Discovering the genetic architecture of sleep regulation: genome-wide association study of device-measured sleep traits.

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Abstract
Sleep is essential for health and regulated by genetic and environmental factors. We performed genome-wide association studies of device-measured sleep duration, efficiency, and REM/NREM phases in 80,013 UK Biobank participants using accelerometer measurements separately validated against polysomnography. We identified 20 autosomal loci, 12 of which were novel, and report the first genome-wide significant signals for REM and NREM sleep duration. MEIS1 showed strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting a regulatory role. Functional enrichment implicated chromatin remodelling, lipid metabolism, and metal ion homeostasis; tissue enrichment highlighted regions including the hypothalamus and frontal cortex. Sex-stratified analyses identified distinct loci: FOXP2 and NRXN3 in females and LRP1B, NPBWR2, and PABPC4 in males. Mendelian randomization supported associations between shorter sleep duration and higher cardiometabolic risk. Our findings highlight novel sex- and phase-specific regulators of human sleep architecture, offering biological insights and potential therapeutic targets.

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