Supplemental Material for: Genetic Evidence Suggesting Potential Associations Between Sleep-Related Phenotypes and Psychiatric Disorders: A Two-Sample Mendelian Randomization Study

Two-sample Mendelian randomization (MR) was performed using self-reported insomnia symptoms, sleep apnea, and habitual sleep duration, as exposures against 10 psychiatric outcomes: ADHD, PTSD, MDD, PPD, BIP, ASD, OCS, SCZ, AN, and PD. GWAS summary statistics were obtained from the UK Biobank, Psychiatric Genomics Consortium, and affiliated consortia. Inverse-variance weighted (IVW) was the primary method, with MR-Egger, weighted median, and MR-PRESSO applied as sensitivity analyses.

Multivariable MR (MVMR) was conducted to estimate independent associations of the sleep-related phenotypes modeled simultaneously.</p><p dir="ltr">Results: Genetically predicted insomnia symptoms showed bonferroni-significant associations with increased risk of ADHD (OR 2.50, 95% CI 1.65–3.78, p < 0.001), PTSD (OR 1.32, 95% CI 1.12–1.56, p < 0.001). Nominal associations were observed for MDD (OR 1.57, 95% CI 1.16–2.12, p = 0.003), PPD (OR 2.35, 95% CI 1.07–5.13, p = 0.033), and BIP (OR 1.67, 95% CI 1.03–2.68, p = 0.036).

Genetically predicted sleep apnea showed nominal associations with OCS (OR 1.20, 95% CI 1.07–1.35, p = 0.002) and AN (OR 1.57, 95% CI 1.17–2.11, p = 0.003). Genetically predicted longer sleep duration showed nominal associations with increased risk of BIP (OR 1.26) and SCZ (OR 1.67), but did not survive multiple-testing correction. MVMR analyses showed associations of longer sleep duration with ADHD (protective; OR 0.16, 95% CI 0.05–0.54, p = 0.004) and AN (OR 37.66, 95% CI 4.12–345.21, p = 0.001); however, these estimates were imprecise and potentially affected by conditional weak-instrument bias.

Sensitivity analyses did not detect significant evidence of directional horizontal pleiotropy based on the MR-Egger intercept test in univariable analyses, although MVMR estimates remained imprecise.</p><p dir="ltr">Conclusion: The sleep-related phenotypes showed heterogeneous patterns of association with psychiatric disorders. Genetically predicted insomnia symptoms were associated with the broadest range of psychiatric outcomes, whereas sleep apnea showed more outcome-specific associations.

These findings highlight the importance of considering multiple dimensions of sleep when evaluating psychiatric disorders.</p>