Insomnia affects the levels of plasma bilirubin and protein metabolism: an observational study and GWGEIS in UK Biobank cohort

Study objectives: We aim to explore the mechanism of relationship between insomnia and liver metabolism by examining the gene × insomnia interactions.

Methods: Individual level genotypic and phenotypic data were obtained from the UK Biobank cohort. Regression analysis was first conducted to test the association of insomnia with plasma total bilirubin (TBil; n = 186,793), direct bilirubin (DBil; n = 159,854) and total protein (TP; n = 171,574) in UK Biobank cohort. Second, genome-wide gene-environment interaction study (GWGEIS) was conducted by PLINK 2.0, and FUMA platform was used to identify enriched pathway terms.

Results: In UK Biobank cohort, we found that TP (P < 2.00 × 10^-16), DBil (P = 1.72 × 10^-3) and TBil (P = 3.38 × 10^-5) were significantly associated with insomnia. GWGEIS of both DBil and TBil observed significant G × INSOMNIA effects between insomnia and UDP Glucuronosyltransferase Family 1 (rs6431558, P = 6.26 × 10^-11) gene. GWGEIS of TP also detected several significant genes interacting with insomnia, such as KLF15, (rs70940816, P = 6.77 × 10^-10) and DOK7, (rs2344205, P = 1.37 × 10^-9). Multiple gene ontology (GO) terms were identified for bilirubin, such as GO_URONIC_ACID_METABOLIC_PROCESS (adjusted P = 4.15 × 10^-26).

Conclusion: Our study results suggested negative associations between insomnia and DBil and TBil; and a positive association between insomnia and TP.