M.H. Azevedo

Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population (‘HapICE’), and two haplotypes located in the 3′ end of NRG1 (all P<0.05). However, association was not detected with HapICE itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.

Snoring in Portuguese Primary School Children

Objective. To determine the prevalence of snoring and its potential associations with sleep problems, such as daytime symptoms, medical conditions, school performance, and behavioral disturbances in Portuguese children attending primary school. Methods. A previously validated questionnaire was sent to the parents of 1381 children attending primary schools in a parish of Coimbra, Portugal. To assess behavioral disturbances, the Portuguese version of Rutters Childrens Behavior Questionnaire for completion by teachers was used. Results. Of the 988 questionnaires returned (71.5%), complete information concerning snoring was obtained for 976 children (496 girls and 480 boys; mean age: 8.1 ± 1.5 years). Loud snoring during sleep was reported as frequent or constantly present (LSn) in 84 children (8.6%), as occasionally present in 299 children (30.6%), and as never present (NSn) by 593 children (60.8%). The LSn and NSn groups did not differ with respect to age, gender, sleep duration, time to fall asleep, frequency of night wakings, bedwetting, daytime tiredness, and school achievement. However, LSn was significantly associated with increased bedtime problems (fears and struggles), increased need for comforting activities to fall asleep, behaviors suggestive of parasomnias (sleep talking, teeth grinding, and night terrors), increased daytime sleepiness and irritability, and behavioral disturbances. Children in the LSn group were also more likely to report recurrent medical problems particularly those involving infections of the respiratory tract. Conclusions. Snoring is a common symptom in Portuguese children that is associated with behavioral daytime and sleep time disturbances. Children with loud snoring may benefit from early evaluation and intervention.

Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.

Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31–5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112–D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases.

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31–q35. This finding was supported by meta-analysis of 20 other schizophrenia genome-wide scans that identified 5q23.2–q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P=0.00062–0.048), GABRP (P=0.0024–0.042), and GABRA6 (P=0.0065–0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P=0.0015–0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABAA receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

Sleep and Academic Performance in Undergraduates: A Multi-measure, Multi-predictor Approach

The present study examined the associations of sleep patterns with multiple measures of academic achievement of undergraduate university students and tested whether sleep variables emerged as significant predictors of subsequent academic performance when other potential predictors, such as class attendance, time devoted to study, and substance use are considered. A sample of 1654 (55% female) full-time undergraduates 17 to 25 yrs of age responded to a self-response questionnaire on sleep, academics, lifestyle, and well-being that was administered at the middle of the semester. In addition to self-reported measures of academic performance, a final grade for each student was collected at the end of the semester. Univariate analyses found that sleep phase, morningness/eveningness preference, sleep deprivation, sleep quality, and sleep irregularity were significantly associated with at least two academic performance measures. Among 15 potential predictors, stepwise multiple regression analysis identified 5 significant predictors of end-of-semester marks: previous academic achievement, class attendance, sufficient sleep, night outings, and sleep quality (R2 = 0.14 and adjusted R2 = 0.14, F(5, 1234) = 40.99, p < .0001). Associations between academic achievement and the remaining sleep variables as well as the academic, well-being, and lifestyle variables lost significance in stepwise regression. Together with class attendance, night outings, and previous academic achievement, self-reported sleep quality and self-reported frequency of sufficient sleep were among the main predictors of academic performance, adding an independent and significant contribution, regardless of academic variables and lifestyles of the students. (Author correspondence: ana.allen@ua.pt)

Sleep and behavioral/emotional problems in children: A population-based study

BACKGROUND The potential relationships between sleep-wake behaviors and emotional/disruptive problems in otherwise healthy school-aged children are unclear. METHODS A parental questionnaire was developed for the epidemiologic survey of childrens sleep and wake behavioral patterns. The questions covered a wide range of features including sleep length (school days, weekends), time to fall asleep, night awakenings, bedtime and nighttime sleep-related behaviors, daytime sleepiness, irritability, and tiredness. To assess psychiatric symptomatology, the Rutter Scale B2 was completed by teachers. In addition to the total score, sub-scores of emotional, hyperactivity, and conduct problems were obtained. The representative population sample comprised 779 children (403 girls), with an age range of 6-11 years. RESULTS Hyperactivity and conduct problems at school in boys were both associated with parental reports of bedtime resistance. Hyperactivity was also associated with longer sleep duration during weekends. Conduct and emotional problems in girls were associated with earlier bedtime during school days. Emotional problems in girls were also associated with longer sleep durations in school days and weekends. CONCLUSION Bedtime resistance was the only sleep behavior associated with either hyperactivity or conduct problems in children, and longer sleep durations appear to occur more frequently in children with both hyperactive or emotional problems. Information about good sleep hygiene at bedtime may help parents setting sleep limits.

Human p53 tumor suppressor gene (TP53) and schizophrenia: Case–control and family studies

The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia.

Longitudinal study on perfectionism and sleep disturbance

Aim. To examine if perfectionism predicts self-reported sleep disturbances over time. Methods. The Hewitt–Flett Perfectionism Scale was used to assess self-oriented, socially-prescribed (SPP) and other-oriented perfectionism. Sleep disturbance was evaluated with two items: difficulty in falling asleep and waking up many times during the night. Out of 870 students who participated at baseline, 592 and 305 completed the same measures 1 year (T1) and 2 years later (T2), respectively. Results. Subjects who reported insomnia at baseline, T1 and T2 (persistent insomnia) had significantly higher scores of baseline SPP (T1 M = 51.5, SD = 15.8; T2 M = 55.0, SD = 19.0) than subjects reporting, in all stages of the study, never/rarely having had sleep problems (T1 M = 41.9, SD = 11.4; T2 M = 42.2, SD = 12.3, P<0.001 in both cases). Regression analyses showed that baseline SPP was the only significant positive predictor of difficulties in falling asleep at T1 and T2 (T1 partial R=0.187; T2 partial R=0.196, P<0.001) and of difficulties maintaining sleep (T1 partial R=0.116; T2 partial R=0.244, P<0.001). Conclusion. SPP was found to be the most reliable predictor of sleep disturbances over time, which constitutes a new important finding.

Is insomnia in late pregnancy a risk factor for postpartum depression/depressive symptomatology?

The aim of the present work was to investigate if insomnia in late pregnancy is a risk factor for postpartum depressive symptomatology/postpartum depression (PPD). 581 women in their last trimester of pregnancy answered questions/questionnaires about lifetime history of insomnia, current sleep perception, current mood and depressive symptomatology. They were interviewed with the Portuguese version of the Diagnostic Interview for Genetic Studies. After delivery 382 (65.7%) mothers participated again in the study. Insomnia in pregnancy was not a risk factor for PPD (DSM-IV or ICD-10) but was a significant predictor of postpartum depressive symptomatology. Negative Affect (NA) was a significant predictor of postpartum depressive symptomatology. Women with higher NA were 4.6 (CI95%=1.69-12.74) and 5.3 times (CI95%=2.26-12.58) more likely of experiencing PPD (DSM-IV/ICD-10, respectively) than women with lower NA. Lifetime Depression was a significant predictor of postpartum depressive symptomatology and ICD-10/PPD (OR=2.6; CI95%=1.16-4.38). Positive Affect (PA) showed to be a protective factor for postpartum depressive symptomatology and DSM-IV/PPD (OR=1.5; CI95%=1.20-2.33). Controlling NA, PA and Lifetime Depression, insomnia lost its predictive role, suggesting these variables might work as mediators. Associations between insomnia, NA, PA and Lifetime Depression should be assessed in pregnancy. This might help to preventively target NA, enhance PA and reduce the likelihood of experiencing postpartum depressive symptomatology.

Perfectionism and eating behaviour in Portuguese adolescents.

OBJECTIVES The main objective was to investigate the association between perfectionism and eating behaviour in a non-clinical sample of adolescents of both genders. METHOD 997 middle and high school students completed the Portuguese versions of the child-adolescent perfectionism scale (CAPS) and of the eating attitudes test -25 (EAT-25). RESULTS In both genders, the perfectionism total score and the sociallyprescribed perfectionism (SPP) score were positive and significantly correlated with the EAT total score and with all EAT dimensions: Drive for Thinness (DT), Bulimic Related Behaviour (BRB), Social Pressure to Eat (SPE). In girls, self-oriented perfectionism (SOP) was also associated with the EAT total score and its dimensions, whereas in boys it was only associated with EAT total score and DT. In both genders SPP was a useful predictor of the EAT-25 total score and of all its dimensions. In which respects SOP, there were some gender differences showing that in boys this dimension should not be considered a predictor of eating behaviours. CONCLUSION These results confirm that high levels of perfectionism (SOP and SPP) are associated with abnormal eating behaviour in both genders.