Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-st...

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Autores: Alonso, Nerea, Garcia Giralt, Natàlia, Lucas, Gavin, 1977-, Elosua Llanos, Roberto, Ralston, Stuart H.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
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:recercat.cat:10230/34251
Acceso en línea:http://hdl.handle.net/10230/34251
http://dx.doi.org/10.1136/annrheumdis-2017-212469
Access Level:acceso abierto
Palabra clave:Osteoporosi
Polimorfisme genètic
Bone mineral density
Gene polymorphism
Osteoporosis
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oai_identifier_str oai:recercat.cat:10230/34251
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
title Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
spellingShingle Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
Alonso, Nerea
Osteoporosi
Polimorfisme genètic
Bone mineral density
Gene polymorphism
Osteoporosis
title_short Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
title_full Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
title_fullStr Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
title_full_unstemmed Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
title_sort Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
dc.creator.none.fl_str_mv Alonso, Nerea
Garcia Giralt, Natàlia
Lucas, Gavin, 1977-
Elosua Llanos, Roberto
Ralston, Stuart H.
author Alonso, Nerea
author_facet Alonso, Nerea
Garcia Giralt, Natàlia
Lucas, Gavin, 1977-
Elosua Llanos, Roberto
Ralston, Stuart H.
author_role author
author2 Garcia Giralt, Natàlia
Lucas, Gavin, 1977-
Elosua Llanos, Roberto
Ralston, Stuart H.
author2_role author
author
author
author
dc.subject.none.fl_str_mv Osteoporosi
Polimorfisme genètic
Bone mineral density
Gene polymorphism
Osteoporosis
topic Osteoporosi
Polimorfisme genètic
Bone mineral density
Gene polymorphism
Osteoporosis
description OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/34251
http://dx.doi.org/10.1136/annrheumdis-2017-212469
url http://hdl.handle.net/10230/34251
http://dx.doi.org/10.1136/annrheumdis-2017-212469
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Annals of the Rheumatic Diseases. 2018 Mar;77(3):378-85
info:eu-repo/grantAgreement/EC/FP7/201865
dc.rights.none.fl_str_mv © BMJ Publishing Group http://ard.bmj.com/content/77/3/378.long
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © BMJ Publishing Group http://ard.bmj.com/content/77/3/378.long
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
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 Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone densityAlonso, NereaGarcia Giralt, NatàliaLucas, Gavin, 1977-Elosua Llanos, RobertoRalston, Stuart H.OsteoporosiPolimorfisme genèticBone mineral densityGene polymorphismOsteoporosisOBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework programme 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. CABRIO was supported by the Instituto de Salud Carlos III and Fondos FEDER from the EU (PI 11/1092 and PI12/615). The AOGC study was funded by the Australian National Health and Medical Research Council (Project grant 511132). Lothian Birth Cohort 1921 phenotype collection was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping of the cohorts was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Research work on Slovenian case and control samples was funded by Slovenian Research Agency (project no. P3-0298 and J3-2330). The Danish National Birth Cohort (DNBC) is a result of major grants from the Danish National Research Foundation, the Danish Pharmacists’ Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. The DNBC biobank is a part of the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. Dr Bjarke Feenstra is supported by an Oak Foundation Fellowship. The Framingham Study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and R01 AR061162; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA‐II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was performed within the Genetic Factors for Osteoporosis (GEFOS) consortium, funded by the European Commission (HEALTH-F2-2008-201865-GEFOS).BMJ Publishing Group201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/34251http://dx.doi.org/10.1136/annrheumdis-2017-212469reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésAnnals of the Rheumatic Diseases. 2018 Mar;77(3):378-85info:eu-repo/grantAgreement/EC/FP7/201865© BMJ Publishing Group http://ard.bmj.com/content/77/3/378.longinfo:eu-repo/semantics/openAccessoai:recercat.cat:10230/342512026-05-29T05:05:01Z
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