@article {1446661, title = {Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures}, journal = {J Bone Miner Res}, year = {2019}, month = {2019 Jun 06}, 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 ), and GALNT1 (β=0.11 per G allele, P=4.4x10 ). 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.}, issn = {1523-4681}, doi = {10.1002/jbmr.3803}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/jbmr.3803}, author = {Zheng, Jie and Maerz, Winfried and Gergei, Ingrid and Kleber, Marcus and Drechsler, Christiane and Wanner, Christoph and Brandenburg, Vincent and Reppe, Sjur and Gautvik, Kaare M and Medina-Gomez, Carolina and Shevroja, Enisa and Gilly, Arthur and Park, Young-Chan and Dedoussis, George and Zeggini, Eleftheria and Lorentzon, Mattias and Henning, Petra and Lerner, Ulf H and Nilsson, Karin and Mov{\'e}rare-Skrtic, Sofia and Baird, Denis and Elsworth, Benjamin and Falk, Louise and Groom, Alix and Capellini, Terence D and Grundberg, Elin and Nethander, Maria and Ohlsson, Claes and Smith, George Davey and Tobias, Jonathan H} }