ArticleGenome biology2025
GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density.
Article in Genome biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Genome-wide CRISPR interference screen identifies Clip2 as a novel regulator of osteocyte maturation and morphology.The Journal of biological chemistry · 2026Article
- Genome-scale mapping of variant, enhancer and gene function in primary human CD4+ T cells.bioRxiv : the preprint server for biology · 2026Article
- Genome topology analysis and transcriptomics of human osteoclasts reveals enhancer-promoter interactions at loci for bone traits and diseases.JBMR plus · 2025Article
- Shared and unique 3D genomic features of substance use disorders across multiple cell types.medRxiv : the preprint server for health sciences · 2025Article
- Loss ofJBMR plus · 2025Article
- Loss ofbioRxiv : the preprint server for biology · 2024Article
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16 authors.
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Abstract
backgroundOver 1100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown.
resultsWe execute a CRISPRi screen in human fetal osteoblasts (hFOBs) with single-cell RNA-seq read-out for 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci. The BMD relevance of hFOBs is supported by heritability enrichment from stratified LD-score regression involving 98 cell types grouped into 15 tissues. Twenty-three genes show perturbation in the screen, with four (ARID5B, CC2D1B, EIF4G2, and NCOA3) exhibiting consistent effects upon siRNA knockdown on three measures of osteoblast maturation and mineralization. Lastly, additional heritability enrichments, genetic correlations, and multi-trait fine-mapping unexpectedly reveal that many BMD GWAS signals are pleiotropic and likely mediate their effects via non-bone tissues.
conclusionsOur results provide a roadmap for how single-cell CRISPRi screens may be applied to the challenging task of resolving effector gene identities at all BMD GWAS loci. Extending our CRISPRi screening approach to other tissues could play a key role in fully elucidating the etiology of BMD.
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