Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures.

Adaptor Proteins, Signal Transducing / blood Aged Animals Bone Density / genetics Bone and Bones / pathology Child DNA Methylation Fractures, Bone / blood Gene Expression Regulation Genome-Wide Association Study Humans Mendelian Randomization Analysis Meta-Analysis as Topic Mice Middle Aged Models, Biological Phenotype Quantitative Trait Loci / genetics RNA, Messenger / genetics
BONE MINERAL DENSITY GENOME-WIDE ASSOCIATION STUDY MENDELIAN RANDOMIZATION SCLEROSTIN

Journal

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640

Informations de publication

Date de publication:
10 2019
Historique:
received: 06 12 2018
revised: 14 05 2019
accepted: 23 05 2019
pubmed: 7 6 2019
medline: 10 7 2020
entrez: 7 6 2019
Statut: ppublish

Résumé

In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (β = 0.20, p = 4.6 × 10

Identifiants

DOI: 10.1002/jbmr.3803 PMID: 31170332 PMC: PMC6899787
pubmed: 31170332
doi: 10.1002/jbmr.3803
pmc: PMC6899787
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
RNA, Messenger 0
SOST protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1824-1836

Subventions

Organisme : Federal Ministry of Education and Research of the Federal Republic of Germany
ID : BMBF 01EO1504
Pays : International
Organisme : NIAMS NIH HHS
ID : R01 AR070139
Pays : United States
Organisme : EU framework program
ID : LSHM-CT-2003-502941
Pays : International
Organisme : CIHR Foundation Grant
ID : FDN-148381
Pays : International
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Organisme : Netherlands Organization for Health Research and Development
ID : ZonMw VIDI 016.136.367
Pays : International
Organisme : UK Medical Research Council
ID : MC_UU_00011/1
Pays : International
Organisme : Oslo University Hospital, Ullevaal
ID : 52009/8029
Pays : International
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NSF grant
ID : BCS-1518596
Pays : International
Organisme : Wellcome Trust
ID : WT102215/2/13/2
Pays : United Kingdom
Organisme : South East Norway Health Authority
ID : 52009/8029
Pays : International
Organisme : UK Medical Research Council
ID : G1001357
Pays : International
Organisme : UK Medical Research Council
ID : MC_UU_00011/4
Pays : International
Organisme : Wellcome Trust
ID : WT088806
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT092830M
Pays : United Kingdom

Informations de copyright

© 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

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Auteurs

Jie Zheng (J)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

Winfried Maerz (W)

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.
Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Ingrid Gergei (I)

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Marcus Kleber (M)

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Christiane Drechsler (C)

Department of Cardiology and Nephrology, Rhein-Maas-Klinikum Würselen, Germany.

Christoph Wanner (C)

Department of Cardiology and Nephrology, Rhein-Maas-Klinikum Würselen, Germany.

Vincent Brandenburg (V)

Department of Cardiology and Nephrology, Rhein-Maas-Klinikum Würselen, Germany.

Sjur Reppe (S)

Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.

Kaare M Gautvik (KM)

Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

Carolina Medina-Gomez (C)

Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Enisa Shevroja (E)

Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Arthur Gilly (A)

Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Young-Chan Park (YC)

Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
University of Cambridge, Cambridge, UK.

George Dedoussis (G)

Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.

Eleftheria Zeggini (E)

Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Mattias Lorentzon (M)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Geriatric Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Geriatric Medicine Clinic, Sahlgrenska University Hospital, Mölndal, Sweden.
ORCID: 0000-0003-0749-1431

Petra Henning (P)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Ulf H Lerner (UH)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Karin H Nilsson (KH)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Sofia Movérare-Skrtic (S)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Denis Baird (D)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

Benjamin Elsworth (B)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

Louise Falk (L)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

Alix Groom (A)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.
Bristol Bioresource Laboratories, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Terence D Capellini (TD)

Human Evolutionary Biology, Harvard University, Boston, MA, USA.
Broad Institute of MIT and Harvard, Boston, MA, USA.

Elin Grundberg (E)

Department of Human Genetics, McGill University, Quebec, Canada.
Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO, USA.

Maria Nethander (M)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Claes Ohlsson (C)

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

George Davey Smith (G)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

Jonathan H Tobias (JH)

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.
Musculoskeletal Research Unit, University of Bristol, Bristol, UK.

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Classifications MeSH

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