Circadian gene variants influence sleep and the sleep electroencephalogram in humans

ABSTRACT

The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25–1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75–4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep.

KEYWORDS:

• Circadian genes
• sleep EEG
• slow-wave sleep
• slow-wave activity

Acknowledgements

We thank the study participants, the staff of the Center for Clinical Investigation of the Brigham and Women’s Hospital (BWH), for collection of the genetic samples and the staff of the Broad Institute, Cambridge, MA, for genotyping assays. We also thank the BWH Sleep & EEG Core, in particular Brandon Lockyer, for PSG analysis and support; and Joseph Ronda for support with an automated sleep summary program. We thank Alana O’Malley, David Klements, Dayna Bradstreet and the recruitment office of the Division of Sleep Medicine for recruitment and screening of study participants; and Shantha Rajaratnam, Ph.D., and Melanie Rüger, Ph.D., for their contributions to the study protocols.

Declaration of interest

This study was funded by National Institute of Health (NIH) grant R21-DK089378, a pilot grant from Harvard Catalyst, Harvard Clinical and Translational Science Center (UL1 RR025758) and financial contributions from Harvard University. Additional funding was provided by NIH grants HL080978, MH045130 and HL077453; National Space Biomedical Research Institute (NSBRI) grant HPF01601; the BWH General Clinical Research Center (NIH M01-02635); and a BWH Faculty Career Development Award to AMC. AMC was supported in part by NIH grant K01-HL115458. DA was supported in part by the German Aerospace Center. SAS was supported in part by NIH grant K24-HL076446. FAJLS and RS were supported by a Harvard Catalyst Pilot Grant, R21-DK089378, R01-DK102696 and R21-HL121728. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, NSBRI or BWH.

None of the authors have conflicts of interest with the work presented but the following financial support is stated in the interest of full disclosure.

Dr. Buxton reports research grant support from the National Institutes of Health outside of the submitted work; consulting with Matsutani America (scientific advisory board) and Harvard T.H. Chan School of Public Health. Travel support and honoraria for speaking from American Academy of Craniofacial Pain; Chevron; New York University; Academy of Nutrition and Dietetics; and Harvard T.H. Chan School of Public Health. Dr. Buxton received two investigator-initiated grants from Sepracor Inc (now Sunovion; ESRC-0004 and ESRC-0977, ClinicalTrials.gov Identifiers NCT00555750, NCT00900159), and two investigator-initiated grants from Cephalon Inc (now Teva; ClinicalTrials.gov Identifier: NCT00895570). OMB received Speaker’s Bureau, CME and non-CME lecture honoraria and an unrestricted educational grant from Takeda Pharmaceuticals North America. OMB serves as a consultant and expert witness for Dinsmore LLC, consulting fees for serving on the Scientific Advisory Board of Matsutani America, and consulting fees from the Wake Forest University Medical Center (NC). OMB received speaking fees and/or travel support for speaking from American Academy of Craniofacial Pain, NHLBI, NIDDK, National Postdoctoral Association, Oklahoma State University, Oregon Health Sciences University, SUNY Downstate Medical Center, American Diabetes Association, and New York University.

Dr. Anderson has served as consultant to the Rail, Bus and Tram Union. National Transport Commission (Australia) and VicPolice. She has also received research support from VicRoads and Sanofi-Aventis, and has received lecturing fees from Brown Medical School/Rhode Island Hospital and Ausmed.

Dr. Czeisler has received consulting fees from or served as a paid member of scientific advisory boards for: Bombardier, Inc.; Boston Bruins; Boston Celtics; Boston Red Sox; Cephalon, Inc. (acquired by Teva Pharmaceutical Industries Ltd. October 2011); Koninklijke Philips Electronics, N.V. (acquired Respironics, Inc. March 2008); Michael Jackson’s mother and children; Novartis; Sleep Multimedia, Inc.; United Parcel Service (UPS); Vanda Pharmaceuticals, Inc.; and Zeo Inc. CAC owns an equity interest in Apple; Lifetrac, Inc.; Microsoft; Somnus Therapeutics, Inc.; Vanda Pharmaceuticals, Inc., and Zeo Inc., and received royalties from McGraw Hill, Penguin Press/Houghton Mifflin Harcourt, and Philips Respironics, Inc. He has also received research support from Cephalon, National Football League Charities, ResMed and Philips Respironics; and has received lecture fees from APSS (Associated Professional Sleep Societies); AWHONN (Association of Women’s Health, Obstetric and Neonatal Nurses); Harvard School of Public Health; Hokkaido University Graduate School of Medicine; Japan Society for Occupational Health; Society of Thoracic Surgeons; University of Washington; the World Federation of Sleep Research and Sleep Medicine Societies and WME Entertainment LLC. CAC has also received research prizes with monetary awards from the American Academy of Sleep Medicine. The Harvard Medical School Division of Sleep Medicine (HMS/DSM), which CAC directs, has received unrestricted research and educational gifts and endowment funds from: Boehringer Ingelheim Pharmaceuticals, Inc., Cephalon, Inc., George H. Kidder, Esq., Gerald McGinnis, GlaxoSmithKline, Herbert Lee, Hypnion, Jazz Pharmaceuticals, Jordan’s Furniture, Merck & Co., Inc., Peter C. Farrell, Ph.D., Pfizer, ResMed, Respironics, Inc., Sanofi-Aventis, Inc., Sealy, Inc., Sepracor, Inc., Simmons, Sleep Health Centers LLC, Spring Aire, Takeda Pharmaceuticals and Tempur-Pedic. The HMS/DSM has received gifts from many outside organizations and individuals including: Cephalon, Inc., Committee for Interns and Residents, Eisai, Inc., Farrell Family Foundation, Fisher & Paykel Healthcare Corporation, Gerald McGinnis, Jazz Pharmaceuticals, Jordan’s Furniture, Lilly USA, LLC, Neurocare Center for Sleep, NeuroScience, Novartis Consumer Health, Philips-Respironics, Inc., Praxair US Homecare, Purdue Pharma, ResMed Foundation, Safeway, Sanofi-Aventis, Inc., Select Comfort Corporation, Sleep HealthCenters LLC, Somaxon Pharmaceuticals, Transcept Pharmaceuticals, United Healthcare, Vanda Pharmaceuticals, Inc., Wake Up Narcolepsy, Inc., Watermark Medical, Weight Watchers International, YMCA of the USA and Zeo, Inc. The HMS/DSM Sleep and Health Education Program has received Educational Grant funding from Cephalon, Inc., Takeda Pharmaceuticals, Sanofi-Aventis, Inc. and Sepracor, Inc. CAC is the incumbent of an endowed professorship provided to Harvard University by Cephalon, Inc. and holds a number of process patents in the field of sleep/circadian rhythms (e.g., photic resetting of the human circadian pacemaker). Since 1985, CAC has also served as an expert witness on various legal cases related to sleep and/or circadian rhythms.

Dr. Lockley has received consulting fees from Naturebright, Sound Oasis, Thomas Jefferson University and Wyle Integrated Science and Engineering (NASA), Blackrock, Cowen & Co, Endurant Capital Management, Far West Capital Management, Fidelity, Frankel Group, Impax Laboratories, Kearney Venture Partners, Lazard Capital Markets, New Horizon Capital, Perceptive Advisors, Polar Capital, ResearchWorks Inc, and Wyvern Funds. He has also received unrestricted equipment gifts from Biological Illuminations LLC, Bionetics Corporation, and Philips Lighting; an unrestricted monetary gift from Swinburne University of Technology, Australia; a fellowship gift from Optalert, Pty, Melbourne, Australia; equity in iSLEEP, Pty, Melbourne, Australia; and advance author payment and royalties from Oxford University Press and from Elsevier. SWL has received honoraria and/or travel and accommodation support from 8th International Conference on Managing Fatigue; 14th Annual Tennessee Perfusion Conference; Brown University; Connecticut Business & Industry Association Health and Safety Conference; Emergency Services Steering Committee; Estee Lauder; Harvard University; Lighting Science Group Corp; Massachusetts General Hospital; MediCom Worldwide, Inc (CME); Midwest Lighting Institute; National Research Council Canada; New England College of Occupational and Environmental Medicine; Ontario Association of Fire Chiefs; Rio Tinto; UMass Memorial; Woolcock Institute of Medical Research; and Wyle Integrated Science and Engineering. He has received investigator-initiated research grants from Biological Illuminations LLC, Philips Lighting, and Vanda Pharmaceuticals and has served as a paid expert on behalf of six public bodies in arbitration hearings related to sleep, circadian rhythms and work hours in firefighters and police.

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