Causality Investigation between Gut Microbiome and Sleep-Related Traits: A Bidirectional Two-Sample Mendelian...

Recent research has highlighted associations between sleep and microbial taxa and pathways. However, the causal effect of these associations remains unknown. To investigate this, we performed a bidirectional two-sample Mendelian randomization (MR) analysis using summary statistics of genome-wide association studies (GWAS) from 412 gut microbiome traits (N = 7738) and GWAS studies from seven sleep-associated traits (N = 345,552 to 386,577). We employed multiple MR methods to assess causality, with Inverse Variance Weighted (IVW) as the primary method, alongside a Bonferroni correction ((p < 2.4 × 10^-4) to determine significant causal associations. We further applied Cochran's Q statistical analysis, MR-Egger intercept, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) for heterogeneity and pleiotropy assessment. IVW estimates revealed 79 potential causal effects of microbial taxa and pathways on sleep-related traits and 45 inverse causal relationships, with over half related to pathways, emphasizing their significance. The results revealed two significant causal associations: genetically determined relative abundance of pentose phosphate decreased sleep duration (p = 9.00 × 10^-5), and genetically determined increase in fatty acid level increased the ease of getting up in the morning (p = 8.06 × 10^-5). Sensitivity analyses, including heterogeneity and pleiotropy tests, as well as a leave-one-out analysis of single nucleotide polymorphisms, confirmed the robustness of these relationships. This study explores the potential causal relationships between sleep and microbial taxa and pathways, offering novel insights into their complex interplay.