Genetically Supported Causality Between Micronutrients and Sleep Behaviors: A Two-Sample Mendelian Randomization Study.

Ruijie Zhang, Liyan Luo, Lu Zhang, Xinao Lin, Chuyan Wu et al.

Other Brain and behavior 2025

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Study Design

Tipo de Estudo: Mendelian randomization

Intervenção: Genetically Supported Causality Between Micronutrients and Sleep Behaviors: A Two-Sample Mendelian Randomization Study. None
Comparador: Placebo
Direção do Efeito: Mixed
Risco de Viés: Low

Abstract

BACKGROUND: Sleep behaviors, defined by the total duration of sleep and chronotype, significantly influence overall health. Compromised sleep quality, which is often manifested through reduced sleep duration and the prevalence of insomnia, has been found to be associated with micronutrient deficiencies. Nonetheless, the existence of a causal relationship between micronutrient levels and sleep behaviors remains to be established. METHODS: A two-sample Mendelian randomization (MR) analysis, utilizing data from genome-wide association studies (GWAS), was employed to examine the associations between 15 micronutrients (copper; calcium; carotene; folate; iron; magnesium; potassium; selenium; vitamins A, B12, B6, C, D, and E; and zinc) and various sleep behaviors, including short and long sleep durations, insomnia, and chronotype. Furthermore, multivariable MR (MVMR) analysis was performed to address potential confounding due to the interrelationships among micronutrients and to discern potential causal relationships. RESULTS: The MR analysis identified a causal association between folate levels and chronotype (odds ratio [OR] = 1.09; 95% confidence interval [CI]: 1.01-1.17; p = 0.02), indicating a tendency toward morningness. Conversely, vitamin B6 (OR = 0.91; 95% CI: 0.86-0.96; p = 1.05 × 10-3) and vitamin D (OR = 0.94; 95% CI: 0.88-1.00; p = 0.03) showed inverse associations with chronotype, indicative of a preference for eveningness. MVMR analysis confirmed the positive association between folate (OR = 1.286, 95% CI = 1.124-1.472, p < 0.001) and chronotype and a negative association with vitamin B6 (OR = 0.750, 95% CI = 0.648-0.868, p < 0.001). No causal relationships were established between micronutrient levels and either sleep duration or insomnia. CONCLUSIONS: Elevated folate levels correlate with morning-type preferences ("morning birds"), while higher concentrations of vitamin B6 are associated with evening-type preferences ("evening owls").

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Figures

FIGURE 1

Study design overview for the two-sample Mendelian randomization analysis examining genetically supported causal relationships between micronutrients and sleep behaviors.

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FIGURE 2

Forest plot of Mendelian randomization estimates for the causal effects of specific micronutrients on total sleep duration.

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FIGURE 3

Causal effect estimates linking genetically predicted micronutrient levels to chronotype preference from the Mendelian randomization analysis.

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FIGURE 4

Sensitivity analyses including MR-Egger and weighted median methods assessing the robustness of micronutrient-sleep behavior causal associations.

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FIGURE 5

Scatter plots of individual SNP effects on micronutrient exposure versus sleep behavior outcomes, visualizing instrument strength and potential outliers.

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FIGURE 6

Leave-one-out analysis evaluating whether any single genetic instrument disproportionately drives the observed causal relationship between micronutrients and sleep.

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