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Background: While the evidence from the large-scale randomized controlled trials is conflicting, there is a paucity of genetic evidence of cardiovascular adverse effects of sclerostin inhibition.

Methods: This work integrated multi-omics data to evaluate the cardiovascular safety of therapeutical inhibition on sclerostin (SOST) and dickkopf-1 (DKK-1). We included 377,585 participants in UK Biobank, including 17,461 atrial fibrillation (AF), 28,653 coronary artery disease (CAD), 6592 heart failure (HF), 9638 stroke, and 14,802 myocardial infarction (MI) cases. The transcriptional datasets were obtained from the eQTLGen consortium, and Genotype-Tissue Expression consortium. Instrumental variables analyses for circulating proteins were performed using data from the INTERVAL study and the largest published genome-wide association meta-analysis.

Findings: None of BMD-associated genetic variants around the SOST gene would confer the risk of CVDs. Consistently, there was an inverse association of SOST expression level (instrumented by cis‐eQTL) with BMD, but not with any CVDs. Although the cis-pQTLs were not genome-wide significantly associated with circulating SOST level, two trans-pQTLs were used to mimic treatment of the SOST inhibition. We found that serum SOST (instrumented by these two variants) was inversely associated with BMD and AF risk. We further found a significant inverse association between the expression of B4GALNT3 gene (which was the nearest gene to the two SOST trans-pQTLs) and AF. Additionally, since SOST were enriched in the Wnt signaling pathway, we found that the polygenic risk score of the Wnt …