A novel approach has been used to identify functional interactions relevant to human disease. Using high-throughput human-yeast genetic interaction screens, a first draft of disease interactome was obtained. This was achieved by firstly searching for candidate human disease genes that confer toxicity in yeast, and secondly identifying modulators of this toxicity. The study found potentially disease-relevant interactions by analyzing the network of functional interactions and focusing on genes implicated in amyotrophic lateral sclerosis (ALS), for instance. In the subsequent proof-of-concept study focused on ALS, similar functional relationships between a specific kinase and ALS-associated genes were observed in mammalian cells and zebrafish, thereby supporting the findings in the human-yeast genetic interaction screens. Finally, results of combined analyses highlighted MAP2K5 kinase as a potential therapeutic target in ALS.