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J Bone Miner Res. 2019 Jun 6. doi: 10.1002/jbmr.3803. [Epub ahead of print]

Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures.

Author information

1
MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom.
2
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria.
3
SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.
4
Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
5
Department of Internal Medicine 1, Division of Nephrology and the Comprehensive Heart Failure Center, University of Würzburg, Germany.
6
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
7
Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
8
Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
9
Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
10
Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
11
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
12
University of Cambridge, Cambridge, UK.
13
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, El. Venizelou 70, Athens, Greece.
14
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Sweden.
15
Geriatric Medicine, Institute of Medicine, University of Gothenburg, Sweden.
16
Geriatric Medicine Clinic, Sahlgrenska University Hospital, Mölndal, Sweden.
17
Bristol Bioresource Laboratories, Population Health Sciences, Bristol Medical School, University of Bristol, UK.
18
Human Evolutionary Biology, Harvard University, USA.
19
Broad Institute of MIT and Harvard, USA.
20
Department of Human Genetics, McGill University, Quebec, Canada.
21
Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, USA.
22
Musculoskeletal Research Unit, University of Bristol, Level 1 Learning and Research Building, Bristol, United Kingdom.

Abstract

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 Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide 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 BMD by heel ultrasound (eBMD; 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=4.6x10-49 ), and GALNT1 (β=0.11 per G allele, P=4.4x10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= -0.12, 95%CI= -0.20 to -0.05) and eBMD (β= -0.12, 95%CI= -0.14 to -0.10), and a positive relationship with fracture risk (β= 0.11,95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. This article is protected by copyright. All rights reserved.

KEYWORDS:

ANALYSIS/QUANTITATION OF BONE; EPIDEMIOLOGY; Human association studies < GENETIC RESEARCH; Osteopetrosis < DISEASES AND DISORDERS OF/RELATED TO BONE; STATISTICAL METHODS

PMID:
31170332
DOI:
10.1002/jbmr.3803

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