Genome-wide mapping identifies beta-1,4-N-acetyl-galactosaminyl-transferase as a novel determinant of sclerostin levels and bone mineral density

ABSTRACT In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Sclerostin is also present at detectable concentrations within the circulation. Our genome wide association study (GWAS) meta-analysis of 10,584 European-descent individuals 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 ), of which the former is a known locus for BMD estimated by heel ultrasound (eBMD). Common variants across the genome explained 16% of the phenotypic variation of serum sclerostin. Mendelian randomization revealed an inverse causal relationship between serum sclerostin and femoral neck BMD and eBMD, and a positive relationship with fracture risk. Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower BMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Renal and cortical bone tissue, and osteoblast cultures, were found to express high levels of B4GALNT3, an N-acetylgalactosaminyltransferase which adds a terminal LacdiNAc disaccharide to target glycocoproteins. Together, these findings raise the possibility that sclerostin is a substrate for B4GALNT3, such that its modification leads to higher levels, possibly through greater stability. GALNT1 , an enzyme causing mucin-type O-linked glycosylation, may act in a similar capacity. We conclude that genetic variation in glycosylation enzymes represents a novel determinant of BMD and fracture risk, acting via alterations in levels of circulating sclerostin.