Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length

Abstract

Observational studies suggest certain sleep traits are associated with telomere length, but the causal nature of these associations is unclear. The study aimed to determine the causal associations between 11 sleep-related traits and leukocyte telomere length (LTL) through two-sample Mendelian randomization and colocalization analyses using the summary statistics from large-scale genome-wide association studies. Univariable Mendelian randomization indicates that genetically determined short sleep is associated with decreased LTL, while morning chronotype is associated with increased LTL. Multivariable Mendelian randomization further supports the findings and colocalization analysis identifies shared common genetic variants for these two associations. No genetic evidence is observed for associations between other sleep-related traits and LTL. Sensitivity MR methods, reverse MR and re-running MR after removing potential pleiotropic genetic variants enhance the robustness of the results. These findings indicate that prioritizing morning chronotype and avoiding short sleep is beneficial for attenuating telomere attrition. Consequently, addressing sleep duration and chronotype could serve as practical intervention strategies.

Fig. 1. The effect of genetically determined sleep-related traits on LTL using UVMR.

Abbreviations: LTL leukocyte telomere length, SNPs single-nucleotide polymorphisms, L5 timing least active 5 h timing, P_FDR FDR-corrected P-value. The error bars indicated the 95% confidence interval corresponding to the estimates of 11 sleep-related traits on LTL.

Fig. 2. Sensitivity analysis leaving one SNP out at a time for the association between sleep-related traits and LTL.

Each boxplot represents the centralized tendency of effect sizes (β coefficients) of a overall sleep duration, b short sleep duration, c long sleep duration, d insomnia, e chronotype, f L5 time, g sleep episodes, h sleep efficiency, i accelerometer-based sleep duration, j daytime sleepiness, k daytime napping on LTL based on the results of leave-one-out analysis where we excluded one SNP at a time and performed IVW using the remaining SNPs. The line in the box indicates the median based on the results of the leave-one-out analysis. The left line of the box represents the first quartile (Q1), which is the 25th percentile. The right line of the box represents the third quartile (Q3), which is the 75th percentile. The width of the box is the interquartile range (IQR). The points outside the whiskers are potential outlying SNPs.

Fig. 3. The direct effect of genetically determined self-reported short sleep duration and morning chronotype on LTL using MVMR adjusted for smoking, alcohol consumption, BMI, and other sleep traits.

Abbreviations: BMI body mass index, LTL leukocyte telomere length, SNPs single-nucleotide polymorphisms. The reference group of self-reported short sleep (≤6 h) is sleep duration between ≥7 h and <9 h every 24 h. The reference group of the chronotype is the evening preference chronotype. The error bars indicated the 95% confidence interval corresponding to the estimates of these exposures on LTL.

Fig. 4. Locus comparing plots for the shared causal variant for the associations of short sleep duration and chronotype with leukocyte telomere length.

a Colocalization analysis results for the association between short sleep duration and LTL in the gene region (Chr6:29632846-30032846), which is located within ±200 kb from rs2517827. In this region, rs2517827 is the lead variant identified in the GWAS of short sleep duration and is strongly correlated with the lead variant identified in the GWAS of LTL (LD r² > 0.6). b Colocalization analysis results for the association between chronotype and LTL in the gene region (Chr3:49714397-50114397), which is located within ±200 kb from rs11712056. In this region, rs11712056 is the lead variant identified in the GWAS of chronotype and is strongly correlated with the lead variant identified in the GWAS of LTL (LD r² > 0.8). Abbreviations: LTL leukocyte telomere length.

Fig. 5. Assumptions and study design of the MR study of the associations between sleep-related traits and leukocyte telomere length.

Abbreviations: IVW inverse-variance weighted, MR-PRESSO Mendelian randomization pleiotropy residual sum and outliers, MVMR multivariable Mendelian randomization, SNP single nucleotide polymorphism, UVMR univariable Mendelian randomization. This picture was created with https://www.biorender.com/.