Harriet A. Ball

Genetic and environmental influences on victims, bullies and bully-victims in childhood

BACKGROUND Three groups of children are involved in bullying: victims, bullies and bully-victims who are both bullies and victims of bullying. Understanding the origins of these groups is important since they have elevated emotional and behavioural problems, especially the bully-victims. No research has examined the genetic and environmental influences on these social roles. METHOD Mother and teacher reports of victimisation and bullying were collected in a nationally representative cohort of 1,116 families with 10-year-old twins. Model-fitting was used to examine the relative influence of genetics and environments on the liability to be a victim, a bully or a bully-victim. RESULTS Twelve percent of children were severely bullied as victims, 13% were frequent bullies, and 2.5% were heavily involved as bully-victims. Genetic factors accounted for 73% of the variation in victimisation and 61% of the variation in bullying, with the remainder explained by environmental factors not shared between the twins. The covariation between victim and bully roles (r = .25), which characterises bully-victims, was accounted for by genetic factors only. Some genetic factors influenced both victimisation and bullying, although there were also genetic factors specific to each social role. CONCLUSIONS Childrens genetic endowments, as well as their surrounding environments, influence which children become victims, bullies and bully-victims. Future research identifying mediating characteristics that link the genetic and environmental influences to these social roles could provide targets for intervention.

Genetic Overlap Between Measures of Hyperactivity/Inattention and Mood in Children and Adolescents

OBJECTIVE Evidence suggests that there is substantial comorbidity between attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder in childhood and adolescence. This study aims to investigate the degree to which etiological factors are shared between the symptoms of these significantly heritable disorders. METHOD A twin study design was used to determine to what extent the covariation between the traits of ADHD and depression is genetically or environmentally mediated, based on parental reports. A general community sample of 645 twin pairs aged 5 to 17 years from the Cardiff Study of All Wales and North England Twins project took part in the study. Parent-rated measures of hyperactivity/inattention (Abbreviated Conners Hyperactivity subscale) and depression (Short Mood and Feelings Questionnaire). RESULTS Phenotypes derived from the scales were significantly correlated in both boys and girls. Bivariate structural equation modeling revealed a large overlap in underlying genetic factors (boys, rA = 0.77; girls, rA = 0.67) along with a smaller influence of nonshared environment. CONCLUSIONS These findings suggest that there are common genes conferring liability to both hyperactive/inattentive and depressive traits in children and adolescents. This has implications for future molecular genetic research into ADHD and major depressive disorder. Additionally, it indicates that the comorbid clinical presentation of these disorders may reflect a common genetic pathway.

Epidemiology and symptomatology of depression in Sri Lanka: A cross-sectional population-based survey in Colombo District

Background It is important to understand the nature of depression in non-Western and lower-income countries, but little such research exists. This study aimed to examine the characteristic features of depression in Sri Lanka, and to identify environmental risk factors. Methods Depression diagnoses, symptoms and impairment were measured using the Composite International Diagnostic Interview, in a population-based sample of 6014 twins and non-twins in the Colombo region of Sri Lanka (the CoTASS sample). Socio-demographic factors and environments were assessed via questionnaires. Results Lifetime-ever depression was reported in 6.6% of participants, rising to 11.2% if the functional impairment criterion was excluded. The symptom profile of depression and its socio-demographic associations were very comparable to those in Western and more economically developed countries, whether functional impairment was included in the definition or not. Standard of living was independently associated with depression, especially among men at the more deprived end of the distribution. Specific associations were found with both financial wellbeing and material characteristics of the home environment. Limitations The observational associations identified are cross-sectional, so do not necessarily imply causal links. Conclusions Aside from a lower prevalence, depression is very similar in this predominantly urban Sri Lankan sample to higher-income, Western countries, and may be under-identified due to a relatively low cultural appropriateness of the assessment of impairment. Under Sri Lankas cultural and environmental context, certain aspects of the material environment are associated with depression among certain segments of society, perhaps because of their particular link to social status and social networks.

Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS).

Recent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.

Trauma, post-traumatic stress disorder and psychiatric disorders in a middle-income setting: prevalence and comorbidity.

Background Most studies of post-traumatic stress disorder (PTSD) in low- and middle-income countries (LMICs) have focused on ‘high-risk’ populations defined by exposure to trauma. Aims To estimate the prevalence of post-traumatic stress disorder (PTSD) in a LMIC, the conditional probability of PTSD given a traumatic event and the strength of associations between traumatic events and other psychiatric disorders. Method Our sample contained a mix of 3995 twins and 2019 non-twins. We asked participants about nine different traumatic exposures, including the category ‘other’, but excluding sexual trauma. Results Traumatic events were reported by 36.3% of participants and lifetime PTSD was present in 2.0%. Prevalence of non-PTSD lifetime diagnosis was 19.1%. Of people who had experienced three or more traumatic events, 13.3% had lifetime PTSD and 40.4% had a non-PTSD psychiatric diagnosis. Conclusions Despite high rates of exposure to trauma, this population had lower rates of PTSD than high-income populations, although the prevalence might have been slightly affected by the exclusion of sexual trauma. There are high rates of non-PTSD diagnoses associated with trauma exposure that could be considered in interventions for trauma-exposed populations. Our findings suggest that there is no unique relationship between traumatic experiences and the specific symptomatology of PTSD.

Colombo Twin and Singleton Study (CoTASS): A description of a population based twin study of mental disorders in Sri Lanka

BackgroundThe Sri Lankan twin registry is one of the first to be established in a developing country, and its design has ensured sampling from a wide range of environmental conditions. It thus has great potential to examine environmental and genetic influences on diverse phenotypes, including psychiatric disorders, in the context of a diversity of environmental exposures, which may not have been fully explored in previous twin studies in developed countries. This paper presents the rationale for the study, describes its context, and the methods for twin ascertainment and data collection.MethodsA population-based twin register was established in the Colombo district of Sri Lanka using infrastructure designed to periodically update the electoral register. We invited a subsample from this register to participate in the project on common mental disorders, using random ascertainment. A separate non-twin sample was randomly selected from the geographical areas where twins were found. Home interviewers collected diagnostic information on common mental disorders, as well as environmental exposures including life events, socio-economic conditions, and the impact of the civil war and the Tsunami of 2004.ResultsWe identified 19,302 individuals in the creation of the population based twin register. We randomly selected a subsample, of whom 4,387 were eligible to participate and 4,024 agreed to be interviewed (including data on 1,954 complete pairs of twins and 5 sets of triplets). Those who refused consent had a similar mean age and sex ratio to those who were interviewed. We invited 2,485 singletons to participate and 2,019 were interviewed.ConclusionInitial exploration of the data suggests the samples are very representative of the Colombo district of Sri Lanka, so we have created a unique resource for understanding the influences on mental disorders in developing countries, and to compare to the influences found in developed countries.

Aetiology of fatigue in Sri Lanka and its overlap with depression

BACKGROUND Fatigue is a common symptom in Western high-income countries but is often medically unexplained and little is known about its presentation in other populations. AIMS To explore the epidemiology and aetiology of fatigue in Sri Lanka, and of its overlap with depression. METHOD A total of 4024 randomly selected twins from a population-based register in Sri Lanka (Colombo district) completed home interviews including the Chalder Fatigue Questionnaire. RESULTS The prevalence of fatigue was similar to that in other countries, although prolonged fatigue may be less common. There was substantial comorbidity with a screen for lifetime depression. Non-shared environmental factors made the largest contributions, although genetic/family factors also contributed. The aetiology appeared consistent across the spectrum of severity. CONCLUSIONS The aetiology of fatigue is broadly similar in Sri Lanka and Western high-income countries. Abnormal experiences of fatigue appear to be the extreme form of more common fatigue, rather than representing independent entities with different genetic or environmental risk factors.

Genetic and Environmental Contributions to the Overlap between Psychological, Fatigue and Somatic Symptoms: A Twin Study in Sri Lanka

BACKGROUND Somatic symptoms often co-occur with psychological symptoms but this overlap is poorly understood. Some aspects of this overlap differ in the South Asian context, but it is not clear whether this is a reporting effect or an underlying difference in experienced illness. METHODS Home interviews were administered to 4,024 twins randomly selected from a population-based twin register in the Colombo district of Sri Lanka (the CoTASS study). These included assessments of psychological, somatic and fatigue symptoms. The data were analyzed using factor analytic and quantitative genetic approaches. RESULTS Confirmatory factor analysis showed that the symptoms from the three scales represented three separate dimensions, rather than all tapping into a single dimension. However, familial correlations among the data were most consistent with a common pathway model. This implies that a portion of the underlying vulnerability is common across psychological, fatigue and somatic symptoms. There were sex differences in the etiology of this model, with shared environmental and genetic influences playing different roles in men and women. CONCLUSIONS There is a complex etiological relationship between psychological, fatigue and somatic symptoms. This is similar in Sri Lanka to Western countries, but there may be a greater influence from the family environment, suggesting that care needs to be taken when generalizing research findings between countries. People who complain of certain fatigue or somatic symptoms may well also have psychological symptoms, or may have genetic or environmental vulnerabilities to such problems.

Association analysis of DAOA and DAO in bipolar disorder: results from two independent case-control studies.

D-amino acid oxidase activator gene [DAOA (previously G72)] is located in a region with a positive linkage peak for bipolar disorder (BD) (13q33.2) (1). The results of case-control and family-based studies of DAOA in BD are inconsistent, with some reporting positive single marker or haplotype association (2–8) and others reporting no association (9, 10). Two meta-analyses of DAOA in BD have also provided conflicting results: one reported positive association (11), while another failed to find evidence for association (12). DAOA is an activator of DAO protein (13); both proteins are involved in the metabolism of D-serine, which plays a role in glutamatergic neurotransmission (14). Thus, there is a clear biological motivation for testing epitasis between these two genes. We explored the association of DAOA and DAO with BD and their statistical interaction in two independent case-control samples from the UK and Canada. The UK sample consisted of 515 BD patients (65% women) with a mean age (SD) of 48.0 (11.4) years. The diagnosis of BD was defined by DSMIV operational criteria using Schedules for Clinical Assessment in Neuropsychiatry (SCAN) (15). Patients with BD were classified as having a positive history of psychosis if they scored positive on at least one of the SCAN items of delusions or hallucinations (n = 232). The control sample consisted of 1,316 subjects (58% women) with a mean age (SD) of 41.7 (13.2) years, screened for lifetime absence of psychiatric disorder. The Canadian sample consisted of 385 patients (63% women) with a mean age (SD) of 46.0 (12.5) years and 312 controls (54% women) with a mean age (SD) of 43.7 (13.1) years. All enrolled subjects were of white European parentage. Both studies were approved by the local Research Ethics Committees and informed written consent was obtained from all participants. Genotyping of 10 single nucleotide polymorphisms (SNPs) was performed using SNPlex Genotyping System (Applied Biosystems, Carlsbad, CA, USA). Five DAOA SNPs: M12, M15, M18, M23, and M24, and DAO SNP were chosen on the basis of previously reported association findings. Others were chosen to get better coverage of the gene area. Overall, 9 markers cover a 95 kb region, including the 5¢ and 3¢ flanking regions of the DAOA locus, constituting the region of interest for linkage disequilibrium (LD) mapping. In total, 1,619 UK and 697 Canadian samples were genotyped. An 80% threshold was applied for the call rate across the SNP set. The call rate for each SNP varied between 94.5% and 99.7%. A total of 176 samples were regenotyped with 100% consistency. For statistical analysis, 1,408 UK and 644 Canadian samples were available. Genotype and allele frequencies were assessed for association with BD using chi-squared tests. Risk magnitudes were estimated by calculating odds ratios (OR) with 95% confidence intervals. Haplotype analysis was conducted using UNPHASED (16). Interaction analysis was performed using the Genetic Association Interaction Analysis (GAIA) application (17). We applied the Bonferroni correction for the number of genes and the number of samples investigated, and assumed that four independent tests were applied (a = 0.013). Allele frequencies of the SNPs are shown in Table 1. All genotype distributions were consistent with Hardy-Weinberg equilibrium (p > 0.05). There were no significant differences in allele or genotype frequency between cases and controls in either the UK or Canadian sample, or in the combined sample. The analysis in the subgroup with psychotic traits did not show any significant differences either (data not shown). No significant differences in global haplotype distribution or individual haplotype frequency were revealed between cases and controls in the investigated samples (Table 2). The pattern of intermarker LD of the DAOA in the two samples was similar to each other and to that in a HapMap Centre d Etude du Polymorphisme Humain (CEPH) sample (http://www.hapmap.org). Bipolar Disorders 2010: 12: 579–581 a 2010 The Authors Journal compilation a 2010 Blackwell Munksgaard

Association analysis of DAOA and DAO in bipolar disorder: Results from two independent case-control studies

D-amino acid oxidase activator gene [DAOA (previously G72)] is located in a region with a positive linkage peak for bipolar disorder (BD) (13q33.2) (1). The results of case-control and family-based studies of DAOA in BD are inconsistent, with some reporting positive single marker or haplotype association (2–8) and others reporting no association (9, 10). Two meta-analyses of DAOA in BD have also provided conflicting results: one reported positive association (11), while another failed to find evidence for association (12). DAOA is an activator of DAO protein (13); both proteins are involved in the metabolism of D-serine, which plays a role in glutamatergic neurotransmission (14). Thus, there is a clear biological motivation for testing epitasis between these two genes. We explored the association of DAOA and DAO with BD and their statistical interaction in two independent case-control samples from the UK and Canada. The UK sample consisted of 515 BD patients (65% women) with a mean age (SD) of 48.0 (11.4) years. The diagnosis of BD was defined by DSMIV operational criteria using Schedules for Clinical Assessment in Neuropsychiatry (SCAN) (15). Patients with BD were classified as having a positive history of psychosis if they scored positive on at least one of the SCAN items of delusions or hallucinations (n = 232). The control sample consisted of 1,316 subjects (58% women) with a mean age (SD) of 41.7 (13.2) years, screened for lifetime absence of psychiatric disorder. The Canadian sample consisted of 385 patients (63% women) with a mean age (SD) of 46.0 (12.5) years and 312 controls (54% women) with a mean age (SD) of 43.7 (13.1) years. All enrolled subjects were of white European parentage. Both studies were approved by the local Research Ethics Committees and informed written consent was obtained from all participants. Genotyping of 10 single nucleotide polymorphisms (SNPs) was performed using SNPlex Genotyping System (Applied Biosystems, Carlsbad, CA, USA). Five DAOA SNPs: M12, M15, M18, M23, and M24, and DAO SNP were chosen on the basis of previously reported association findings. Others were chosen to get better coverage of the gene area. Overall, 9 markers cover a 95 kb region, including the 5¢ and 3¢ flanking regions of the DAOA locus, constituting the region of interest for linkage disequilibrium (LD) mapping. In total, 1,619 UK and 697 Canadian samples were genotyped. An 80% threshold was applied for the call rate across the SNP set. The call rate for each SNP varied between 94.5% and 99.7%. A total of 176 samples were regenotyped with 100% consistency. For statistical analysis, 1,408 UK and 644 Canadian samples were available. Genotype and allele frequencies were assessed for association with BD using chi-squared tests. Risk magnitudes were estimated by calculating odds ratios (OR) with 95% confidence intervals. Haplotype analysis was conducted using UNPHASED (16). Interaction analysis was performed using the Genetic Association Interaction Analysis (GAIA) application (17). We applied the Bonferroni correction for the number of genes and the number of samples investigated, and assumed that four independent tests were applied (a = 0.013). Allele frequencies of the SNPs are shown in Table 1. All genotype distributions were consistent with Hardy-Weinberg equilibrium (p > 0.05). There were no significant differences in allele or genotype frequency between cases and controls in either the UK or Canadian sample, or in the combined sample. The analysis in the subgroup with psychotic traits did not show any significant differences either (data not shown). No significant differences in global haplotype distribution or individual haplotype frequency were revealed between cases and controls in the investigated samples (Table 2). The pattern of intermarker LD of the DAOA in the two samples was similar to each other and to that in a HapMap Centre d Etude du Polymorphisme Humain (CEPH) sample (http://www.hapmap.org). Bipolar Disorders 2010: 12: 579–581 a 2010 The Authors Journal compilation a 2010 Blackwell Munksgaard