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

Authors

  • Andrew S. P. Lim MD,

    1. Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre; University of Toronto, Toronto, Ontario, Canada
    2. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
    3. Division of Sleep Medicine, Harvard Medical School, Boston, MA
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  • Anne-Marie Chang PhD,

    1. Division of Sleep Medicine, Harvard Medical School, Boston, MA
    2. Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
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  • Joshua M. Shulman MD, PhD,

    1. Harvard MedicalSchool, Boston, MA
    2. Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
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  • Towfique Raj PhD,

    1. Harvard MedicalSchool, Boston, MA
    2. Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Lori B. Chibnik PhD,

    1. Harvard MedicalSchool, Boston, MA
    2. Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
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  • Sean W. Cain PhD,

    1. Division of Sleep Medicine, Harvard Medical School, Boston, MA
    2. Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
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  • Katherine Rothamel BS,

    1. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA
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  • Christophe Benoist PhD,

    1. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA
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  • Amanda J. Myers PhD,

    1. Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL
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  • Charles A. Czeisler MD, PhD,

    1. Division of Sleep Medicine, Harvard Medical School, Boston, MA
    2. Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
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  • Aron S. Buchman MD,

    1. Rush Alzheimer Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
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  • David A. Bennett MD,

    1. Rush Alzheimer Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
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  • Jeanne F. Duffy PhD,

    1. Division of Sleep Medicine, Harvard Medical School, Boston, MA
    2. Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA
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  • Clifford B. Saper MD, PhD,

    1. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA
    2. Division of Sleep Medicine, Harvard Medical School, Boston, MA
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  • Philip L. De Jager MD, PhD

    Corresponding author
    1. Harvard MedicalSchool, Boston, MA
    2. Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA
    3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
    • Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 168C, Boston, MA 02115
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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 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.

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. ANN NEUROL 2012;72:324–334.

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