Mendelian Randomization of Sleep and Circadian Traits

Maintaining proper circadian rhythm and good sleep quality is essential for proper physical, mental, and behavioral performance. The sleep-wake cycle represents one of the most conserved circadian rhythms; however, its molecular mechanisms are not fully understood. Interruption of the circadian rhythm is known to have a major impact on sleep quality and can result in several short- and long-term health complications. The causal association relationship of disruption of sleep and circadian patterns with disease states has been ambiguous. Several observational studies and clinical trials have attempted to establish causal relationships, but the presence of confounding factors has made drawing conclusions challenging. The discovery of a genetic component in the pathogenesis of circadian and sleep patterns has opened up a whole new perspective in understanding the pathophysiology of circadian disruption and sleep disturbances with respect to their role in disease presentation. The advent of large prospective studies, including the establishing of biobanks, has made genome wide association studies (GWAS) possible and enabled the identification of genetic variants statistically significantly associated with circadian rhythms and sleep traits. A major objective downstream of the discovery of these genetic variants has been the investigation of a possible causal relationship between circadian and sleep disturbances with health complications. Mendelian randomization (MR) is an analytical approach that utilizes these genetic variants as instruments to establish causal effects between circadian and sleep disturbances and disease outcomes. Given that genetic variants are randomly inherited at birth, MR allows the bypassing of confounding biases commonly experienced in traditional analyses in order to establish reliable causal conclusions. In this chapter, we highlight the concept and importance of MR and illustrate the many causal relationships identified by MR analyses between sleep and circadian traits and various health/disease outcomes.