Genome‐wide pathogenesis interpretation using a heat diffusion‐based systems genetics method and implications for gene function annotation

BACKGROUND: Genetics is best dedicated to interpreting pathogenesis and revealing gene functions. The past decade has witnessed unprecedented progress in genetics, particularly in genome‐wide identification of disorder variants through Genome‐Wide Association Studies (GWAS) and Phenome‐Wide Association Studies (PheWAS). However, it is still a great challenge to use GWAS/PheWAS‐derived data to elucidate pathogenesis. METHODS: In this study, we used HotNet2, a heat diffusion‐based systems genetics algorithm, to calculate the networks for disease genes obtained from GWAS and PheWAS, with an attempt to get deeper insights into disease pathogenesis at a molecular level. RESULTS: Through HotNet2 calculation, significant networks for 202 (for GWAS) and 167 (for PheWAS) types of diseases were identified and evaluated, respectively. The GWAS‐derived disease networks exhibit a stronger biomedical relevance than PheWAS counterparts. Therefore, the GWAS‐derived networks were used for pathogenesis interpretation by integrating the accumulated biomedical information. As a result, the pathogenesis for 64 diseases was elucidated in terms of mutation‐caused abnormal transcriptional regulation, and 47 diseases were preliminarily interpreted in terms of mutation‐caused varied protein‐protein interactions. In addition, 3,802 genes (including 46 function‐unknown genes) were assigned with new functions by disease network information, some of which were validated through mice gene knockout experiments. CONCLUSIONS: Systems genetics algorithm HotNet2 can efficiently establish genotype‐phenotype links at the level of biological networks. Compared with original GWAS/PheWAS results, HotNet2‐calculated disease‐gene associations have stronger biomedical significance, hence provide better interpretations for the pathogenesis of genome‐wide variants, and offer new insights into gene functions as well. These results are also helpful in drug development.