Functional characterization of the C7ORF76 genomic region, a prominent GWAS signal for osteoporosis in 7q21.3.

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RECERCAT Home > Universitat de Barcelona > IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer > Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) > View document

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dc.contributor.author	Roca Ayats, Neus
dc.contributor.author	Martínez-Gil, Núria
dc.contributor.author	Cozar, Mónica
dc.contributor.author	Gerousi, Marina
dc.contributor.author	Garcia Giralt, Natàlia
dc.contributor.author	Ovejero, Diana
dc.contributor.author	Mellibovsky, Leonardo
dc.contributor.author	Nogués Solán, Xavier
dc.contributor.author	Díez Pérez, Adolfo
dc.contributor.author	Grinberg Vaisman, Daniel Raúl
dc.contributor.author	Balcells Comas, Susana
dc.date	2019-03-28T15:40:52Z
dc.date	2019-03-14
dc.date	2019-03-28T15:40:52Z
dc.identifier	8756-3282
dc.identifier	689372
dc.identifier.uri	http://hdl.handle.net/2445/131029
dc.description	Genome-wide association studies (GWAS) have repeatedly identified genetic variants associated with bone mineral density (BMD) and osteoporotic fracture in non-coding regions of C7ORF76, a poorly studied gene of unknown function. The aim of the present study was to elucidate the causality and molecular mechanisms underlying the association. We re-sequenced the genomic region in two extreme BMD groups from the BARCOS cohort of postmenopausal women to search for functionally relevant variants. Eight selected variants were tested for association in the complete cohort and 2 of them (rs4342521 and rs10085588) were found significantly associated with lumbar spine BMD and nominally associated with osteoporotic fracture. cis-eQTL analyses of these 2 SNPs, together with SNP rs4727338 (GWAS lead SNP in Estrada et al., Nat Genet. 44:491-501, 2012), performed in human primary osteoblasts, disclosed a statistically significant influence on the expression of the proximal neighbouring gene SLC25A13 and a tendency on the distal SHFM1. We then studied the functionality of a putative upstream regulatory element (UPE), containing rs10085588. Luciferase reporter assays showed transactivation capability with a strong allele-dependent effect. Finally, 4C-seq experiments in osteoblastic cell lines showed that the UPE interacted with different tissue-specific enhancers and a lncRNA (LOC100506136) in the region. In summary, this study is the first one to analyse in depth the functionality of C7ORF76 genomic region. We provide functional regulatory evidence for the rs10085588, which may be a causal SNP within the 7q21.3 GWAS signal for osteoporosis.
dc.format	9 p.
dc.format	application/pdf
dc.language	eng
dc.publisher	Elsevier B.V.
dc.relation	Versió postprint del document publicat a: https://doi.org/10.1016/j.bone.2019.03.014
dc.relation	Bone, 2019, vol. 123, p. 39-47
dc.relation	https://doi.org/10.1016/j.bone.2019.03.014
dc.rights	cc-by-nc-nd (c) Elsevier B.V., 2019
dc.rights	http://creativecommons.org/licenses/by-nc-nd/3.0/es
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Osteoporosi
dc.subject	Genoma humà
dc.subject	Osteoporosis
dc.subject	Human genome
dc.title	Functional characterization of the C7ORF76 genomic region, a prominent GWAS signal for osteoporosis in 7q21.3.
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/acceptedVersion

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