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

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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 Crespo, Diana
• dc.contributor.author Mellibovsky, Leonardo
• dc.contributor.author Nogués Solan, Francesc Xavier
• dc.contributor.author Díez Pérez, Adolfo
• dc.contributor.author Grinberg, Daniel
• dc.contributor.author Balcells, Susana
• dc.date.accessioned 2019-11-19T10:18:58Z
• dc.date.issued 2019
• dc.description.abstract 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.description.sponsorship This work was supported by the following grants: SAF2014-56562-R, SAF2016-75948-R (Spanish MINECO), 2014SGR932 (Generalitat de Catalunya), CIBERER (U720), and FEIOMM Investigación 2014. NRA is a recipient of an FPU predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte; NMG is a recipient of a FI predoctoral fellowship from Generalitat de Catalunya.
• dc.format.mimetype application/pdf
• dc.identifier.citation Roca-Ayats N, Martínez-Gil N, Cozar M, Gerousi M, Garcia-Giralt N, Ovejero D. et al. Functional characterization of the C7ORF76 genomic region, a prominent GWAS signal for osteoporosis in 7q21.3. Bone. 2019 Jun;123:39-47. DOI 10.1016/j.bone.2019.03.014
• dc.identifier.doi http://dx.doi.org/10.1016/j.bone.2019.03.014
• dc.identifier.issn 1873-2763
• dc.identifier.uri http://hdl.handle.net/10230/42893
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-56562-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75948-R
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.bone.2019.03.014
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword 4C
• dc.subject.keyword C7ORF76
• dc.subject.keyword Enhancer
• dc.subject.keyword GWAS signal
• dc.subject.keyword Non-coding regulatory variant
• dc.subject.keyword Osteoporosis
• 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.version info:eu-repo/semantics/acceptedVersion