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

By Alessandra Chesi, Yadav Wagley, Matthew E. Johnson, Elisabetta Manduchi, Chun Su, Sumei Lu, Michelle E. Leonard, Kenyaita M. Hodge, James A. Pippin, Kurt D. Hankenson, Andrew D. Wells, Struan F.A. Grant

Posted 31 Aug 2018
bioRxiv DOI: 10.1101/405142

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 'variant to gene mapping' in a relevant primary human cell type. We developed 'SPATIaL-seq' (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 'CPED1-WNT16' and EPDR1 at 'STARD3NL', had pronounced inhibitory effects on osteoblastogenesis. Our approach therefore aids target discovery in osteoporosis and can be applied to other common genetic diseases.

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