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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Chesi A,Wagley Y,Johnson ME,Manduchi E,Su C,Lu S,Leonard ME,Hodge KM,Pippin JA,Hankenson KD,Wells AD,Grant SFA

doi

10.1038/s41467-019-09302-x

subject

Has Abstract

pub_date

2019-03-19 00:00:00

pages

1260

issue

1

issn

2041-1723

pii

10.1038/s41467-019-09302-x

journal_volume

10

pub_type

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