The impact of Mendelian sleep and circadian genetic variants in a population setting.
Level 3 - non-randomized controlled study
Observational population-based cohort genetic association study
PubMed 36137075 · doi:10.1371/journal.pgen.1010356
What was done
The authors performed genetic association and gene burden analyses of variants in 10 genes previously reported to cause Mendelian sleep and circadian disorders (familial natural short sleep, advanced sleep phase, and delayed sleep phase). Data were analyzed from 191,929 individuals with whole-exome or whole-genome sequencing across four population cohorts: UK Biobank, FINRISK, Health-2000-2001, and MESA. Sleep phenotypes and timing measures were derived from self-report, primary care and hospital records, and accelerometry.
What was found
Carriers were identified for 10 of 12 previously reported pathogenic variants across 8 genes, ranging from 1 individual (CSNK1D) to 1,574 individuals (PER3); no carriers were found for reported NPSR1 or PER2 variants. None of the analyzed variants were associated with extreme sleep or circadian phenotypes. PER3 and CRY1 variants showed modest associations with sleep midpoint (~7 minutes earlier and ~5 minutes later, respectively). In burden testing, only protein-truncating variants (PTVs) in PER2 and PER3 showed significant effects; 64 individuals with PER2 PTVs had an odds ratio of 4.4 for being "definitely a morning person" (P = 4x10-8) and a 57-minute earlier sleep midpoint (P = 5x10-7).
Why it matters
This study demonstrates that genetic variants identified through clinically ascertained families with extreme sleep traits have low penetrance and markedly attenuated effect sizes when detected incidentally in the general population.
Limits
Certain reported variants were absent (NPSR1, PER2) or extremely rare (e.g., single carrier in CSNK1D), limiting statistical power for those specific alleles. Sleep timing and duration relied heavily on self-reports and accelerometry rather than in-laboratory polysomnography.
Cited by
- context Only about 3% of the population does well with less than seven hours of sleep per night.