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

Area of Science:

• Genetics
• Sleep Medicine
• Pharmacogenomics

Background:

• Sleep disorders impact over 30% of the U.S. population, increasing disease risk and mortality.
• The genetic basis of sleep disorders and their relationship to habitual sleep traits remain poorly understood.
• It is unclear if clinical sleep disorders represent extreme variations of normal sleep patterns.

Purpose of the Study:

• To systematically investigate the genetic architecture of seven clinical sleep disorders and 16 sleep medications.
• To determine the overlap between genetic factors for sleep disorders and habitual sleep traits.
• To explore if clinical sleep disorders are extremes of normal sleep variation.

Main Methods:

• Genome-wide association studies (GWAS) were conducted on 1,600,000 individuals.
• Analysis included genetic associations for sleep apnea, insomnia, restless legs syndrome, narcolepsy, and combined sleep disorders.
• Genetic associations with sleep medication use were also investigated.

Main Results:

• Identified 590 genetic associations for sleep disorders, with 367 being novel.
• Discovered 142 genetic associations related to sleep medication use.
• Found shared genetic architecture across sleep traits but also unique genetic factors for specific disorders (e.g., autoimmune in narcolepsy, skeletal in sleep apnea).
• Sleep genetic factors demonstrated broad multi-omic impacts on gene and protein expression.

Conclusions:

• Clinical sleep disorders share genetic architecture with each other and with general population sleep variations.
• These disorders involve unique biological mechanisms beyond extremes of normal sleep.
• Findings advance understanding of sleep disorders and suggest potential therapeutic targets.