Rare Coding Variants Reveal Distinct Genetic Architectures Across Multidimensional Sleep Phenotypes.

Area of Science:

• Genetics
• Sleep Medicine
• Pharmacogenomics

Background:

• Common genetic variants extensively studied for sleep traits.
• Contribution of rare coding variation to sleep phenotypes remains largely unknown.

Purpose of the Study:

• Investigate the role of rare coding variants in diverse sleep phenotypes.
• Identify novel genes associated with sleep traits and medication use.
• Explore genetic correlations and temporal expression patterns of sleep-associated genes.

Main Methods:

• Whole-exome and whole-genome sequencing data from UK Biobank and All of Us research programs.
• Meta-analysis of 36 sleep phenotypes including self-report, diagnoses, medication use, and accelerometry.
• Replication analysis in the Mass General Brigham Biobank.
• Temporal gene expression trajectory analysis.

Main Results:

• Identified 260 genes associated with sleep phenotypes, with 29 novel associations for sleep medication use.
• Observed significant rare variant heritability for sleep traits.
• Found strong genetic correlations between sleep medication use, insomnia, and fatigue.
• Distinct prenatal expression patterns for genes linked to self-reported sleep versus sleep medication use.

Conclusions:

• Rare coding variation plays a significant role in sleep phenotypes.
• Different sleep measurement sources capture distinct biological mechanisms.
• Identified novel, rare-variant-informed therapeutic targets for sleep disorders.