Genetic and experimental studies of seasonal affective disorder and related phenotypes
Author: Johansson, Carolina
Date: 2003-04-04
Location: Karolinska Sjukhusets aula, huvudbyggnaden, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för molekylär medicin / Department of Molecular Medicine
Abstract
Seasonal affective disorder (SAD) is a subtype of recurrent depressive or bipolar disorder, in which episodes reoccur and remit during a particular season each year. A genetic component in vulnerability to winter SAD has been suggested, and the goal of this thesis was to increase the understanding of SAD and seasonal variations in mood, by obtaining self-report assessments of related traits, examining genetic variations in genes hypothesised to influence the phenotypes in question, and to investigate effects of different photoperiods and stress in an animal model.
Self-reported diurnal preference was found to be associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. Genetic association studies were conducted, using case-control materials and a population based sample set of individuals with extremely high or low seasonality scores. When analysing polymorphisms in four circadian clock related genes, a significant difference in NPAS2 471 Leu/Ser genotype distribution was found between patients and controls, indicating that the Leu/Leu genotype might increase susceptibility to SAD. In addition, Period3 647 Val/Gly, previously found to be associated with delayed sleep phase syndrome, was associated with diurnal preference, supporting the evidence for an effect of genetic variations in Period3 on circadian rhythms in humans. Previously, a deletion in the promoter region of the serotonin transporter gene, with a dominant negative effect on gene expression, has been reported to be associated with both SAD and seasonality. In the present study, no association was found for this polymorphism, called 5-HTTLPR, or six other serotonin or signal transduction related gene variants. Analysis of additional case-control samples, the seasonality extreme material and a pooled analysis of all known studies of 5-HTTLPR, SAD and seasonality was performed (ntotal=1150). The overall conclusion was that the 5-HTTLPR deletion appears not to have a substantial effect on susceptibility to SAD, but there were some indications for influence on seasonality.
Changes in hours of daylight are thought to be the main environmental trigger for SAD, and a long photoperiod is suggested to produce antidepressant-like actions in rats. The biological effects of a prolonged photoperiod were explored by studying hypothalamic gene expression, plasma stress hormone levels and anxiety-like behaviours, in male rats exposed to different light and stress conditions. No behavioural or stress response differences were found, however, microarray analysis revealed several genes with altered expression; the results suggest that a prolonged photoperiod changes mainly the expression of genes involved in signal transduction and the immune system, while stress induction activated primarily genes encoding transcription regulating and signal transducting proteins. These findings provide insights into pathways putatively involved in hypothalamic photoperiod biology and stress response, and have potential relevance for related human disorders, such as seasonal depression.
Self-reported diurnal preference was found to be associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. Genetic association studies were conducted, using case-control materials and a population based sample set of individuals with extremely high or low seasonality scores. When analysing polymorphisms in four circadian clock related genes, a significant difference in NPAS2 471 Leu/Ser genotype distribution was found between patients and controls, indicating that the Leu/Leu genotype might increase susceptibility to SAD. In addition, Period3 647 Val/Gly, previously found to be associated with delayed sleep phase syndrome, was associated with diurnal preference, supporting the evidence for an effect of genetic variations in Period3 on circadian rhythms in humans. Previously, a deletion in the promoter region of the serotonin transporter gene, with a dominant negative effect on gene expression, has been reported to be associated with both SAD and seasonality. In the present study, no association was found for this polymorphism, called 5-HTTLPR, or six other serotonin or signal transduction related gene variants. Analysis of additional case-control samples, the seasonality extreme material and a pooled analysis of all known studies of 5-HTTLPR, SAD and seasonality was performed (ntotal=1150). The overall conclusion was that the 5-HTTLPR deletion appears not to have a substantial effect on susceptibility to SAD, but there were some indications for influence on seasonality.
Changes in hours of daylight are thought to be the main environmental trigger for SAD, and a long photoperiod is suggested to produce antidepressant-like actions in rats. The biological effects of a prolonged photoperiod were explored by studying hypothalamic gene expression, plasma stress hormone levels and anxiety-like behaviours, in male rats exposed to different light and stress conditions. No behavioural or stress response differences were found, however, microarray analysis revealed several genes with altered expression; the results suggest that a prolonged photoperiod changes mainly the expression of genes involved in signal transduction and the immune system, while stress induction activated primarily genes encoding transcription regulating and signal transducting proteins. These findings provide insights into pathways putatively involved in hypothalamic photoperiod biology and stress response, and have potential relevance for related human disorders, such as seasonal depression.
List of papers:
I. Johansson C, Smedh C, Partonen T, Pekkarinen P, Paunio T, Ekholm J, Peltonen L, Lichtermann D, Palmgren J, Adolfsson R, Schalling M (2001). Seasonal affective disorder and serotonin-related polymorphisms. Neurobiol Dis. 8(2): 351-7.
Pubmed
II. Johansson C, Willeit M, Levitan R, Partonen T, Smedh C, Del Favero J, Bel Kacem S, Praschak-Rieder N, Neumeister A, Masellis M, Basile V, Zill P, Bondy B, Paunio T, Kasper S, Van Broeckhoven C, Nilsson LG, Lam R, Schalling M, Adolfsson R (2003). The serontin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality. Psychological Medicine. [Accepted]
III. Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppa T, Lichtermann D, Praschak-Rieder N, Neumeister A, Nilsson LG, Kasper S, Peltonen L, Adolfsson R, Schalling M, Partonen T (2003). Circadian Clock-Related Polymorphisms in Seasonal Affective Disorder and their Relevance to Diurnal Preference. Neuropsychopharmacology. 28(4): 734-9.
Pubmed
IV. Johansson C, Willeit M, Aron L, Smedh C, Ekholm J, Paunio T, Kieseppa T, Lichtermann D, Praschak-Rieder N, Neumeister A, Kasper S, Peltonen L, Adolfsson R, Partonen T, Schalling M (2003). Seasonal affective disorder and the G-protein beta-3-subunit C825T polymorphism. [Submitted]
V. Johansson C, Kelsoe J, Schalling M, Arborelius L (2003). Biological effects of a prolonged photoperiod and acute stress in rats. [Manuscript]
I. Johansson C, Smedh C, Partonen T, Pekkarinen P, Paunio T, Ekholm J, Peltonen L, Lichtermann D, Palmgren J, Adolfsson R, Schalling M (2001). Seasonal affective disorder and serotonin-related polymorphisms. Neurobiol Dis. 8(2): 351-7.
Pubmed
II. Johansson C, Willeit M, Levitan R, Partonen T, Smedh C, Del Favero J, Bel Kacem S, Praschak-Rieder N, Neumeister A, Masellis M, Basile V, Zill P, Bondy B, Paunio T, Kasper S, Van Broeckhoven C, Nilsson LG, Lam R, Schalling M, Adolfsson R (2003). The serontin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality. Psychological Medicine. [Accepted]
III. Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppa T, Lichtermann D, Praschak-Rieder N, Neumeister A, Nilsson LG, Kasper S, Peltonen L, Adolfsson R, Schalling M, Partonen T (2003). Circadian Clock-Related Polymorphisms in Seasonal Affective Disorder and their Relevance to Diurnal Preference. Neuropsychopharmacology. 28(4): 734-9.
Pubmed
IV. Johansson C, Willeit M, Aron L, Smedh C, Ekholm J, Paunio T, Kieseppa T, Lichtermann D, Praschak-Rieder N, Neumeister A, Kasper S, Peltonen L, Adolfsson R, Partonen T, Schalling M (2003). Seasonal affective disorder and the G-protein beta-3-subunit C825T polymorphism. [Submitted]
V. Johansson C, Kelsoe J, Schalling M, Arborelius L (2003). Biological effects of a prolonged photoperiod and acute stress in rats. [Manuscript]
Issue date: 2003-03-14
Publication year: 2003
ISBN: 91-7349-481-x
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