Genetically supported targets and drug repurposing for sleep disorders: a Mendelian randomization systematic study.
Abstract
Sleep disorders present major public health issues because of their associations with chronic diseases. Despite extensive research efforts, the underlying biological mechanisms remain inadequately understood. We performed bidirectional two-sample Mendelian randomization (MR) to investigate relationships between sleep disorders and common brain diseases, followed by summary-data-based Mendelian randomization (SMR), heterogeneity in dependent instruments (HEIDI), and colocalization analyses integrating protein quantitative trait locus (pQTL) and expression quantitative trait locus (eQTL) data to prioritize genetically supported candidate genes. Compound-gene associations were subsequently evaluated, and selected clinically used compounds underwent exploratory molecular docking and molecular dynamics simulation. Two-step MR mediation analyses and MR phenome-wide association study (MR-PheWAS) were used to investigate potential mediating traits and broader phenotypic associations. Multi-omic genetic analyses prioritized six candidate genes-BCAN, HDGF, MEPE, PAM, PRR4, and IGLON5-with BCAN, HDGF, and MEPE showing the strongest genetic support. Compound prioritization retained four clinically used drugs associated with the candidate genes for structure-based assessment. Exploratory molecular docking yielded the most favorable predicted Vina score for the BCAN-danazol pair, and molecular dynamics simulation showed persistent local BCAN-danazol contacts despite substantial global conformational rearrangement of BCAN during the trajectory. Mediation analyses identified several risk factors, cerebrospinal fluid metabolites, and structural connectivity measures showing statistical evidence consistent with partial mediation of selected gene/protein-sleep disorder associations. MR-PheWAS further characterized broader phenotypic associations of the genetically supported genes. Integrating genetic and multi-omic evidence identified candidate molecular targets and compound-gene associations relevant to sleep disorders. These findings provide hypotheses for subsequent functional and pharmacological validation.