Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module

Highlights

• Integrating GWAS and networks can predict causal GWAS genes

• BMD GWAS data and a bone network identified the Osteoblast Functional Module (OFM)

• The OFM was used to predict causal genes for 30 of 64 BMD GWAS loci

• Predicted genes, SPTBN1 and MARK3, regulate BMD and are potential casual GWAS genes

Summary

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Genome-wide association studies (GWAS) for BMD have identified dozens of associations; yet, the genes responsible for most associations remain elusive. Here, we used a bone co-expression network to predict causal genes at BMD GWAS loci based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. By mapping genes implicated by BMD GWAS onto a bone co-expression network, we predicted and inferred the function of causal genes for 30 of 64 GWAS loci. We experimentally confirmed that two of the genes predicted to be causal, SPTBN1 and MARK3, are potentially responsible for the effects of GWAS loci on chromosomes 2p16.2 and 14q32.32, respectively. This approach provides a roadmap for the dissection of additional BMD GWAS associations. Furthermore, it should be applicable to GWAS data for a wide range of diseases.