Lack of genetic correlation and causal association between specific gut microbiota and osteoporosis

Several observational studies have reported the change in gut microbiota (GM) composition in individuals with osteoporosis (OP); however, the genetic correlation and causal association between GM and OP remain undetermined. Large-scale genome-wide association study summary analysis of GM from the MiBio-Gen consortium and OP from the UK Biobank were used for analysis. Bivariate linkage disequilibrium score regression was conducted to explore the genetic correlation between GM and OP. Bidirectional 2-sample Mendelian randomization (MR) studies were then used to determine the causal association between GM and OP. genome-wide association study summary analysis of OP from the FinnGen consortium was used to replicate the MR analysis. Colocalization analysis was used to validate the suggestive association between GM and OP. No significant genetic correlation between OP and any taxa of GM was found in bivariate linkage disequilibrium score regression. Inverse variance weighted (IVW) estimates showed 5 microbial taxa including Lachnospiraceae UCG001 (IVW odds ratio [OR], 0.996; 95% confidence interval [CI], 0.994-0.999; P = .003), Christensenellaceae R.7 group (IVW OR, 0.996; 95% CI, 0.993-0.999; P = .028), Howardella (IVW OR, 1.002; 95% CI, 1.001-1.003; P = .033), Eubacterium nodatum group (IVW OR, 1.002; 95% CI, 1.000-1.005; P = .046) and Coprococcus3 (IVW OR, 0.997; 95% CI, 0.994-0.999; P = .046) have suggestive association with OP. However, none of the microbial taxa was causally associated with OP after false discovery rate correction (q < 0.1). Reverse analysis also found no evidence of a causal effect of OP on GM. The replication of the MR analysis confirmed a lack of evidence for the causal association between GM and OP. Colocalization analysis did not support sharing genetic variants between GM and OP. Our study reveals the lack of genetic correlation and causal associations between GM and OP. Potential confounding factors such as diet and physical activity may contribute to the previously observed association.