Degree Adjusted Large-Scale Network Analysis Reveals Novel Putative Metabolic Disease Genes

SIMPLE SUMMARY: To explore some of the low-degree but topologically important nodes in the Metabolic disease (MD) network, we propose a background-corrected betweenness centrality (BC) and identify 16 novel candidates likely to play a role in MD. MD specific protein–protein interaction networks (PPINs) were constructed using two known databasesHuman Protein Reference Database (HPRD) and BioGRID. The identified candidates have been found to play a role in diverse conditions including co-morbidities of MD, neurological and immune system-related conditions. ABSTRACT: A large percentage of the global population is currently afflicted by metabolic diseases (MD), and the incidence is likely to double in the next decades. MD associated co-morbidities such as non-alcoholic fatty liver disease (NAFLD) and cardiomyopathy contribute significantly to impaired health. MD are complex, polygenic, with many genes involved in its aetiology. A popular approach to investigate genetic contributions to disease aetiology is biological network analysis. However, data dependence introduces a bias (noise, false positives, over-publication) in the outcome. While several approaches have been proposed to overcome these biases, many of them have constraints, including data integration issues, dependence on arbitrary parameters, database dependent outcomes, and computational complexity. Network topology is also a critical factor affecting the outcomes. Here, we propose a simple, parameter-free method, that takes into account database dependence and network topology, to identify central genes in the MD network. Among them, we infer novel candidates that have not yet been annotated as MD genes and show their relevance by highlighting their differential expression in public datasets and carefully examining the literature. The method contributes to uncovering connections in the MD mechanisms and highlights several candidates for in-depth study of their contribution to MD and its co-morbidities.