Genome-wide association studies of human and rat BMI converge on synapse, epigenome, and hormone signaling networks

A vexing observation in genome-wide association studies (GWASs) is that parallel analyses in different species may not identify orthologous genes. Here, we demonstrate that cross-species translation of GWASs can be greatly improved by an analysis of co-localization within molecular networks. Using body mass index (BMI) as an example, we show that the genes associated with BMI in humans lack significant agreement with those identified in rats. However, the networks interconnecting these genes show substantial overlap, highlighting common mechanisms including synaptic signaling, epigenetic modification, and hormonal regulation. Genetic perturbations within these networks cause abnormal BMI phenotypes in mice, too, supporting their broad conservation across mammals. Other mechanisms appear species specific, including carbohydrate biosynthesis (humans) and glycerolipid metabolism (rodents). Finally, network co-localization also identifies cross-species convergence for height/body length. This study advances a general paradigm for determining whether and how phenotypes measured in model species recapitulate human biology. [Display omitted] •Disparate genetics in humans and rats converge on a conserved molecular network•A systems map of 27 interacting gene communities defines shared BMI biology•Conserved BMI genes are linked to mechanisms of BMI via the Mouse Genome Database•Neuronal pathways are a critical shared mechanism of BMI in humans and rodents Wright et al. identify a conserved molecular network underlying body mass index in humans and rats. Genes in this network, which are also associated with body-size phenotypes in mice, describe key processes including neuronal, epigenetic, and hormonal regulation. This work advances a general paradigm for cross-species GWAS translation.