A common polymorphism near PER1 and the timing of human behavioral rhythms

Abstract

Objective: Circadian rhythms influence the timing of behavior, neurological diseases, and even death. Rare mutations in homologs of evolutionarily conserved clock genes are found in select pedigrees with extreme sleep timing, and there is suggestive evidence that certain common polymorphisms may be associated with self-reported day/night preference. However, no common polymorphism has been associated with the timing of directly observed human behavioral rhythms or other physiological markers of circadian timing at the population level.

Methods: We performed a candidate gene association study with replication, evaluating associations between polymorphisms in homologs of evolutionarily conserved clock genes and the timing of behavioral rhythms measured by actigraphy. For validated polymorphisms, we evaluated associations with transcript expression and time of death in additional cohorts.

Results: rs7221412, a common polymorphism near period homolog 1 (PER1), was associated with the timing of activity rhythms in both the discovery and replication cohorts (joint p = 2.1 × 10(-7) ). Mean activity timing was delayed by 67 minutes in rs7221412(GG) versus rs7221412(AA) homozygotes. rs7221412 also showed a suggestive time-dependent relationship with both cerebral cortex (p = 0.05) and CD14+ CD16- monocyte (p = 0.02) PER1 expression and an interesting association with time of death (p = 0.015) in which rs7221412(GG) individuals had a mean time of death nearly 7 hours later than rs7221412(AA/AG) .

Interpretation: A common polymorphism near PER1 is associated with the timing of human behavioral rhythms, and shows evidence of association with time of death. This may be mediated by differential PER1 expression. These results may facilitate individualized scheduling of shift work, medical treatments, or monitoring of vulnerable patient populations.

Fig 1. Example actigraphic record

The activity acrophase for each day, defined as the midpoint of the eight consecutive hours of each day with the greatest activity, is indicated by a horizontal black bar. The vertical divisions indicate midnight.

Fig 2. Association between the average timing of the acrophase of activity and genotype at rs7221412

Dots indicate angular means, and bars indicate 95% confidence intervals of the mean. All significance values calculated using Fisher-Lee regression using an additive model, and adjusted for age, sex, and presence or absence of dementia. In the joint analysis, source cohort was added as an additional covariate. A: MAP cohort. B: BWH Circadian Cohort. C: Joint Analysis.

Fig 3. Local association plot in the PER1 locus

The plot displays the significance, as indicated by the −log₁₀(p-value), of the associations between timing of the circadian acrophase, and genotype at polymorphisms flanking rs7221412. All significance values calculated with Fisher-Lee regression using an additive model, and adjusted for age, sex, and presence or absence of dementia. Blue squares indicate directly-genotyped polymorphisms; black square indicate polymorphisms whose genotypes were imputed (imputation quality score >0.90 for all imputed polymorphisms). Vertical black bars indicate the extent of the association peak. The black diamond indicates the index SNP rs7221412. The horizontal dotted line indicates the Bonferroni-corrected threshold for significance.

Fig 4. Adjusted cortical and CD14⁺CD16⁻ monocyte PER1 transcript expression as a function of genotype at rs7221412

A: cerebral cortex, NIA cohort, all participants. B: cerebral cortex, NIA cohort, participants inferred to have died during the night (see Supplementary Methods). C: cerebral cortex, NIA cohort, participants inferred to have died during the day (see Supplementary Methods). D: CD14⁺CD16⁻ monocytes, PhenoGenetic cohort, all participants. Dots indicate means, and bars indicate 95% confidence intervals of the mean. Y-axis indicates log₂ expression levels adjusted for methodological and clinical covariates as described in the Materials and Methods.