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Nat Commun. 2019 Mar 19;10(1):1260. doi: 10.1038/s41467-019-09302-x.

Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density.

Author information

1
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA.
2
Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.
3
Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, PA, USA.
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, PA, USA.
5
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA. grants@email.chop.edu.
6
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, PA, USA. grants@email.chop.edu.
7
Divisions of Genetics and Endocrinology, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA. grants@email.chop.edu.

Abstract

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.

PMID:
30890710
PMCID:
PMC6425012
DOI:
10.1038/s41467-019-09302-x
[Indexed for MEDLINE]
Free PMC Article

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