From Normal Variation in Sleep to Clinical Sleep Disorders: Genetic Insights from Over One Million Individuals

Sleep disorders affect over 30% of the U.S population and are linked to increased disease risk and mortality. However, the genetic architecture of sleep disorders and the overlap of sleep disorders with habitual sleep quality, quantity, and timing have been poorly characterized. In addition, it is unknown if clinical sleep disorders are extremes of habitual sleep traits. Here, we systematically investigated the genetic basis of seven clinical sleep disorder traits, and sixteen medications used for sleep problems in 1,600,000 individuals. We identified 590 genetic associations for sleep apnea, insomnia, restless legs syndrome, narcolepsy and a combined sleep disorder phenotype, of which 367 were previously unreported. Additionally, we discovered 142 genetic associations with sleep medication use. While overall genetic architecture was shared across sleep traits, we found unique genetic factors for the different sleep disorders that reflect fundamentally different biological mechanisms including for example autoimmune processes with narcolepsy and skeletal morphology in sleep apnea. Furthermore, sleep genetic factors showed a broad multi-omic impact on gene and protein expression levels. These findings suggest that while clinical sleep disorders share genetic architecture with each other and with variation in sleep patterns within the general population, they are not simply extremes of normal sleep variation but involve unique biological mechanisms. These results advance our understanding of sleep disorders and suggest potential novel therapeutic targets.