PER3 Polymorphism Predicts Cumulative Sleep Homeostatic but Not Neurobehavioral Changes to Chronic Partial Sleep Deprivation

Background The variable number tandem repeat (VNTR) polymorphism 5-repeat allele of the circadian gene PERIOD3 (PER35/5) has been associated with cognitive decline at a specific circadian phase in response to a night of total sleep deprivation (TSD), relative to the 4-repeat allele (PER34/4). PER35/5 has also been related to higher sleep homeostasis, which is thought to underlie this cognitive vulnerability. To date, no study has used a candidate gene approach to investigate the response to chronic partial sleep deprivation (PSD), a condition distinct from TSD and one commonly experienced by millions of people on a daily and persistent basis. We evaluated whether the PER3 VNTR polymorphism contributed to cumulative neurobehavioral deficits and sleep homeostatic responses during PSD. Methodology/Principal Findings PER35/5 (n = 14), PER34/5 (n = 63) and PER34/4 (n = 52) healthy adults (aged 22–45 y) demonstrated large, but equivalent cumulative decreases in cognitive performance and physiological alertness, and cumulative increases in sleepiness across 5 nights of sleep restricted to 4 h per night. Such effects were accompanied by increasing daily inter-subject variability in all groups. The PER3 genotypes did not differ significantly at baseline in habitual sleep, physiological sleep structure, circadian phase, physiological sleepiness, cognitive performance, or subjective sleepiness, although during PSD, PER35/5 subjects had slightly but reliably elevated sleep homeostatic pressure as measured physiologically by EEG slow-wave energy in non-rapid eye movement sleep compared with PER34/4 subjects. PER3 genotypic and allelic frequencies did not differ significantly between Caucasians and African Americans. Conclusions/Significance The PER3 VNTR polymorphism was not associated with individual differences in neurobehavioral responses to PSD, although it was related to one marker of sleep homoeostatic response during PSD. The comparability of PER3 genotypes at baseline and their equivalent inter-individual vulnerability to sleep restriction indicate that PER3 does not contribute to the neurobehavioral effects of chronic sleep loss.

[1]  H. Landolt,et al.  Pharmacogenetics of Modafinil After Sleep Loss: Catechol‐O‐Methyltransferase Genotype Modulates Waking Functions But Not Recovery Sleep , 2009, Clinical pharmacology and therapeutics.

[2]  D. Dinges,et al.  Neurocognitive consequences of sleep deprivation. , 2005, Seminars in neurology.

[3]  H. Landolt.  Genotype-dependent differences in sleep, vigilance, and response to stimulants. , 2008, Current pharmaceutical design.

[4]  Erin L. McDearmon,et al.  The genetics of mammalian circadian order and disorder: implications for physiology and disease , 2008, Nature Reviews Genetics.

[5]  John A Groeger,et al.  Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. , 2008, Sleep.

[6]  Scott M. Williams,et al.  Genetic Differences in Human Circadian Clock Genes among Worldwide Populations , 2008, Journal of biological rhythms.

[7]  D. Dinges,et al.  Sleep Deprivation and Vigilant Attention , 2008, Annals of the New York Academy of Sciences.

[8]  B. Bioulac,et al.  Sharp and sleepy: evidence for dissociation between sleep pressure and nocturnal performance , 2008, Journal of sleep research.

[9]  G. O'Connor,et al.  Genome-wide association of sleep and circadian phenotypes , 2007, BMC Medical Genetics.

[10]  D. Dinges,et al.  Behavioral and physiological consequences of sleep restriction. , 2007, Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine.

[11]  Hans P A Van Dongen,et al.  Trait interindividual differences in the sleep physiology of healthy young adults , 2007, Journal of sleep research.

[12]  D. Dijk,et al.  PER3 Polymorphism Predicts Sleep Structure and Waking Performance , 2007, Current Biology.

[13]  D. Dijk,et al.  Age‐related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities , 2007, Journal of sleep research.

[14]  T. Balkin,et al.  Age and individual variability in performance during sleep restriction , 2006, Journal of sleep research.

[15]  H. Colten,et al.  Sleep Disorders and Sleep Deprivation , 2006 .

[16]  H. Colten,et al.  Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem , 2006 .

[17]  M. Weale,et al.  Evolution of a Length Polymorphism in the Human PER3 Gene, a Component of the Circadian System , 2005, Journal of biological rhythms.

[18]  D. Dinges,et al.  Sleep, circadian rhythms, and psychomotor vigilance. , 2005, Clinics in sports medicine.

[19]  D. Dinges,et al.  Individual differences in adult human sleep and wakefulness: Leitmotif for a research agenda. , 2005, Sleep.

[20]  T. Mulrooney,et al.  Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects , 2005 .

[21]  Meir H. Kryger,et al.  Principles and Practice of Sleep Medicine, 4th Edition , 2005 .

[22]  D. Dinges,et al.  Chapter 6 – Chronic Sleep Deprivation , 2005 .

[23]  Nelson A. M. Lemos,et al.  Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? , 2005, Sleep.

[24]  D. Dinges,et al.  Neurocognitive Consequences of Sleep Deprivation , 2005, Seminars in neurology.

[25]  Pietro Badia,et al.  Inter‐ and intra‐individual variability in performance near the circadian nadir during sleep deprivation , 2004, Journal of sleep research.

[26]  C. Kushida.  Sleep Deprivation : Clinical Issues, Pharmacology, and Sleep Loss Effects , 2004 .

[27]  D. Dinges,et al.  Psychomotor Vigilance Performance: Neurocognitive Assay Sensitive to Sleep Loss , 2004 .

[28]  B. Rahm,et al.  Planning Abilities and the Tower of London: Is This Task Measuring a Discrete Cognitive Function? , 2004, Journal of clinical and experimental neuropsychology.

[29]  E. Bixler,et al.  Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. , 2004, The Journal of clinical endocrinology and metabolism.

[30]  D. Dinges,et al.  Systematic interindividual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability. , 2004, Sleep.

[31]  Greg Maislin,et al.  Dealing with inter-individual differences in the temporal dynamics of fatigue and performance: importance and techniques. , 2004, Aviation, space, and environmental medicine.

[32]  Jillian Dorrian,et al.  Sleep, waking and neurobehavioural performance. , 2003, Frontiers in bioscience : a journal and virtual library.

[33]  Josephine Arendt,et al.  A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. , 2003, Sleep.

[34]  D. Dinges,et al.  The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. , 2003, Sleep.

[35]  Maria L. Thomas,et al.  Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose‐response study , 2003, Journal of sleep research.

[36]  E. F. Colecchia,et al.  Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[37]  C. Drake,et al.  Effects of rapid versus slow accumulation of eight hours of sleep loss. , 2001, Psychophysiology.

[38]  C. Degueldre,et al.  The Functional Anatomy of Inhibition Processes Investigated with the Hayling Task , 2001, NeuroImage.

[39]  G. Jackson,et al.  A Neurocognitive Account of Frontal Lobe Involvement in Orthographic Lexical Retrieval: An fMRI Study , 2001, NeuroImage.

[40]  Kazuhiko Fukuda,et al.  Proposed supplements and amendments to ‘A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects’, the Rechtschaffen & Kales (1968) standard , 2001, Psychiatry and clinical neurosciences.

[41]  Yuichi Inoue,et al.  Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome , 2001, EMBO reports.

[42]  A. Pack,et al.  Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. , 1997, Sleep.

[43]  Tim Shallice,et al.  The Hayling and Brixton Tests , 1997 .

[44]  T. Shallice,et al.  Response suppression, initiation and strategy use following frontal lobe lesions , 1996, Neuropsychologia.

[45]  W C Dement,et al.  The Sleep Disorders Questionnaire. I: Creation and multivariate structure of SDQ. , 1994, Sleep.

[46]  S. Crowe,et al.  Dissociation of two frontal lobe syndromes by a test of verbal fluency. , 1992, Journal of clinical and experimental neuropsychology.

[47]  Mark C. Jones.  PRINCIPLES AND PRACTICE OF SLEEP MEDICINE , 1990 .

[48]  T. Åkerstedt,et al.  Subjective and objective sleepiness in the active individual. , 1990, The International journal of neuroscience.

[49]  Carlla S. Smith,et al.  Evaluation of three circadian rhythm questionnaires with suggestions for an improved measure of morningness. , 1989, The Journal of applied psychology.

[50]  O. Spreen,et al.  Predicting premorbid IQ: A revision of the national adult reading test , 1989 .

[51]  Timothy H. Monk,et al.  A visual analogue scale technique to measure global vigor and affect , 1989, Psychiatry Research.

[52]  David F. Dinges,et al.  Microcomputer analyses of performance on a portable, simple visual RT task during sustained operations , 1985 .

[53]  M. Mitler,et al.  Maintenance of wakefulness test: a polysomnographic technique for evaluation treatment efficacy in patients with excessive somnolence. , 1982, Electroencephalography and clinical neurophysiology.

[54]  M. Carskadon,et al.  Cumulative effects of sleep restriction on daytime sleepiness. , 1981, Psychophysiology.

[55]  E. Wolpert.  A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. , 1969 .

[56]  A. Rechtschaffen,et al.  A manual of standardized terminology, technique and scoring system for sleep stages of human subjects , 1968 .

[57]  H. Eysenck.  Biological Basis of Personality , 1963, Nature.

[58]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.