Abstract
OBJECTIVE: To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD). METHODS: We conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects. RESULTS: We found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, p = 0.001), shorter sleep duration (self-reported: β = -0.006, p = 1.9 × 10(-4); accelerometer based: β = -0.015, p = 6.9 × 10(-5)), less likely to report long sleep (β = -0.003, p = 7.3 × 10(-7)), earlier timing of the least active 5 hours (β = -0.024, p = 1.7 × 10(-13)), and a smaller number of sleep episodes (β = -0.025, p = 5.7 × 10(-14)) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, p = 7 × 10(-13)). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. CONCLUSION: We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.