Abstract. The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of Europ

Background The identification and characterisation of somatic cancer driver mutations in the non-coding genome remains challenging. Objective To broadly characterise non-coding driver mutations for p...

Background The identification and characterisation of somatic cancer driver mutations in the non-coding genome remains challenging. Objective To broadly characterise non-coding driver mutations for p...

Background Over 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. Results We 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. Conclusions Our 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.

Apply for Post Doctoral Research Fellow – Circadian Biology and Genomics job with Children’s Hospital of Philadelphia in Philadelphia, Pennsylvania, United States of America. Fellows, Students & Inter...

Apply for Post Doctoral Research Fellow – Circadian Biology and Genomics job with Children’s Hospital of Philadelphia in Philadelphia, Pennsylvania, United States of America. Fellows, Students & Inter...

The constraints that govern the evolution of gene expression patterns across development remain unclear. Single-cell RNA sequencing can detail these constraints by systematically profiling homologous ...