1. ¹Neurogenetics Unit, Department of Molecular Medicine, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden
2. ²Department of General Psychiatry, Vienna University, Vienna, Austria
3. ³Department of Clinical Sciences, Division of Psychiatry, University of Umeå, Umeå, Sweden
4. ⁴Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
5. ⁵Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
6. ⁶Department of Psychiatry, University of Bonn, Bonn, Germany
7. ⁷Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD, USA
8. ⁸Department of Psychology, Stockholm University, Stockholm, Sweden
9. ⁹Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA, USA

Correspondence: C Johansson, Neurogenetics Unit, CMM L8:00, Karolinska Hospital, S-171 76 Stockholm, Sweden. Tel: +46 8 5177 6407; Fax: +46 8 5177 3909; E-mail: carolina.johansson@cmm.ki.se

Received 22 July 2002; Revised 30 October 2002; Accepted 26 November 2002.

Abstract

Disturbed circadian rhythms have been observed in seasonal affective disorder (SAD). The aim of this study was to further investigate this connection, and to test for potential association between polymorphisms in circadian clock-related genes and SAD, seasonality (seasonal variations in mood and behavior), or diurnal preference (morningness–eveningness tendencies). A total of 159 European SAD patients and 159 matched controls were included in the genetic analysis, and subsets were screened for seasonality (n=177) and diurnal preference (n=92). We found that diurnal preference was associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. The complete case–control material was genotyped for polymorphisms in the CLOCK, Period2, Period3, and NPAS2 genes. A significant difference between patients and controls was found for NPAS2 471 Leu/Ser (²=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (²=6.61, Bonferroni corrected P=0.050). Period3 647 Val/Gly was associated with self-reported morningness–eveningness scores (n=92, one-way ANOVA: F=4.99, Bonferroni corrected P=0.044), with higher scores found in individuals with at least one glycine allele (t=3.1, Bonferroni corrected P=0.013). A second, population-based sample of individuals selected for high (n=127) or low (n=98) degrees of seasonality, was also genotyped for NPAS2 471 Leu/Ser. There was no significant difference between these seasonality extreme groups, and none of the polymorphisms studied were associated with seasonality in the SAD case–control material (n=177). In conclusion, our results suggest involvement of circadian clock-related polymorphisms both in susceptibility to SAD and diurnal preference.