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...
| Autores: | ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Tipo de documento: | Artigo |
| Estado: | Published version |
| Data de publicação: | 2025 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositório: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:dnet:recercat____::ec8c6aa59529bb3560cbdc8781735344 |
| Acesso em linha: | https://hdl.handle.net/10230/73122 http://dx.doi.org/10.1007/s00198-025-07413-4 |
| Nível de acesso: | Acesso aberto |
| Palavra-chave: | COL1A2 Bone mineral density Osteogenesis imperfecta Osteoporosis Rare variants |
| _version_ | 1878732055248896001 |
|---|---|
| author | Patiño, Juan David |
| 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 |
| author_browse | Alcaide-Consuegra, Estefanía Balcells, Susana Gabernet, Marc Garcia Giralt, Natàlia Grinberg, Daniel Martínez-Gil, Núria Mellibovsky, Leonardo Nogués Solán, Xavier Ovejero Crespo, Diana Patiño, Juan David Rabionet Janssen, Raquel |
| 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 |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_3bf084ecc0f2ec9c205ea73035ffd566 |
| institution | 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) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:dnet:recercat____::ec8c6aa59529bb3560cbdc8781735344 |
| publishDate | 2025 |
| publishDateSort | 2025 |
| publisher | Springer |
| publisherStr | Springer |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | Identifying rare variants in genes related to bone phenotypes in a cohort of postmenopausal women 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 COL1A2 Bone mineral density Osteogenesis imperfecta Osteoporosis Rare variants 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. 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. Springer https://hdl.handle.net/10230/73122 http://dx.doi.org/10.1007/s00198-025-07413-4 |
| 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 |
| status_str | publishedVersion |
| title | 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_short | 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 |
| topic | COL1A2 Bone mineral density Osteogenesis imperfecta Osteoporosis Rare variants |
| topic_facet | COL1A2 Bone mineral density Osteogenesis imperfecta Osteoporosis Rare variants |
| url | https://hdl.handle.net/10230/73122 http://dx.doi.org/10.1007/s00198-025-07413-4 |