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A trans-eQTL network regulates osteoclast multinucleation and bone mass


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.

Type Journal
ISBN 2050-084X (Electronic) 2050-084X (Linking)
Authors Pereira, M.; Ko, J. H.; Logan, J.; Protheroe, H.; Kim, K. B.; Tan, A. L. M.; Croucher, P. I.; Park, K. S.; Rotival, M.; Petretto, E.; Bassett, J. D.; Williams, G. R.; Behmoaras, J.
Responsible Garvan Author Prof Peter Croucher
Publisher Name eLife
Published Date 2020-06-19
Published Volume 9
Status Always Electronic
DOI 10.7554/eLife.55549
URL link to publisher's version