A common polymorphism near PER1 and the timing of human behavioral rhythms
Version of Record online: 2 OCT 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 3, pages 324–334, September 2012
How to Cite
Lim, A. S. P., Chang, A.-M., Shulman, J. M., Raj, T., Chibnik, L. B., Cain, S. W., Rothamel, K., Benoist, C., Myers, A. J., Czeisler, C. A., Buchman, A. S., Bennett, D. A., Duffy, J. F., Saper, C. B. and De Jager, P. L. (2012), A common polymorphism near PER1 and the timing of human behavioral rhythms. Ann Neurol., 72: 324–334. doi: 10.1002/ana.23636
- Issue online: 2 OCT 2012
- Version of Record online: 2 OCT 2012
- Accepted manuscript online: 26 APR 2012 06:07AM EST
- Manuscript Accepted: 23 APR 2012
- Manuscript Revised: 9 APR 2012
- Manuscript Received: 3 JAN 2012
- Canadian Institutes of Health Research Bisby Fellowship
- American Academy of Neurology Clinical Research Training Fellowship
- Dana Foundation Clinical Neuroscience Grant
- NIH. Grant Numbers: R01 NS072337, R01 AG24480, R01 AG17917, R01 AG151819, R01 AG30146, P30 AG10161, R01 HL080978, P01 AG09975, R21 AT02571, ARRA RC2 GM093080, AFOSR FA 9550-06-0080/O5NL132, 5R01AG034504
- Translational Genomics Research Institute
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.
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.
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 rs7221412GG versus rs7221412AA 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 rs7221412GG individuals had a mean time of death nearly 7 hours later than rs7221412AA/AG.
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. ANN NEUROL 2012;72:324–334.