AUTHOR=Yu Xing-Hao , Cao Rong-Rong , Yang Yi-Qun , Zhang Lei , Lei Shu-Feng , Deng Fei-Yan 

TITLE=Systematic evaluation for the causal effects of blood metabolites on osteoporosis: Genetic risk score and Mendelian randomization

JOURNAL=Frontiers in Public Health

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2022.905178

DOI=10.3389/fpubh.2022.905178

ISSN=2296-2565

ABSTRACT=Purpose Osteoporosis is associated with metabolic alterations, but the causal roles of serum metabolites have not been identified.
Methods Based on the large individual-level datasets from UK Biobank as well as GWAS summary datasets, we first constructed genetic risk scores (GRSs) for 308 of 486 human serum metabolites and evaluated the effect of each GRS on 2 major osteoporosis phenotypes, i.e., estimated bone miner density (eBMD) and fracture, respectively. Then two-sample Mendelian Randomization (MR) was performed to validate the casual metabolites that were related to osteoporosis. Multivariable MR analysis was conducted to test whether the effects of metabolites on osteoporosis are independent from possible confounders. Finally, we conducted metabolic pathway analysis for metabolites involved in the bone metabolism.
Results We identified causal effects of 18 metabolites on eBMD and 1 metabolite on fracture with GRS method after adjusting for multiple tests. Then 9 of them were further validated with MR as replication, where comprehensive sensitive analysis proved the robust of the causal associations. Although not identified in GRS, 3 metabolites were found to be associated with at least three osteoporosis traits in MR results. Multivariable MR analysis determined independent causal effect of several metabolites on osteoporosis. Besides, 23 metabolic pathways were proved to be involved in bone metabolism, such as valine, leucine, isoleucine biosynthesis (p = 0.053), Aminoacyl-tRNA biosynthesis (p = 0.076) and D-Glutamine and D-glutamate metabolism (p = 0.004). 
Conclusions Comprehensive evidence from the systematic causal analyses strongly suggested that blood metabolites have causal effects on osteoporosis risk.