literature-based and lacks interpretation of pre-disposed genomic variants and transcriptomic measurables. Objective: In this study, we aim to identify shared genetic variants and dysregulated genes in AD and T2DM and explore their functional roles in the comorbidity between the diseases. Methods: The genetic variants for AD and T2DM were retrieved from GWAS catalog, GWAS central, dbSNP, and DisGeNet and subjected to linkage disequilibrium analysis. Next, shared variants were prioritized using RegulomeDB and Polyphen-2. Afterwards, a knowledge assembly embedding prioritized variants and their corresponding genes was created by mining relevant literature using Biological Expression Language. Finally, coherently perturbed genes from gene expression meta-analysis were mapped to the knowledge assembly to pinpoint biological entities and processes and depict a mechanistic link between AD and T2DM. Results: Our analysis identified four genes (i.e., ABCG1, COMT, MMP9, and SOD2) that could have dual roles in both AD and T2DM. Using cartoon representation, we have illustrated a set of causal events surrounding these genes which are associated to biological processes such as oxidative stress, insulin resistance, apoptosis and cognition. Conclusion: Our approach of using data as the driving force for unraveling disease etiologies eliminates literature bias and enables identification of novel entities that serve as the bridge between comorbid conditions.

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Section: Introductionmentioning

confidence: 99%

Data-Driven Modeling of Knowledge Assemblies in Understanding Comorbidity Between Type 2 Diabetes Mellitus and Alzheimer’s Disease

Karki

Madan

Gadiya

et al. 2020

JAD

Self Cite

View full text Add to dashboard Cite

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“…For instance, the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leads to the cardinal motor symptoms in PD ( Kalia and Lang, 2015 ), whereas the degeneration of hippocampal and cortical neurons results in memory impairment, cognitive dysfunction, and dementia in AD ( Oboudiyat et al, 2013 ). In spite of these clinical differences, NDs present substantial neuropathological and genetic overlap ( Naz et al, 2017 ; Gan et al, 2018 ; Karch et al, 2018 ). Pathways altered in various NDs include protein quality control, the autosomal-lysosome pathway, mitochondrial homeostasis, protein seeding, propagation of stress granules, synaptic toxicity, and network dysfunction ( Gan et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Retrotransposons as a Source of DNA Damage in Neurodegeneration

Peze‐Heidsieck

Bonnifet

Znaidi

et al. 2022

Front. Aging Neurosci.

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The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.

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Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

Cited by 2 publications

References 78 publications

Data-Driven Modeling of Knowledge Assemblies in Understanding Comorbidity Between Type 2 Diabetes Mellitus and Alzheimer’s Disease

Data-Driven Modeling of Knowledge Assemblies in Understanding Comorbidity Between Type 2 Diabetes Mellitus and Alzheimer’s Disease

Retrotransposons as a Source of DNA Damage in Neurodegeneration

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