Causal relationship between nonalcoholic fatty liver disease and different sleep traits: a bidirectional Mendelian randomized study

Background and aims: Non-alcoholic fatty liver disease(NAFLD) is common worldwide and has previously been reported to be associated with sleep traits. However, it is not clear whether NAFLD changes sleep traits or whether the changes in sleep traits lead to the onset of NAFLD. The purpose of this study was to investigate the causal relationship between NAFLD and changes in sleep traits using Mendelian randomization.

Methods: We proposed a bidirectional Mendelian randomization (MR) analysis and performed validation analyses to dissect the association between NAFLD and sleep traits. Genetic instruments were used as proxies for NAFLD and sleep. Data of genome-wide association study(GWAS) were obtained from the center for neurogenomics and cognitive research database, Open GWAS database and GWAS catalog. Three MR methods were performed, including inverse variance weighted method(IVW), MR-Egger, weighted median.

Results: In total,7 traits associated with sleep and 4 traits associated with NAFLD are used in this study. A total of six results showed significant differences. Insomnia was associated with NAFLD (OR(95% CI)= 2.25(1.18,4.27), P = 0.01), Alanine transaminase levels (OR(95% CI)= 2.79(1.70, 4.56), P =4.71×10-5) and percent liver fat(OR(95% CI)= 1.31(1.03,1.69), P = 0.03). Snoring was associated with percent liver fat (1.15(1.05,1.26), P =2×10-3), alanine transaminase levels (OR(95% CI)= 1.27(1.08,1.50), P =0.04).And dozing was associated with percent liver fat(1.14(1.02,1.26), P =0.02).For the remaining 50 outcomes, no significant or definitive association was yielded in MR analysis.

Conclusion: Genetic evidence suggests putative causal relationships between NAFLD and a set of sleep traits, indicating that sleep traits deserves high priority in clinical practice. Not only the confirmed sleep apnea syndrome, but also the sleep duration and sleep state (such as insomnia) deserve clinical attention. Our study proves that the causal relationship between sleep characteristics and NAFLD is the cause of the change of sleep characteristics, while the onset of non-NAFLD is the cause of the change of sleep characteristics, and the causal relationship is one-way.