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

  • Zheng, Jie1
  • Maerz, Winfried2, 3, 4
  • Gergei, Ingrid4
  • Kleber, Marcus4
  • Drechsler, Christiane5
  • Wanner, Christoph5
  • Brandenburg, Vincent5
  • Reppe, Sjur6, 7
  • Gautvik, Kaare M7, 8
  • Medina-Gomez, Carolina9
  • Shevroja, Enisa9
  • Gilly, Arthur10, 11
  • Park, Young-Chan10, 12
  • Dedoussis, George13
  • Zeggini, Eleftheria10, 11
  • Lorentzon, Mattias14, 15, 16
  • Henning, Petra14
  • Lerner, Ulf H14
  • Nilsson, Karin H14
  • Movérare-Skrtic, Sofia14
  • And 10 more
  • 1 MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.
  • 2 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. , (Austria)
  • 3 SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany. , (Germany)
  • 4 Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. , (Germany)
  • 5 Department of Cardiology and Nephrology, Rhein-Maas-Klinikum Würselen, Germany. , (Germany)
  • 6 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. , (Norway)
  • 7 Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway. , (Norway)
  • 8 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. , (Norway)
  • 9 Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands. , (Netherlands)
  • 10 Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • 11 Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. , (Germany)
  • 12 University of Cambridge, Cambridge, UK.
  • 13 Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. , (Greece)
  • 14 Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. , (Sweden)
  • 15 Geriatric Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. , (Sweden)
  • 16 Geriatric Medicine Clinic, Sahlgrenska University Hospital, Mölndal, Sweden. , (Sweden)
  • 17 Bristol Bioresource Laboratories, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • 18 Human Evolutionary Biology, Harvard University, Boston, MA, USA.
  • 19 Broad Institute of MIT and Harvard, Boston, MA, USA.
  • 20 Department of Human Genetics, McGill University, Quebec, Canada. , (Canada)
  • 21 Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO, USA.
  • 22 Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
Published Article
Journal of Bone and Mineral Research
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2019
DOI: 10.1002/jbmr.3803
PMID: 31170332


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 × 10-49 ) and GALNT1 (β = 0.11 per G allele, p = 4.4 × 10-11 ). 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 single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β = -0.12, 95% confidence interval [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. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

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