Huang, JianJianHuangZuber, VerenaVerenaZuberMatthews, PaulPaulMatthewsTzoulaki, IoannaIoannaTzoulakiElliott, PaulPaulElliottDehghan, AbbasAbbasDehghan2020-07-242021-08-192020-10-06Neurology, 2020, 95 (14)0028-3878http://hdl.handle.net/10044/1/80967Objective To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer’s disease (AD). Methods We conducted bi-directional two-sample Mendelian randomisation analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (N=446,118), the Psychiatric Genomics Consortium (N=18,759), and the International Genomics of Alzheimer’s Project (N=63,926). We used the inverse variance weighted Mendelian randomisation method to estimate causal effects, and weighted median and MR-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 adjusting 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 either 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.© 2020 American Academy of Neurology.1103 Clinical Sciences1109 Neurosciences1702 Cognitive SciencesNeurology & NeurosurgeryJournal Articlehttps://www.dx.doi.org/10.1212/WNL.0000000000010463Health Data Research UKMR/L01341X/14050641385HQR00720N/AN/A