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

Recently, the 9omnigenic9 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 9core-like9 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 9core9 module for BMD and provides a resource for expanding our understanding of the genetics of bone mass.