Timo Partonen

Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference.

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 (χ2=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (χ2=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.

Three circadian clock genes Per2, Arnt1, and Npas2 contribute to winter depression

Background. Multiple lines of evidence suggest that the circadian clock contributes to the pathogenesis of winter depression or seasonal affective disorder (SAD). We hypothesized that sequence variations in three genes, including Per2, Arntl, and Npas2, which form a functional unit at the core of the circadian clock, predispose to winter depression. Methods. In silico analysis of the biological effects of allelic differences suggested the target single‐nucleotide polymorphisms (SNPs) to be analyzed in a sample of 189 patients and 189 matched controls. The most relevant SNP in each gene was identified for the interaction analysis and included in the multivariate assessment of the combined effects of all three SNPs on the disease risk. Results. SAD was associated with variations in each of the three genes in gene‐wise logistic regression analysis. In combination analysis of variations of Per2, Arntl, and Npas2, we found additive effects and identified a genetic risk profile for the disorder. Carriers of the risk genotype combination had the odds ratio of 4.43 of developing SAD as compared with the remaining genotypes, and of 10.67 as compared with the most protective genotype combination. Conclusion. Variations in the three circadian clock genes Per2, Arntl, and Npas2 are associated with the disease, supporting the hypothesis that the circadian clock mechanisms contribute to winter depression.

Trends in self-reported sleep duration and insomnia-related symptoms in Finland from 1972 to 2005: a comparative review and re-analysis of Finnish population samples

A hypothesis concerning habitual sleep reduction and its adverse consequences among general population in modern societies has received wide publicity in the mass media, although scientific evidence supporting the hypothesis is scarce. Similarly, there is an extensively distributed belief, at least in Finland, that the prevalence of insomnia‐related symptoms is increasing, but evidence for this is even sparser. These issues are important because of the known increased risk of mortality and health risks associated with sleep duration deviating from 7 to 8 h. To reveal possible trends in self‐reported sleep duration and insomnia‐related symptoms, we reanalyzed all available data from surveys carried out in Finland from 1972 to 2005. The main results were that a minor decrease of self‐reported sleep duration has taken place in Finland, especially among working aged men. However, the size of the reduction (about 4%) was relatively small, approximately 5.5 min per each 10 years during the 33 years’ time interval under study. The proportion of 7 h sleepers has increased and, correspondingly, the proportion of 8 h sleepers has decreased, but the extreme ends of the sleep duration distribution remained unchanged. Tentative evidence suggesting an increase in insomnia‐related symptoms among working aged population during the last 10 years was found. In conclusion, the Finnish data during the past 33 years indicate a general decrease in self‐reported sleep duration of about 18 min and an increase of sleep complaints, especially among the employed middle‐aged population.

Bright light improves vitality and alleviates distress in healthy people.

BACKGROUND The relative shortage of light during the decreasing photoperiod may compromise well-being. Earlier studies suggest that bright-light exposure may be of help to alleviate winter-bound symptoms. METHODS We carried out a field study with exposure to bright light on office employees during winter. RESULTS Repeated bright-light exposure improved vitality and reduced depressive symptoms. The benefit was observed not only in healthy subjects with season-dependent symptoms but also in those not having the seasonal variation. CONCLUSIONS Bright-light exposure during winter appears to be effective at improving the health-related quality of life and alleviating distress in healthy subjects. CLINICAL IMPLICATIONS Administration of bright light is a useful option to improve vitality and mood among subjects working indoors in wintertime. LIMITATIONS OF STUDY: Our field setting used self-reports, not interviews, for the assessment of outcome.

A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia

We have previously reported evidence of linkage and association between markers on 1q42 and schizophrenia in a study sample of 498 multiply affected Finnish nuclear families, leading to the recent identification of four significantly associated haplotypes that specifically implicate the Translin-Associated Factor X (TRAX) and Disrupted in Schizophrenia 1 and 2 (DISC1 and DISC2) genes in the genetic etiology of schizophrenia. Previously, the DISC genes were found to be disrupted by a balanced translocation (1;11)(q42.1;q14.3) that cosegregated with schizophrenia and related disorders in a large Scottish pedigree. Interestingly, we also reported earlier suggestive linkage between endophenotypic quantitative traits of visual and verbal memory and microsatellite markers in close proximity to TRAX/DISC, on 1q41. Here, we tested if the identified allelic haplotypes of TRAX/DISC would be associated with visual and/or verbal memory function impairments that are known to aggregate with schizophrenia in families. One haplotype of DISC1, HEP3, displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contribute to the observed association to visual working memory. These results provide genetic support to the view that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short-term visual memory functions. This finding should stimulate studies aiming at the molecular characterization of how the specific alleles of DISC1 affect the visual memory functions and eventually participates in the development of schizophrenia.

DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder.

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73±95% confidence interval (CI) 1.42–5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64±95% CI 1.23–2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27±95% CI 1.07–1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.

Determinants and Outcomes of Serious Attempted Suicide: A Nationwide Study in Finland, 1996–2003

Suicide is among the 10 leading causes of death. Attempted suicide is 10-40 times more frequent than completed suicide and is the strongest single predictor of subsequent suicide. The current study population included all persons in Finland who were hospitalized with a diagnosis of attempted suicide between 1996 and 2003 (N = 18,199). Information on background variables and mortality was obtained by register linkage. The risk of repeated attempted suicide was 30% and the risk of suicide was 10%. The risks of repeated attempted suicide, completed suicide, and death from any cause were high immediately after discharge from the hospital. Analysis of competing causes of death revealed that while alcohol-related disorder was not associated with suicide, it markedly increased the risk of other violent death: The subdistribution hazards rate (SHR) was 2.61 (95% confidence interval (CI): 2.12, 3.21). Schizophrenia-related disorders (SHR = 1.87, 95% CI: 1.57, 2.21) and mood disorders (SHR = 1.72, 95% CI: 1.47, 2.01) were associated with the risk of suicide. The risks of suicide and all-cause mortality were extremely high immediately after hospitalization for attempted suicide.

Self-reported sleep duration and cognitive functioning in the general population

This study investigated the relationship between self‐reported sleep factors (sleep duration, insomnia, use of sleeping medicine, probable sleep apnoea and feelings of fatigue and tiredness) with cognitive functioning in 5177 people aged 30 years or older from a cross‐sectional representative sample of the adult population in Finland (The Finnish Health 2000 Survey). Previous studies have indicated a U‐shaped association between increased health risks and sleep duration; we hypothesized a U‐shaped association between sleep duration and cognitive functioning. Objective cognitive functioning was assessed with tasks derived from the Consortium to Establish a Registry for Alzheimer’s Disease test battery (verbal fluency, encoding and retaining verbal material). Subjective cognitive functioning and sleep‐related factors were assessed with questionnaires. Health status was assessed during a health interview. Depressive and alcohol use disorders were assessed with the Composite International Diagnostic Interview. Medication was recorded during the health examination. Short and long sleep duration, tiredness and fatigue were found to be associated with both objectively assessed and self‐reported decreased cognitive functioning. The association was stronger between sleep factors and subjective cognitive function than with objective cognitive tests. These data suggest that self‐reported habitual short and long sleep duration reflect both realization of homeostatic sleep need and symptom formation in the context of the individual’s health status.

Relation of Chronotype to Sleep Complaints in the General Finnish Population

Individuals show variation in their preference for the daily timing of activities. In this study the authors analyzed whether chronotypes associate with sleep duration and sleep-related complaints. The authors used the National FINRISK Study 2007 Survey data on 3696 women and 3162 men, representative of the Finnish population aged 25 yrs and older, for the assessment of chronotype and self-reported sleep. Evening types experienced insomnia symptoms, had nightmares, and had used recently hypnotics significantly more often than other chronotypes among both men and women. In a multinominal logistic regression model predicting insufficient sleep, the association of eveningness with insufficient sleep was not abolished after adjustment for sex, age, and sleep duration. The prevalence of short sleepers was significantly higher in evening types among men than among women, whereas that of long sleepers was significantly higher in evening types among both men and women, as compared with the other chronotypes. These results indicate that eveningness predisposes individuals to a range of sleep complaints. (Author correspondence: ilona.merikanto@helsinki.fi)

Sleep-related disturbances and physical inactivity are independently associated with obesity in adults

Objective:To study relationships between obesity, physical inactivity and sleep-related disturbances (obstructive sleep apnea (OSA), sleep duration, sleep disturbances concomitant with daytime tiredness) in adults (⩾30 years).Design:Cross-sectional study with a random population sample.Participants:A total of 3377 men (mean age 52.3, s.d. 14.8, years) and 4264 women (56.4, s.d. 17.2, years).Main outcome measures:Dependent variables, measured: Waist circumference (WC) and body mass index (BMI). Independent variables, from a detailed interview/questionnaire: probable OSA, other sleep-related disturbances, sleep duration, type and frequency of leisure physical activity. Age, mental health, smoking and education were included in analyses as potential confounders.Results:In men, OSA and physical inactivity increased likelihood for abdominal obesity (WC ⩾102 cm). Physical inactivity also increased, but long (⩾9 h/day) sleep decreased likelihood for abdominal overweight (WC: 94–101 cm) in men. In women, abdominal obesity (WC ⩾88 cm) was associated positively with OSA, moderate sleep-related disturbances, and physical inactivity. Education modulated the influence of age on abdominal obesity in both genders. Using BMI as the dependent variable did not change the general information obtained by the model. In addition, abdominal obesity was found to be an independent risk factor also in multivariable models predicting categories of a combined sleep duration and sleep disturbances.Conclusions:Sleep duration and sleep-related disturbances are associated with obesity, even after controlling for OSA and physical inactivity. The results support the hypothesis of vicious circle between sleep and obesity.