Jayanti Chotai

Anticipation in Swedish families with bipolar affective disorder.

Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.

On the lod score method in linkage analysis

Genetic epidemiology deals with the interaction of environmental and genetic determinants in common diseases. Linkage analysis is an important branch of this field. The current practice of claiming linkage between two genetic loci when the maximum lod score z(θ) exceeds 3 has not received theoretical justification, whether considered as a sequential or as a fixed sample size test. Within the framework of significance testing, Walds (1947) formulae are not applicable to allow this procedure a sequential interpretation. Considered as a fixed sample size test, we find that a X2 approximation would instead be very adequate. Since repeated significance testing is performed on linkage data, the nominal significance level should be more stringent for each test than the overall level. Some recent developments in group sequential trials by Pocock (1977) and in repeated significance testing by Woodroofe (1979) seem to indicate that the critical value of the maximum lod score should lie roughly between 0·9 and 3·3, depending on the maximum number of repetitions anticipated, on whether the significance level is desired to be 0·05, 0·01 or 0·001, and on whether the test is derived from a one‐sided or a two‐sided consideration. In terms of the group sequential approach, if a maximum of twenty repetitions is allowed, if z(θ) > log10 A is considered as a one‐sided test and assumed to be symmetric when linkage is absent, then the type I error is approximately given by 1/A. We also treat the confidence interval approach for exclusion of unlikely recombination values.

Effect of trauma on quality of life as mediated by mental distress and moderated by coping and social support among postconflict displaced Ethiopians.

ObjectiveAn understanding of how quality of life is affected by severe trauma and mental distress may facilitate better intervention strategies for postconflict internally displaced persons, by identifying mediators, moderators, and independent risk factors. We investigate the pathways involved in this process and also study the moderating roles of coping strategies and perceived social support.MethodA random sample of 1193 (62% women) internally displaced Ethiopian adults living in shelters in Addis Ababa were interviewed with instruments capturing the relevant concepts, including SCL-90-R and WHOQOL-BREF. Path analysis was employed to elaborate the mediating and moderating effects. Self-reported living conditions were also assessed.ResultsMental distress increased and quality of life decreased with age. Mental distress mediated the effects of trauma in reducing the quality of life, and some trauma also reduced quality of life directly. These effects remained after adjusting for living conditions. Living conditions were related to quality of life also on their own. Coping strategies and perceived social support influenced mental distress and quality of life directly as well as indirectly by moderation, in part gender specific.ConclusionsIntervention strategies aimed at reducing mental distress, modifying coping strategies, and encouraging social support may turn out to be useful in increasing the overall quality of life in postconflict situations, and are worth considering as complements to strategies that improve the living conditions.

Further results on the association between morningness-eveningness preference and the season of birth in human adults.

Morningness-eveningness preference by the self-rated Morningness-Eveningness Questionnaire (MEQ) has earlier been shown to be associated with the subjects’ season of birth. Here, we obtain this result for a new sample of 2,125 university students and for the sample obtained by pooling the data with the earlier study, yielding totally 3,709 Italian and Spanish subjects. An nonlinear regression of MEQ as a cosine curve according to the month of birth, adjusting for age and gender, gave a maximum (morningness) around the transition between the birth months December and January, and a minimum (eveningness) around the transition between the birth months June and July. Multiple logistic regressions showed that for females as well as for males, the group born during the half-year April to September containing summer had a significantly lower proportion of morning types as compared with the group born during the half-year October to March containing winter. This was more pronounced for males. Moreover, a significantly higher proportion of morning types among females compared with males was found only in the group born during April to September, but not in the group born during October to March. There was a weak but statistically significant positive correlation between MEQ and age in the sample’s limited age range of 17–30 years. We discuss the results in terms of the mutually inhibitory systems of melatonin and dopamine, and find further support for a hypothesis that it is the variation in the length of photoperiod during the gestational or perinatal period that contributes significantly to the season of birth variation found in the morningness-eveningness preference among adults.

Season of Birth Variations in the Temperament and Character Inventory of Personality in a General Population

Background: Since several studies show season of birth variations in morbidity, suicidal behavior and CSF (cerebrospinal fluid) monoamine metabolites, we investigated season of birth variations in personality in the population. Methods: We analyzed by multiple logistic regressions the Temperament and Character Inventory (TCI) for 2,130 individuals taking part in the Betula prospective random cohort study of Umeå, Sweden. Results: The personality dimensions were correlated significantly with age and gender. We stratified the data according to age, gender and the season of TCI measurement. By the median split in each stratum, a high-value group and a low-value group were obtained for each of the personality dimensions. Those born during February to April were significantly more likely than those born during October to January to have high NS (novelty seeking) among women, particularly the subscale NS2 (impulsiveness vs. reflection), and to have high PS (persistence) among men. Temperament profiles also showed season of birth variations. Conclusions: We discuss the associations in the literature between personality and the monoamines serotonin and dopamine, and suggest that our results are compatible with a hypothesis of season of birth variation in the monoamine turnover. The personality traits are likely to be influenced by several genetic and environmental factors, one of them being the season of birth.

Comparison of two self-rating scales to detect depression: HADS and PHQ-9

BACKGROUND More than half of patients with depression go undetected. Self-rating scales can be useful in screening for depression, and measuring severity and treatment outcome. AIM This study compares the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire (PHQ-9) with regard to their psychometric properties, and investigates their agreement at different cut-off scores. METHOD Swedish primary care patients and psychiatric outpatients (n = 737) who reported symptoms of depression completed the self-rating scales. Data were collected from 2006 to 2007. Analyses with respect to internal consistency, factor analysis, and agreement (Cohens kappa) at recommended cut-offs were performed. RESULTS Both scales had high internal consistency (alpha = 0.9) and stable factor structures. Using severity cut-offs, the PHQ-9 (> or =5) diagnosed about 30% more patients than the HADS depression subscale (HADS-D; > or =8). They recognised the same prevalence of mild and moderate depression, but differed in relation to severe depression. When comparing recommended screening cut-offs, HADS-D > or =11 (33.5% of participants) and PHQ-9 > or =10 (65.9%) agreement was low (kappa = 0.35). Using the lower recommended cut-off in the HADS-D (> or =8), agreement with PHQ-9 > or =10 was moderate (kappa = 0.52). The highest agreement (kappa = 0.56) was found comparing HADS-D > or =8 with PHQ-9 > or =12. This also equalised the prevalence of depression found by the scales. CONCLUSION The HADS and PHQ-9 are both quick and reliable. The HADS has the advantage of evaluating both depression and anxiety, and the PHQ-9 of being strictly based upon the Diagnostic and Statistical Manual of Mental Disorders. The agreement between the scales at the best suitable cut-off is moderate, although the identified prevalence was similar. This indicates that the scales do not fully identify the same cases. This difference needs to be further explored.

Gene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms

Genetic and environmental factors, as well as their interactions, are likely to be involved in psychiatric disorders. Considerable progress has been made in association and linkage studies with various candidate genes, at times with conflicting or ambiguous results. An environmental factor that has persistently shown associations with several psychiatric and neurological disorders is the season of birth. If it is the interaction of a specific gene allele with a specific season of birth that constitutes an increased (or decreased) risk for a disorder, then the individuals with this disorder are likely to have a season of birth variation in this gene allele. We investigated the variations in TPH, 5-HTTLPR and DRD4 gene polymorphisms according to seasonality of birth in 954 patients with unipolar affective disorder, bipolar affective disorder, and schizophrenia, respectively, and in 395 controls. We first analyzed season of birth variations in the gene alleles with one cycle or two cycles per year, and then compared specified birth seasons with each other. We found season of birth variations in these gene alleles that were different for different psychiatric disorders. Significant differences between cases and controls could be obtained when restricting the analysis within certain birth seasons but not within others. Our results thus suggest an interaction between the seasons of birth and the expression of the candidate genes, and that season of birth is a confounding variable when investigating the role of the candidate genes in susceptibility to psychiatric disorders.

Variations in CSF Monoamine Metabolites According to the Season of Birth

The cerebrospinal fluid (CSF) concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as well as their ratios and correlations were analyzed in relation to the season of birth. The sample consisted of 241 drug-free patients participating in psychobiological programs and comprising the DSM-III-R diagnoses of mood, anxiety and adjustment disorders. Significant season-of-birth variations were found even after adjusting for sex, age, height, the diagnostic category and the month of lumbar puncture. Those born during February to April had significantly lower values of 5-HIAA. Values of HVA and of the ratios HVA/5-HIAA and HVA/MHPG were significantly higher for those born during October to January. Correlation coefficients also showed season-of-birth variations. These results may provide an important link for the season-of-birth variations reported for several neuropsychiatric disorders.

Converging evidence suggests that monoamine neurotransmitter turnover in human adults is associated with their season of birth

Separate studies on adults, including those in suicidology and another regarding personality in the general population, have indicated associations with their season of birth. We analyse each of these studies by multiple nonlinear regression employing a cosine function for the month of birth, and compare these studies regarding the birth months giving the maxima and minima. The method of suicide in suicide studies shows a significant month-of-birth variation similar to that for the serotonin metabolite 5-HIAA in the separate study on cerebrospinal fluid, with a peak around the birth month September and a nadir around birth in March. When comparing the personality study with the study on cerebrospinal fluid, the trait novelty seeking varies similar to that for the dopamine metabolite HVA or the norepinephrine metabolite MHPG, and the trait reward dependence varies similar to that for HVA. The trait self-transcendence varies similar to the ratio of the dopamine and serotonin metabolites. Dopamine turnover in adults thus shows a peak around the birth months November-December, and a nadir around the birth months May-June, suggesting a possible involvement of the length of photoperiod during their perinatal period. These results provide strong evidence for the influence of season of birth on adult monoamine neurotransmitter turnover, and give further support for the monoaminergic modulation of the temperament and character traits.

Anticipation in unipolar affective disorder

Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity and/or decrease in age at onset in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in a neuromuscular disease, various neurodegenerative disorders and mental retardation. We have studied parent-offspring differences in age at onset and disease severity in 31 pairs with unilineal inheritance of unipolar affective disorder (UPAD). Life-table analyses showed a significant decrease in survival to 1st episode of major depression in the offspring generation compared with the parental generation (P = 0.0007). There was also a significant difference in age at onset (P < 0.001) between parents and offsprings. The offspring generation experienced onset 15.6 years earlier and illness 1.5 x more severe than did the parent generation. Furthermore, there was a significant correlation (P < 0.05) in age at onset between parent and offspring generations. When we excluded pairs where the affected parent has an age of onset greater than the age of the child at the time of ascertainment (i.e., 23 pairs left), there was still a significant (P = 0.02) decrease in age at onset (8.4 years) and 1.5 x more severe disease in the offspring generation. No evidence for specific maternal or paternal inheritance was found. We found evidence of anticipation in 75-80% of this sample of unilineal family pairs of UPAD. Anticipation is, thus, an inheritance pattern in a large group of UPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in this group of UPAD. The findings of anticipation in this study of families with UPAD and previous findings in families with BPAD suggest that the variable expression of unstable expansions of trinucleotide repeats may turn out to be the basis of the continuum of liability in affective disorders.