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

Abstract

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.

Linking COVID-19 and heme-driven pathophysiologies: A combined computational-experimental approach

“…Taken together, these clinical observations suggest a correlation between both processes, which we aimed to analyze by superimposing the two KGs of both pathophysiologies [42,54]. We overlayed Heme KG with COVID-19 KG to identify similarities, as successfully shown in the earlier reported approach for type II Diabetes and Alzheimer's disease [50,51,53]. Indeed, the results of the knowledge-driven analysis revealed a core of similar shared molecular patterns.…”

“…This knowledge gap can be addressed by using custom-made models, such as Knowledge Graphs (KGs) [50]. Placing research data in the right context by employing KGs supports the elucidation of biochemical mechanisms, the generation of novel hypotheses, and the identi cation of targets for drug repurposing [50][51][52][53]. Two of our recent scienti c publications focused on KGs around heme as well as COVID-19 [42,54].…”

Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach

“…Taken together, these clinical observations suggest a correlation between both processes, which we aimed to analyze by superimposing the two KGs of both pathophysiologies [ 42 , 54 ]. We overlayed the Heme KG with the COVID-19 KG to identify similarities, as successfully shown in the earlier reported approach for type II diabetes and Alzheimer’s disease [ 50 , 51 , 53 ]. Indeed, the results of the knowledge-driven analysis revealed a core of similar shared molecular patterns.…”

“…This knowledge gap can be addressed by using custom-made models such as knowledge graphs (KGs) [ 50 ]. Placing research data in the right context by employing KGs supports the elucidation of biochemical mechanisms, the generation of novel hypotheses, and the identification of targets for drug repurposing [ 50 , 51 , 52 , 53 ]. Two of our recent scientific publications focused on KGs around heme as well as COVID-19 [ 42 , 54 ].…”

Exploring the Genetic Conception of Obesity via the Dual Role of FoxO

“…Many experiments suggested that impaired metabolism in obesity, overweight, or type 2 diabetes mellitus (T2DM) influences the physiological actions of the brain, such as memory and cognitive function [ 6 , 7 ]. Adipose tissue regulates metabolism and energy balance throughout the body and is a significant targeted therapy for metabolic syndrome.…”