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Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a  trans -regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene  Bcat1  and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global ( Pik3cb -/-  ,  Atp8b2 +/-  ,  Igsf8 -/-  ,  Eml1 -/-  ,  Appl2 -/-  ,  Deptor -/-  ) and myeloid-specific  Slc40a1  knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.

A trans-eQTL network regulates osteoclast multinucleation and bone mass