Bidirectional causal relationship between sleep disorders and thyroid function: a Mendelian randomization study

Sleep disorders and thyroid dysfunction are prevalent global health issues, significantly impairing physiological function and quality of life. Although studies suggest an association, the causal mechanisms remain unclear. This study employed bidirectional Mendelian randomization (MR) to investigate causality and identify key genes and pathways. Using large-scale European GWAS data, inverse-variance-weighted and sensitivity analyses assessed causal robustness, alongside functional enrichment and gene screening. Forward MR showed excessive daytime sleepiness and prolonged sleep duration negatively correlated with free triiodothyronine (FT3) and thyroxine (FT4), while insomnia negatively correlated with TSH. Reverse MR linked low FT3 and high TSH to increased sleep apnea risk, with high TSH potentially promoting morning preference. Functional enrichment implicated dopaminergic synapses, gap junctions, and unsaturated fatty acid biosynthesis. Key genes included GRM5, CRHR1, DRD2, SLC6A3, and GABRA2 (sleep-to-thyroid effects) and ITPK1, MBIP, PDE10A, PDE8B, and PRDM11 (thyroid-to-sleep effects). The study confirms bidirectional causality, with dopaminergic pathways potentially driving pathogenesis.