Lipidome profiles and sleep disorders: A Mendelian randomization analysis of insomnia, sleep terrors, sleep apnea, and circadian rhythm disturbances

Sleep disorders, such as insomnia, sleep terrors, sleep apnea, and sleep-wake schedule disorders, pose a significant public health challenge worldwide, yet their underlying pathophysiological mechanisms are not fully understood. Lipids, beyond being structural membrane components, actively regulate neuroinflammation, circadian rhythms, and neuronal signaling, all implicated in sleep disorder pathophysiology. This study employed two-sample Mendelian randomization (TSMR) to explore the causal relationships between the lipidome and these sleep disorders, analyzing a comprehensive GWAS dataset with 179 lipid species. Heterogeneity and pleiotropy were assessed using Cochran Q test, MR-Egger intercept test, and MR-PRESSO global test, and sensitivity analyses were done to check the influence of individual single nucleotide polymorphisms. The analysis revealed significant causal associations between specific lipid species and sleep disorders. For insomnia, several lipid species, including sterol ester (27:1/20:3), ceramides (d40:1, d42:1, d42:2), phosphatidylcholine (15:0_18:2), and sphingomyelin (d40:1), demonstrated potential protective effects (OR < 1). In contrast, for sleep terrors, phosphatidylcholines (16:0_22:4, O-16:0_16:1, O-16:0_18:2) and sphingomyelin (d34:0) were associated with increased risk (OR > 1), while triacylglycerol (46:2) showed a protective effect. For sleep apnea, cholesterol levels exhibited a protective effect (OR = 0.96), whereas specific phosphatidylcholines (16:1_18:0) and triacylglycerols (52:2, 52:3, 58:8) were associated with increased risk. Circadian rhythm disturbances were influenced by various lipid species, with diacylglycerol (18:1_18:3) and phosphatidylcholine (16:1_18:0) posing risk-increasing effects, while phosphatidylethanolamines (O-16:1_20:4, O-18:1_20:4) demonstrated protective roles. This study elucidates the complex interplay between lipid metabolism and sleep regulation, identifying specific lipid species that may serve as potential biomarkers or therapeutic targets for sleep disorders.