Systems biology approaches to the search for disease genes in Hirschsprung‘s disease

Abstract

The availability of new methodologies of high performance has revolutionized our ability to discovery. However, the high resolution of such technologies can become a double-edged sword. Reduced sample sizes available in rare diseases are often an obstacle for the detection of candidate genes or the study of their molecular basis. The limitations of the approaches based on isolated genes can be overcome using systems biology approaches. This study shows as a combination of pathway-based analysis (PBA) and network analysis allowed to discover four new loci (RASGEF1A and IQGAP2, DLC1 CHRNA7) related to signalling and migration processes associated with the disease, which were then validated in a cohort of 106 independent trios. The further study of an international cohort of 162 HSCR trios allowed us to confirm the molecular bases of disease using PBA. We found a significant association of processes related to signalling and its regulation as well as formation of the enteric nervous system. Although the genes associated with HSCR varied in different populations, the functions and interaction of affected networks of proteins were always the same, which reflects the complexity of the disease. This methodology of prioritization of candidate genes can be extrapolated to any technology of high performance (WES, RNA-seq, etc.).