Oct 29, 2018

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

BioRxiv : the Preprint Server for Biology
Jie ZhengJonathan Tobias

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 (beta=0.20, P=4.6x10-49), and GALNT1 (beta=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 (beta= -0.12, 95%CI= -0.2...Continue Reading

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Mentioned in this Paper

Genome-Wide Association Study
B4GALNT3 gene
Mendelian Randomization Analysis
Sclerostin
Meta-Analysis (Publications)
N-acetylgalactosaminyl-1-4-N-acetylglucosamine
Meta Analysis (Statistical Procedure)
Magnetic Resonance Imaging
Enzymes, antithrombotic
Mucin-1 protein

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