Dissecting the genetic and causal relationship between sleep-related traits and common brain disorders

Background There is a profound connection between abnormal sleep patterns and brain disorders, suggesting a shared influential association. However, the shared genetic basis and potential causal relationships between sleep-related traits and brain disorders are yet to be fully elucidated. Methods Utilizing linkage disequilibrium score regression (LDSC) and bidirectional two-sample univariable Mendelian Randomization (UVMR) analyses with large-scale GWAS datasets, we investigated the genetic correlations and causal associations across six sleep traits and 24 prevalent brain disorders. Additionally, a multivariable Mendelian Randomization (MVMR) analysis evaluated the cumulative effects of various sleep traits on each brain disorder, complemented by genetic loci characterization to pinpoint pertinent genes and pathways. Results LDSC analysis identified significant genetic correlations in 66 out of 144 (45.8%) pairs between sleep-related traits and brain disorders, with the most pronounced correlations observed in psychiatric disorders (66%, 48/72). UVMR analysis identified 29 causal relationships (FDR<0.05) between sleep traits and brain disorders, with 19 associations newly discovered according to our knowledge. Notably, major depression, attention-deficit/hyperactivity disorder, bipolar disorder, cannabis use disorder, and anorexia nervosa showed bidirectional causal relations with sleep traits, especially insomnia's marked influence on major depression (IVW beta 0.468, FDR=5.24E-09). MVMR analysis revealed a nuanced interplay among various sleep traits and their impact on brain disorders. Genetic loci characterization underscored potential genes, such as HOXB2, while further enrichment analyses illuminated the importance of synaptic processes in these relationships. Conclusions This study provides compelling evidence for the causal relationships and shared genetic backgrounds between common sleep-related traits and brain disorders.