Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women

Rare genetic variants in genes previously described to be involved in bone monogenic disorders were identified in postmenopausal women split into two groups according to extreme bone mineral density (BMD) values and lumbar spine Z-scores. A pathogenic variant in COL1A2 gene found in a woman with low...

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Autores: Patiño, Juan David, Ovejero Crespo, Diana, Gabernet, Marc, Martínez-Gil, Núria, Alcaide-Consuegra, Estefanía, Mellibovsky, Leonardo, Nogués Solán, Xavier, Grinberg, Daniel, Balcells, Susana, Rabionet Janssen, Raquel, Garcia Giralt, Natàlia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:dnet:recercat____::ec8c6aa59529bb3560cbdc8781735344
Acceso en línea:https://hdl.handle.net/10230/73122
http://dx.doi.org/10.1007/s00198-025-07413-4
Access Level:acceso abierto
Palabra clave:COL1A2
Bone mineral density
Osteogenesis imperfecta
Osteoporosis
Rare variants
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oai_identifier_str oai:dnet:recercat____::ec8c6aa59529bb3560cbdc8781735344
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
title Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
spellingShingle Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
Patiño, Juan David
COL1A2
Bone mineral density
Osteogenesis imperfecta
Osteoporosis
Rare variants
title_short Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
title_full Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
title_fullStr Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
title_full_unstemmed Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
title_sort Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women
dc.creator.none.fl_str_mv Patiño, Juan David
Ovejero Crespo, Diana
Gabernet, Marc
Martínez-Gil, Núria
Alcaide-Consuegra, Estefanía
Mellibovsky, Leonardo
Nogués Solán, Xavier
Grinberg, Daniel
Balcells, Susana
Rabionet Janssen, Raquel
Garcia Giralt, Natàlia
author Patiño, Juan David
author_facet Patiño, Juan David
Ovejero Crespo, Diana
Gabernet, Marc
Martínez-Gil, Núria
Alcaide-Consuegra, Estefanía
Mellibovsky, Leonardo
Nogués Solán, Xavier
Grinberg, Daniel
Balcells, Susana
Rabionet Janssen, Raquel
Garcia Giralt, Natàlia
author_role author
author2 Ovejero Crespo, Diana
Gabernet, Marc
Martínez-Gil, Núria
Alcaide-Consuegra, Estefanía
Mellibovsky, Leonardo
Nogués Solán, Xavier
Grinberg, Daniel
Balcells, Susana
Rabionet Janssen, Raquel
Garcia Giralt, Natàlia
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COL1A2
Bone mineral density
Osteogenesis imperfecta
Osteoporosis
Rare variants
topic COL1A2
Bone mineral density
Osteogenesis imperfecta
Osteoporosis
Rare variants
description Rare genetic variants in genes previously described to be involved in bone monogenic disorders were identified in postmenopausal women split into two groups according to extreme bone mineral density (BMD) values and lumbar spine Z-scores. A pathogenic variant in COL1A2 gene found in a woman with low BMD highlights the overlap between osteogenesis imperfecta and osteoporosis, which may share their genetic etiology. Other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis. Purpose: We aimed to evaluate whether extreme values of bone mineral density (BMD) in a population-based cohort of postmenopausal women (BARCOS) could be determined by rare genetic variants in genes related to monogenic bone disorders. Methods: A panel of 127 genes related to different skeletal phenotypes was designed. Massive sequencing by targeted capture of these genes was performed in 104 DNA samples from those women of the BARCOS cohort that exhibited the highest (HZ group) and lowest (LZ group) LS Z-scores, ranging from + 0.70 to + 3.80 and from - 2.35 to - 4.26, respectively. 5'UTR, 3'UTR, splice region, missense, nonsense, and short indel variants with MAF < 0.01 were annotated with CADD version 1.6 and considered in the analysis. Results: After filtering those variants with CADD > 25 and present only in one of the groups (either LZ or HZ), six variants were detected, most of which (5/6) were in the LZ group in TCIRG1, COL1A2, SEC24D, LRP4, and ANO5 genes, while only one, in the LMNA gene, was in the HZ group. According to the ClinVar database, the COL1A2 variant, causative of a recessive form of osteogenesis imperfecta, is described as pathogenic, while the other variants are considered of uncertain significance (VUS). Conclusion: The variant identified in COL1A2 in a woman from the LZ group highlights the genetic overlap between monogenic diseases such as osteogenesis imperfecta and complex diseases like osteoporosis. However, the other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/10230/73122
http://dx.doi.org/10.1007/s00198-025-07413-4
url https://hdl.handle.net/10230/73122
http://dx.doi.org/10.1007/s00198-025-07413-4
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Osteoporosis International. 2025;36(4):637-44
info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal womenPatiño, Juan DavidOvejero Crespo, DianaGabernet, MarcMartínez-Gil, NúriaAlcaide-Consuegra, EstefaníaMellibovsky, LeonardoNogués Solán, XavierGrinberg, DanielBalcells, SusanaRabionet Janssen, RaquelGarcia Giralt, NatàliaCOL1A2Bone mineral densityOsteogenesis imperfectaOsteoporosisRare variantsRare genetic variants in genes previously described to be involved in bone monogenic disorders were identified in postmenopausal women split into two groups according to extreme bone mineral density (BMD) values and lumbar spine Z-scores. A pathogenic variant in COL1A2 gene found in a woman with low BMD highlights the overlap between osteogenesis imperfecta and osteoporosis, which may share their genetic etiology. Other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis. Purpose: We aimed to evaluate whether extreme values of bone mineral density (BMD) in a population-based cohort of postmenopausal women (BARCOS) could be determined by rare genetic variants in genes related to monogenic bone disorders. Methods: A panel of 127 genes related to different skeletal phenotypes was designed. Massive sequencing by targeted capture of these genes was performed in 104 DNA samples from those women of the BARCOS cohort that exhibited the highest (HZ group) and lowest (LZ group) LS Z-scores, ranging from + 0.70 to + 3.80 and from - 2.35 to - 4.26, respectively. 5'UTR, 3'UTR, splice region, missense, nonsense, and short indel variants with MAF < 0.01 were annotated with CADD version 1.6 and considered in the analysis. Results: After filtering those variants with CADD > 25 and present only in one of the groups (either LZ or HZ), six variants were detected, most of which (5/6) were in the LZ group in TCIRG1, COL1A2, SEC24D, LRP4, and ANO5 genes, while only one, in the LMNA gene, was in the HZ group. According to the ClinVar database, the COL1A2 variant, causative of a recessive form of osteogenesis imperfecta, is described as pathogenic, while the other variants are considered of uncertain significance (VUS). Conclusion: The variant identified in COL1A2 in a woman from the LZ group highlights the genetic overlap between monogenic diseases such as osteogenesis imperfecta and complex diseases like osteoporosis. However, the other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funds for the study include grants PID2019-107188RB-C21 (Spanish MICINN) and CIBERER (U720). JDP was a recipient of the FI-SDUR predoctoral fellowship from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR). The research was also supported by the Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (grant number CB16/10/00245) and European Union Fund. DO is recipient of a Miquel Servet grant from ISCIII.Springer2026202620252026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/10230/73122http://dx.doi.org/10.1007/s00198-025-07413-4reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésOsteoporosis International. 2025;36(4):637-44info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your ntended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0http://creativecommons.org/licenses/by-nc/4.0info:eu-repo/semantics/openAccessoai:dnet:recercat____::ec8c6aa59529bb3560cbdc87817353442026-05-29T05:05:01Z
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