title: 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) .
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew S P
authors.initials: AS
authors.lastname: Lim
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Chang
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Sean W
authors.initials: SW
authors.lastname: Cain
authors.forename: Katherine
authors.initials: K
authors.lastname: Rothamel
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.forename: Charles A
authors.initials: CA
authors.lastname: Czeisler
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Duffy
authors.forename: Clifford B
authors.initials: CB
authors.lastname: Saper
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D056044:Actigraphy; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000235:genetics*; D056950:Period Circadian Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D017452:Receptors, IgG / Q000378:metabolism; D012189:Retrospective Studies; D013998:Time Perception / Q000502:physiology*; D055815:Young Adult
chemical_list: D018950:Lipopolysaccharide Receptors; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D017452:Receptors, IgG