Genetic interactions of schizophrenia using gene-based statistical epistasis exclusively identify nervous system-related pathways and key hub genes

Background: The relationship between genotype and phenotype is governed by numerous genetic interactions (GIs), and the mapping of GI networks is of interest for two main reasons: 1) By modelling biological robustness, GIs provide a powerful opportunity to infer compensatory biological mechanisms via the identification of functional relationships between genes, which is of interest for biological discovery and translational research. Biological systems have evolved to compensate for genetic (i.e., variations and mutations) and environmental (i.e., drug efficacy) perturbations by exploiting compensatory relationships between genes, pathways and biological processes; 2) GI facilitates the identification of the direction (alleviating or aggravating interactions) and magnitude of epistatic interactions that influence the phenotypic outcome. The generation of GIs for human diseases is impossible using experimental biology approaches such as systematic deletion analysis. Moreover, the generation of disease-specific GIs has never been undertaken in humans. Methods: We used our Indian schizophrenia case-control (case-816, controls-900) genetic dataset to implement the workflow. Standard GWAS sample quality control procedure was followed. We used the imputed genetic data to increase the SNP coverage to analyse epistatic interactions across the genome comprehensively. Using the odds ratio (OR), we identified the GIs that increase or decrease the risk of a disease phenotype. The SNP-based epistatic results were transformed into gene-based epistatic results. Results: We have developed a novel approach by conducting gene-based statistical epistatic analysis using an Indian schizophrenia case-control genetic dataset and transforming these results to infer GIs that increase the risk of schizophrenia. There were similar to 9.5 million GIs with a p-value <= 1 xx 10(-5). Approximately 4.8 million GIs showed an increased risk (OR > 1.0), while similar to 4.75 million GIs had a decreased risk (OR <1.0) for schizophrenia. Conclusion: Unlike model organisms, this approach is specifically viable in humans due to the availability of abundant disease-specific genome-wide genotype datasets. The study exclusively identified brain/nervous system-related processes, affirming the findings. This computational approach fills a critical gap by generating practically non-existent heritable disease-specific human GIs from human genetic data. These novel datasets can train innovative deep-learning models, potentially surpassing the limitations of conventional GWAS.