Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease
Chai, R. C.; Lundberg, M.; Freudenthal, B.; Smith, J. T.; Boughton, A. P.; Zhang, Y.; Flynn, K. A.; Frysz, M.; Corr, A. P.; Khoo, W. H.; Komla-Ebri, D.; Dack, M. R. G.; Guilfoyle, S. E.; Logan, J. G.; Butterfield, N. C.; Leitch, V. D.; Pollard, A. S.; Makitie, R. E.; McDonald, M. M.; Youlten, S. E.; Sergio, C. M.; Evans, D. M.; Powell, J. E.; de Leeuw, C. A.; Ewing, A. D.; Eisman, J. A.; Blank, R. D.; Phan, T. G.; International Federation of Musculoskeletal Research Societies (IFMRS) Big Data Working Group, ; Baldock, P. A.; Duncan, E. L.; Williams, G. R.; Bassett, J. H. D.; Croucher, P. I.;
Show abstract
Musculoskeletal diseases are a major global health burden. Development of new bone-active therapies is hindered by limited understanding of the complex interactions between the cells and genes that regulate the skeleton. To unravel this complexity, we systematically annotated all cells in bone and defined the genes that control their function at single-cell resolution. Integration with data from human gene-mapping studies of rare skeletal disorders and common skeletal disease traits identified novel disease genes, which we validated by functional analysis in more than one thousand genetic mouse models. This multiscale approach expands the repertoire of cells that regulate bone to include endothelial and vascular smooth muscle cells. This also revealed hundreds of skeletal disease-associated genes in this landscape of cells as potential drug targets. The cellular and genetic mechanisms revealed by this approach overcomes knowledge gaps and helps to accelerate development of next generation therapies to treat skeletal diseases.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease 97%
- Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin 97%
- Basigin Links Altered Skeletal Stem Cell Lineage Dynamics with Glucocorticoid-induced Bone Loss and Impaired Angiogenesis 95%
Similar papers in this journal
- Cell type-specific network analysis in Diversity Outbred mice identifies genes potentially responsible for human bone mineral density GWAS associations 96%
- A trans-eQTL network regulates osteoclast multinucleation and bone mass 95%
- Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic mice 95%
Similar papers in this journal
- Valid inference for machine learning-assisted GWAS 94%
- In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation 93%
- Unsupervised representation learning improves genomic discovery and risk prediction for respiratory and circulatory functions and diseases 92%
Similar papers in this journal
- Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass 94%
- Evolutionary insights into primate skeletal gene regulation using a comparative cell culture model 93%
- Ubiquitin-protein ligase Ubr5 cooperates with Hedgehog signalling to promote skeletal tissue homeostasis 93%
Similar papers in this journal
- Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual through variant-to-gene mapping 93%
- The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans 92%
- Impact of cell-type and context-dependent regulatory variants on human immune traits 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.