Genome-scale Capture C promoter interaction analysis implicates novel effector genes at GWAS loci for bone mineral density

Osteoporosis is a devastating disease with an essential genetic component. Genome wide association studies (GWAS) have discovered genetic variants robustly associated with bone mineral density (BMD), however they only report genomic signals and not necessarily the precise localization of culprit effector genes. Therefore, we sought to carry out physical and direct 9variant to gene mapping9 in a relevant primary human cell type. We developed 9SPATIaL-seq9 (genome-Scale, Promoter-focused Analysis of chromaTIn Looping), a massively parallel, high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our SPATIaL-seq and ATAC-seq data from human mesenchymal progenitor cell-derived osteoblasts, we observed consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~30% of the 110 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 9CPED1-WNT169 and EPDR1 at 9STARD3NL9, had pronounced inhibitory effects on osteoblastogenesis. Our approach therefore aids target discovery in osteoporosis and can be applied to other common genetic diseases.