Time to wake up: No impact of COMT Val158Met gene variation on circadian preferences, arousal regulation and sleep Philippe Jawinski a,b,c *, Sophie Tegelkamp b *, Christian Sander a,b,c , Madlen Häntzsch a,d , Jue Huang b , Nicole Mauche a,b , Markus Scholz a,e , Janek Spada b,c , Christine Ulke a,c , Ralph Burkhardt a,d , Andreas Reif f , Ulrich Hegerl a,b,c , and Tilman Hensch a,b a LIFE – Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; b Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany; c Depression Research Center of the German Depression Foundation, Leipzig, Germany; d Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; e Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; f Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt, Frankfurt, Germany ABSTRACT Dopamine has been implicated in the regulation of sleep–wake states and the circadian rhythm. However, there is no consensus on the impact of two established dopaminergic gene variants: the catechol-O-methyltransferase Val158Met (COMT Val158Met; rs4680) and the dopamine D4 recep- tor Exon III variable-number-of-tandem-repeat polymorphism (DRD4 VNTR). Pursuing a multi-method approach, we examined their potential effects on circadian preferences, arousal regulation and sleep. Subjects underwent a 7-day actigraphy assessment (SenseWear Pro3), a 20- minute resting EEG (analyzed using VIGALL 2.0) and a body mass index (BMI) assessment. Further, they completed the Morningness–Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). The sample comprised 4625 subjects (19–82 years) genotyped for COMT Val158Met, and 689 elderly subjects (64–82 years) genotyped for DRD4 VNTR. The number of subjects varied across phenotypes. Power calculations revealed a minimum required phenotypic variance explained by genotype ranging between 0.5% and 1.5% for COMT Val158Met and between 3.3% and 6.0% for DRD4 VNTR. Analyses did not reveal significant genotype effects on MEQ, ESS, PSQI, BMI, actigraphy and EEG variables. Additionally, we found no compelling evidence in sex- and age-stratified subsamples. Few associations sur- passed the threshold of nominal significance (p < .05), providing some indication for a link between DRD4 VNTR and daytime sleepiness. Taken together, in light of the statistical power obtained in the present study, our data particularly suggest no impact of the COMT Val158Met polymorphism on circadian preferences, arousal regulation and sleep. The suggestive link between DRD4 VNTR and daytime sleepiness, on the other hand, might be worth investigation in a sample enriched with younger adults. ARTICLE HISTORY Received 29 January 2016 Revised 04 April 2016 Accepted 11 April 2016 KEYWORDS actigraph; arousal; chronotypes; circadian rhythm; COMT Val158Met; DRD4 Exon III VNTR; rs4680; sleep; VIGALL; vigilance Introduction Circadian rhythm and sleep disruptions are pre- valent across a broad range of mental illnesses with particular salience in affective disorders and ADHD (Hegerl & Hensch, 2014; Landgraf et al., 2014; Wulff et al., 2010). Accumulating evidence suggests that dopamine plays a pivotal role in the regulation of sleep–wake states and the circadian rhythm. Aside from diurnal oscillations in extra- cellular brain dopamine tone (Castañeda et al., 2004; Léna et al., 2005), previous studies reported higher burst firing rates of dopaminergic neurons and higher dopamine release rates during waking (Monti & Monti, 2007). In keeping with this, wake-promoting effects in humans and mice have been demonstrated by inhibiting the dopamine transporter, and by applying dopamine releasing agents and dopamine receptor agonists (Berridge et al., 2006; Gruner et al., 2009; Wisor et al., 2001). Beyond this, prior research suggests an involve- ment of dopamine in regulating the expression of molecular clock genes (Yujnovsky et al., 2006). In CONTACT Philippe Jawinski philippe.jawinski@medizin.uni-leipzig.de Neurobiology Research, Department of Psychiatry, University of Leipzig, Semmelweisstr. 10, 04103, Leipzig, Germany. Tel: +49 (0)341 97 24 505. Fax: +49 (0)341 97 24 539. *These authors contributed equally to this work. Supplemental data for this article can be accessed at www.tandfonline.com/ICBI. CHRONOBIOLOGY INTERNATIONAL http://dx.doi.org/10.1080/07420528.2016.1178275 © 2016 Taylor & Francis