GWAS-Informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density.

ABSTRACT: Over 1,100 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. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblasts (hFOBs). The BMD relevance of hFOBs was supported by heritability enrichment from stratified LD-score regression involving 98 cell types grouped into 15 tissues. 23 genes showed perturbation in the screen, with four (ARID5B, CC2D1B, EIF4G2, and NCOA3) exhibiting consistent effects upon siRNA knockdown on three measures of osteoblast m

SUBMITTER: Conery M 

PROVIDER: S-EPMC10983984 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature