Ackert-Bicknell, C. L. | Search bioRxiv

bioRxiv2019

Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

Osteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.

genetics↗

bioRxiv2019

Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

Recently, the \"omnigenic\" model of the genetic architecture of complex traits proposed two general categories of causal genes, core and peripheral. Core genes are hypothesized to play a direct role in regulating disease; thus, their identification has the potential to reveal critical regulators and novel therapeutic targets. Here, we sought to identify genes with \"core-like\" characteristics for bone mineral density (BMD), one of the most significant predictors of osteoporotic fracture. This was accomplished by analyzing genome-wide association study (GWAS) data through the lens of a cell-type and timepoint-specific gene co-expression network for mineralizing osteoblasts. We identified a single co-expression network module that was enriched for genes implicated by GWAS and partitioned BMD heritability, correlated with in vitro osteoblast mineralization, and enriched for genes, which when mutated in humans or mice, led to a skeletal phenotype. Further characterization of this module identified four novel genes (B4GALNT3, CADM1, DOCK9, and GPR133) located within BMD GWAS loci with colocalizing expression quantitative trait loci (eQTL) and altered BMD in mouse knockouts, suggesting they are causal genetic drivers of BMD in humans. Our network-based approach identified a \"core\" module for BMD and provides a resource for expanding our understanding of the genetics of bone mass.

genetics↗