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Sci Rep. 2019 Mar 29;9(1):5350. doi: 10.1038/s41598-019-41712-1.

Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans.

Chang AM1,2,3,4, Duffy JF5,6, Buxton OM7,5,6,8, Lane JM9,10, Aeschbach D5,6,11, Anderson C5,6,12, Bjonnes AC9,10, Cain SW5,6,12, Cohen DA5,6, Frayling TM13, Gooley JJ5,6,14, Jones SE13, Klerman EB5,6, Lockley SW5,6, Munch M5,6,15, Rajaratnam SMW5,6,12, Rueger M5,6, Rutter MK16,17, Santhi N5,6,18, Scheuermaier K5,6,19, Van Reen E5,6,20, Weedon MN13, Czeisler CA5,6, Scheer FAJL21,22, Saxena R5,9,10.

Author information

1
Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania, 16802, USA. amchang@psu.edu.
2
Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA. amchang@psu.edu.
3
Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA. amchang@psu.edu.
4
Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, 02142, USA. amchang@psu.edu.
5
Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA.
6
Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA.
7
Department of Biobehavioral Health, Pennsylvania State University, University Park, Pennsylvania, 16802, USA.
8
Department of Social and Behavioral Sciences, Harvard Chan School of Public Health, Boston, Massachusetts, 02115, USA.
9
Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, 02142, USA.
10
Department of Anesthesia, Critical Care and Pain Medicine and Center for Genomic Medicine; Massachusetts General Hospital, Boston, Massachusetts, 02114, USA.
11
Department of Sleep and Human Factors Research, Institute of Aerospace Medicine, German Aerospace Center, Cologne, 51147, Germany.
12
Monash Institute of Cognitive and Clinical Neurosciences and School of Psychological Sciences, Monash University, Clayton, VIC, Australia.
13
Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
14
Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore, Singapore.
15
Sleep/Wake Research Centre, College of Health, Massey University, Wellington, New Zealand.
16
Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
17
Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
18
Surrey Sleep Research Centre, University of Surrey, Guildford, UK.
19
Wits Sleep Laboratory, Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
20
Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
21
Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA. fscheer@bwh.harvard.edu.
22
Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA. fscheer@bwh.harvard.edu.

Abstract

The PERIOD2 (PER2) gene is a core molecular component of the circadian clock and plays an important role in the generation and maintenance of daily rhythms. Rs35333999, a missense variant of PER2 common in European populations, has been shown to associate with later chronotype. Chronotype relates to the timing of biological and behavioral activities, including when we sleep, eat, and exercise, and later chronotype is associated with longer intrinsic circadian period (cycle length), a fundamental property of the circadian system. Thus, we tested whether this PER2 variant was associated with circadian period and found significant associations with longer intrinsic circadian period as measured under forced desynchrony protocols, the 'gold standard' for intrinsic circadian period assessment. Minor allele (T) carriers exhibited significantly longer circadian periods when determinations were based on either core body temperature or plasma melatonin measurements, as compared to non-carriers (by 12 and 11 min, respectively; accounting for ~7% of inter-individual variance). These findings provide a possible underlying biological mechanism for inter-individual differences in chronotype, and support the central role of PER2 in the human circadian timing system.

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