Intersection of network medicine and machine learning towards investigating the key biomarkers and pathways underlying amyotrophic lateral sclerosis: a systematic review

Das, Trishala; Kaur, Harbinder; Gour, Pratibha; Prasad, Kartikay; Lynn, Andrew M.; Prakash, Amresh; Kumar, Vijay

doi:10.1093/bib/bbac442

Cited by 9 publications

(2 citation statements)

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“…Network based approaches assume that the intricacies of biological systems can be deciphered by analyzing the structures within biological networks. To this end, various biological networks, including protein-protein interaction networks [22][23][24], metabolic networks [25][26][27][28], gene regulatory networks [29,30], and epistatic networks [31], have been proposed to describe the complex processes that drive traits and diseases.…”

Section: Introductionmentioning

confidence: 99%

Distinct Network Patterns Emerge from Cartesian and XOR Epistasis Models: A Comparative Network Science Analysis

Sha,

Freda,

Bhandary

et al. 2024

Preprint

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Background Epistasis, the phenomenon where the effect of one gene (or variant) is masked or modified by one or more other genes, can significantly contribute to the observed phenotypic variance of complex traits. To date, it has been generally assumed that genetic interactions can be detected using a Cartesian, or multiplicative, interaction model commonly utilized in standard regression approaches. However, a recent study investigating epistasis in obesity-related traits in rats and mice has identified potential limitations of the Cartesian model, revealing that it only detects some of the genetic interactions occurring in these systems. By applying an alternative approach, the exclusive-or (XOR) model, the researchers detected a greater number of epistatic interactions and identified more biologically relevant ontological terms associated with the interacting loci. This suggests that the XOR model may provide a more comprehensive understanding of epistasis in these species and phenotypes. To further explore these findings and determine if different interaction models also make up distinct epistatic networks, we leverage network science to provide a more comprehensive view into the genetic interactions underlying BMI in this system. Results Our comparative analysis of networks derived from Cartesian and XOR interaction models in rats (Rattus norvegicus) uncovers distinct topological characteristics for each model-derived network. Notably, we discover that networks based on the XOR model exhibit an enhanced sensitivity to epistatic interactions. This sensitivity enables the identification of network communities, revealing novel trait-related biological functions through enrichment analysis. Furthermore, we identify triangle network motifs in the XOR epistatic network, suggestive of higher-order epistasis, based on the topology of lower-order epistasis. Conclusions These findings highlight the XOR model's ability to uncover meaningful biological associations as well as higher-order epistasis from lower-order epistatic networks. Additionally, our results demonstrate that network approaches not only enhance epistasis detection capabilities but also provide more nuanced understandings of genetic architectures underlying complex traits. The identification of community structures and motifs within these distinct networks, especially in XOR, points to the potential for network science to aid in the discovery of novel genetic pathways and regulatory networks. Such insights are important for advancing our understanding of phenotype-genotype relationships.

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Section: Introductionmentioning

confidence: 99%

Distinct Network Patterns Emerge from Cartesian and XOR Epistasis Models: A Comparative Network Science Analysis

Sha,

Freda,

Bhandary

et al. 2024

Preprint

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“…To better understand the mechanisms associated with clinical heterogeneity, different transcriptomic studies have been performed to understand the mechanisms of neurodegeneration [30][31][32][33]. Transcriptome investigation of ALS patients' frontal cortical and motor neurons revealed splicing alterations, dysregulation of RNA processing pathways, and alternative polyadenylation in sporadic and C9orf72 HRE carriers [30,34,35].…”

Section: Introductionmentioning

confidence: 99%

Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features

Prasad,

Hassan,

Raghuvanshi

et al. 2024

PLoS ONE

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Background Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive research the progress from diagnosis to prognosis in ALS and frontotemporal dementia (FTD) has been slow which represents suboptimal understanding of disease pathophysiological processes. In recent studies, several genes have been associated with the ALS and FTD diseases such as SOD1, TDP43, and TBK1, whereas the hexanucleotide GGGGCC repeat expansion (HRE) in C9orf72 gene is a most frequent cause of ALS and FTD, that has changed the understanding of these diseases. Methods The goal of this study was to identify and spatially determine differential gene expression signature differences between cerebellum and frontal cortex in C9orf72-associated ALS (C9-ALS), to study the network properties of these differentially expressed genes, and to identify miRNAs targeting the common differentially expressed genes in both the tissues. This study thus highlights underlying differential cell susceptibilities to the disease mechanisms in C9-ALS and suggesting therapeutic target selection in C9-ALS. Results In this manuscript, we have identified that the genes involved in neuron development, protein localization and transcription are mostly enriched in cerebellum of C9-ALS patients, while the UPR-related genes are enriched in the frontal cortex. Of note, UPR pathway genes were mostly dysregulated both in the C9-ALS cerebellum and frontal cortex. Overall, the data presented here show that defects in normal RNA processing and the UPR pathway are the pathological hallmarks of C9-ALS. Interestingly, the cerebellum showed more strong transcriptome changes than the frontal cortex. Conclusion Interestingly, the cerebellum region showed more significant transcriptomic changes as compared to the frontal cortex region suggesting its active participation in the disease process. This nuanced understanding may offer valuable insights for the development of targeted therapeutic strategies aimed at mitigating disease progression in C9-ALS.

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Neurotoxicity of Pyrethroids in neurodegenerative diseases: From animals' models to humans’ studies

Arsuffi-Marcon,

Souza,

Santos-Miranda

et al. 2024

Chemico-Biological Interactions

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Intersection of network medicine and machine learning towards investigating the key biomarkers and pathways underlying amyotrophic lateral sclerosis: a systematic review

Cited by 9 publications

References 145 publications

Distinct Network Patterns Emerge from Cartesian and XOR Epistasis Models: A Comparative Network Science Analysis

Distinct Network Patterns Emerge from Cartesian and XOR Epistasis Models: A Comparative Network Science Analysis

Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features

Neurotoxicity of Pyrethroids in neurodegenerative diseases: From animals' models to humans’ studies

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