Psychiatric outcomes of bullying victimization: a study of discordant monozygotic twins.

BACKGROUND: Bullying victimization in childhood is associated with a broad array of serious mental health disturbances, including anxiety, depression, and suicidal ideation and behavior. The key goal of this study was to evaluate whether bullying victimization is a true environmental risk factor for psychiatric disturbance using data from 145 bully-discordant monozygotic (MZ) juvenile twin pairs from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and their follow-up into young adulthood. METHOD: Since MZ twins share an identical genotype and familial environment, a higher rate of psychiatric disturbance in a bullied MZ twin compared to their non-bullied MZ co-twin would be evidence of an environmental impact of bullying victimization. Environmental correlations between being bullied and the different psychiatric traits were estimated by fitting structural equation models to the full sample of MZ and DZ twins (N = 2824). Environmental associations were further explored using the longitudinal data on the bullying-discordant MZ twins. RESULTS: Being bullied was associated with a wide range of psychiatric disorders in both children and young adults. The analysis of data on the MZ-discordant twins supports a genuine environmental impact of bullying victimization on childhood social anxiety [odds ratio (OR) 1.7], separation anxiety (OR 1.9), and young adult suicidal ideation (OR 1.3). There was a shared genetic influence on social anxiety and bullying victimization, consistent with social anxiety being both an antecedent and consequence of being bullied. CONCLUSION: Bullying victimization in childhood is a significant environmental trauma and should be included in any mental health assessment of children and young adults.

Siblings of individuals with Smith-Magenis syndrome: an investigation of the correlates of positive and negative behavioural traits.

BACKGROUND: Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder that affects approximately one out of 25,000 births worldwide. To date, no research has been conducted to investigate how having an individual with SMS in a family is a positive or negative influence on siblings. METHODS: To investigate this question we conducted a study involving 79 siblings and 60 parents of individuals with SMS to assess perceptions of how having a sibling with SMS positively and negative influence siblings' behavioural traits. RESULTS: Our findings show that age of siblings of individuals with SMS was associated with a significant increase in positive behavioural traits and a significant decrease in negative behavioural traits. Additionally, siblings who perceive benefits from having a sibling with SMS demonstrate significantly more positive behavioural traits and significantly fewer negative behavioural traits. Parents accurately assess the changes in sibling behavioural traits with age, and parents who perceive their child as having experienced benefits from the sibling relationship report that siblings demonstrate significantly more positive behavioural traits and significantly fewer negative behavioural traits. CONCLUSIONS: Our research shows that although individuals experience difficulties as a result of having a sibling with SMS, overall, siblings tend to fare well and parents appreciate both the positive and negative behavioural effects that result from having a sibling with SMS.

Monoamine oxidase A and childhood adversity as risk factors for conduct disorder in females.

BACKGROUND: Recent studies among males have reported a genotype-environment interaction (GxE) in which low-activity alleles at the monoamine oxidase A (MAOA) locus conferred greater sensitivity to the effects of childhood adversity on risk for conduct disorder (CD). So far, few studies of females have controlled for gene-environment correlation or used females heterozygous for this X-linked gene. METHOD: Logistic regression analysis of a sample of 721 females ages 8-17 years from the longitudinal Virginia Twin Study of Adolescent Behavioral Development (VTSABD) assessed the additive effects of MAOA genotypes on risk for CD, together with the main effect of childhood adversity and parental antisocial personality disorder (ASP), as well as the interaction of MAOA with childhood adversity on risk for CD. RESULTS: A significant main effect of genotype on risk for CD was detected, where low-activity MAOA imparted the greatest risk to CD in girls while controlling for the significant effects of maternal ASP and childhood adversity. Significant GxE with weak effect was detected when environmental exposure was untransformed, indicating a higher sensitivity to childhood adversity in the presence of the high-activity MAOA allele. The interaction was no longer statistically significant after applying a ridit transformation to reflect the sample sizes exposed at each level of childhood adversity. CONCLUSIONS: The main effect of MAOA on risk for CD in females, its absence in males and directional difference of interaction is suggestive of genotype-sex interaction. As the effect of GxE on risk for CD was weak, its inclusion is not justified.

Making sense of informant disagreement for overanxious disorder.

A community sample of 2798 8-17-year-old twins and their parents completed a personal interview about the child's current psychiatric history on two occasions separated by an average of 18 months. Parents also completed a personal interview about their own lifetime psychiatric history at entry to the study. Results indicate that informant agreement for overanxious disorder (OAD) was no better than chance, and most cases of OAD were based on only one informant's ratings. Disagreement about level of OAD symptoms or presence of another disorder (mostly phobias or depression) accounted for most cases of informant disagreement: 60% of cases based only on child interview, 67% of cases based only on maternal interview, and 100% of cases based only on paternal interview. OAD diagnosed only by maternal interview was also distinguished by an association with maternal alcoholism and increasingly discrepant parental reports of marital difficulties. Given the substantial overlap in case assignments for DSM-III-R OAD and DSM-IV GAD, these findings may identify sources of informant disagreement that generalize to juvenile GAD.

Analysing the contributions of genes and parent-child interaction to childhood behavioural and emotional problems: a model for the children of twins.

BACKGROUND: Despite the demonstrable influence of both genes and the family environment on children's behavioural and emotional development, the mechanisms by which these factors are transmitted from parents to their children are not known. Numerous aspects of the family have long been associated with behavioural and emotional problems in children; it is not clear, however, whether these family variables represent genuine environmental risks or secondary consequences of the underlying genetic liability shared between parents and their children. METHOD: In this study we present a model for analysing the non-genetic contributions of family background to risk for childhood and adolescent depression and conduct disturbance using simulated data on adult MZ and DZ twins, their spouses and children. RESULTS: The twin offspring design provides substantial power to detect remarkably small non-genetic effects on parent-offspring resemblance against the background of genetic transmission. As presented, the model is able to resolve the direction of transmission from both parent to child (passive genotype environment correlation) and child to parent (evocative genotype environment correlation). CONCLUSIONS: Unlike many other genetic studies, a study of twins and their children can sort out which putative family environmental risk factors do actually have a significant environmental impact on the child and which ones only appear to do so because they are associated with genetic mediation.

Assessment of genetic and environmental influences on differential ratings of within-family experiences and relationships in twins.

BACKGROUND: Although there is evidence that genetic factors influence individual differences in environmental risk exposure, there are few findings on genetic effects on differential parenting. The present study sought to examine this issue. METHODS: The sample comprised 1,117 pairs of like-sex male and female twins, aged 8-16 years, and their parents, recruited from the school population of Virginia. Differential ratings of the within-family experiences were provided by the Twin Inventory of Relationships and Experiences (TIRE). RESULTS: Dimensions describing the within-family environment based on differential ratings contrasting the twins with one another, were influenced, to an approximately equal extent, by both genetic and environmental factors. CONCLUSIONS: The findings suggest that genetic differences between like-sex siblings lead them to experience their family environment differently, but also that environmental influences significantly affect interactions within the family.

Genetic effects on the variation and covariation of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder/conduct disorder (Odd/CD) symptomatologies across informant and occasion of measurement.

BACKGROUND: Previous studies have shown that the presence of conduct disorder may contribute to the persistence of attention deficit-hyperactivity disorder (ADHD) symptomatology into adolescence; however, the aetiological relationship between the two phenotypes remains undetermined. Furthermore, studies utilizing multiple informants have indicated that teacher ratings of these phenotypes are more valid than maternal reports. METHODS: The genetic structure underlying the persistence of ADHD and oppositional-defiant disorder/conduct disorder (ODD/CD) symptomatologies as rated by mothers and teachers at two occasions of measurement was investigated on a sample of 494 male and 603 female same sex adolescent twin pairs participating in the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). RESULTS: Using structural modelling techniques, one common genetic factor was shown to govern the covariation between the phenotypes across informants and occasion of measurement with additional genetic factors specific to ODD/CD symptomatology and persistence of symptomatology at reassessment. Genetic structures underlying the phenotypes were, to some extent, informant dependent. CONCLUSIONS: The findings indicate that it is unlikely that the co-morbidity between ADHD and ODD/CD is due to environmental influences that are independent of ADHD. Rather it is likely to be due to a shared genetic liability either operating directly, or indirectly through gene-environment correlations or interactions. The covariation between phenotypes across informants and time is governed by a common set of genes, but it seems that ODD/CD is also influenced by additional genetic factors. Developmentally, different forms of genetic liability control ADHD in males and inattention in females.

The effects of child sexual abuse: Comment on Rind, Tromovitch, and Bauserman (1998).

B. Rind, P. Tromovitch, and R. Bauserman (1998) examined the long-term effects of childhood sexual abuse (CSA) by meta-analyzing studies of college students. The authors reported that effects "were neither pervasive nor typically intense" and that "men reacted much less negatively than women" (p. 22) and recommended value-neutral reconceptualization of the CSA construct. The current analysis revealed numerous problems in that study that minimized CSA-adjustment relations, including use of a healthy sample, an inclusive definition of CSA, failure to correct for statistical attenuation, and misreporting of original data. Rind et al.'s study's main conclusions were not supported by the original data. As such, attempts to use their study to argue that an individual has not been harmed by sexual abuse constitute a serious misapplication of its findings.

Child psychiatric symptoms and psychosocial impairment: relationship and prognostic significance.

BACKGROUND: Relatively little is known about the relationships between psychiatric symptoms, diagnosis and psychosocial impairment. AIMS: To examine these contemporaneous relationships and prognostic significance in a large general population sample. METHOD: Symptoms of major depression, conduct and oppositional defiant disorders were assessed by interview in two waves of the Virginia Twin Study of Adolescent behavioural Development (2800 children aged 8-16 years). RESULTS: Many children below the DSM-III-R diagnostic threshold, especially for depression, had symptom-related impairment, whereas many children reaching the symptom threshold for conduct and oppositional defiant disorders were little impaired. Impairment score was linearly related to symptom count, with no evidence of any additional impairment at the diagnostic threshold. For depression, only symptoms predicted later symptoms and diagnosis. For conduct and oppositional defiant disorders, impairment was additionally predictive of later symptoms and diagnosis. CONCLUSIONS: Impairment, in addition to symptoms, is important for both nosology and prognosis.

Transfer of sulfur from IscS to IscU during Fe/S cluster assembly.

The cysteine desulfurase enzymes NifS and IscS provide sulfur for the biosynthesis of Fe/S proteins. NifU and IscU have been proposed to serve as template or scaffold proteins in the initial Fe/S cluster assembly events, but the mechanism of sulfur transfer from NifS or IscS to NifU or IscU has not been elucidated. We have employed [(35)S]cysteine radiotracer studies to monitor sulfur transfer between IscS and IscU from Escherichia coli and have used direct binding measurements to investigate interactions between the proteins. IscS catalyzed transfer of (35)S from [(35)S]cysteine to IscU in the absence of additional thiol reagents, suggesting that transfer can occur directly and without involvement of an intermediate carrier. Surface plasmon resonance studies and isothermal titration calorimetry measurements further revealed that IscU binds to IscS with high affinity (K(d) approximately 2 microm) in support of a direct transfer mechanism. Transfer was inhibited by treatment of IscU with iodoacetamide, and (35)S was released by reducing reagents, suggesting that transfer of persulfide sulfur occurs to cysteinyl groups of IscU. A deletion mutant of IscS lacking C-terminal residues 376-413 (IscSDelta376-413) displayed cysteine desulfurase activity similar to the full-length protein but exhibited lower binding affinity for IscU, decreased ability to transfer (35)S to IscU, and reduced activity in assays of Fe/S cluster assembly on IscU. The findings with IscSDelta376-413 provide additional support for a mechanism of sulfur transfer involving a direct interaction between IscS and IscU and suggest that the C-terminal region of IscS may be important for binding IscU.

Genetic moderation of environmental risk for depression and anxiety in adolescent girls.

BACKGROUND: There is huge individual variation in people's response to negative life events. AIMS: To test the hypothesis that genetic factors moderate susceptibility to the environmentally mediated risks associated with negative life events. METHOD: The Virginia Twin Study of Adolescent Behavioral Development (VTSABD) was used to study the effects of independent life events (assessed from maternal interview) on depression/anxiety (assessed from child interview) in 184 same-gender female twin pairs, aged 14--7 years, measured on two occasions. RESULTS: There was no genetic effect on the independent negative life events studied. A significant gene-environment interaction was found using structural equation modelling. There was no effect of independent life events on adolescents' depression in the absence of parental emotional disorder, but a significant effect in its presence. CONCLUSIONS: There is an environmentally mediated effect of life events on depression/anxiety. Genetic factors play a significant role in individual differences in susceptibility to these environmentally mediated risks.

Genetic and environmental influences on the temporal association between earlier anxiety and later depression in girls.

BACKGROUND: The purpose of the present study was to investigate the role of genetic and environmental factors in the association between depressive symptoms and symptoms of overanxious disorder, simple phobias, and separation anxiety in 8-13-year-old and 14-17-year-old girls. METHODS: Multivariate genetic models were fitted to child-reported longitudinal symptom data gathered from clinical interview on 415 MZ [corrected] and 194 DZ [corrected] female twin pairs from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) [corrected]. RESULTS: Model-fitting results suggest there are distinct etiological [corrected] patterns underlying the association between depression and the different anxiety syndromes during the course of development: 1) specific genetic influences on depression after age 14 reflect liability to symptoms of earlier overanxious disorder (OAD) and simple phobias; 2) aspects of the shared environment that influence symptoms of depression before age 14 contribute to symptoms of separation anxiety and simple phobias later in adolescence [corrected]; 3) the shared environmental influence on [corrected] depression in 14+ girls also affects liability to symptoms of concurrent OAD and persistent separation anxiety. CONCLUSIONS: These results suggest that depression before and after age 14 may be etiologically distinct syndromes. Earlier symptoms of OAD and (to a lesser extent phobic symptoms) [corrected] reflect the same genetic risk, and separation anxiety symptoms both before and after age 14 reflect the same environmental risk that influence liability to depressive symptoms expressed in middle to late adolescence.

Comparison of multiple measures of ADHD symptomatology: a multivariate genetic analysis.

The phenotypic and genetic interrelationships underlying ADHD symptomatology assessed by various instruments were examined on a sample of 735 male and 819 female same-sex twin pairs, aged 8 to 16 years, participating in the first phase of the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). Multivariate analyses were applied to parental and teacher ratings from an investigator-based interview, the CAPA, and three questionnaires (the CBCL and the Rutter Parent and Teacher Scales). Results from patterns of intercorrelations and factor analyses of maternal measures suggested that at the phenotypic level, these assessed the same underlying behavioural construct, which differed from other emotional and behavioural constructs. However, genetic analyses showed that in addition to a common factor underlying the expression of ADHD as assessed across the range of measures, additional genetic factors were identified that were method- and rater-specific. The findings suggest that although the investigator-based interview and the behavioural checklists tap similar aspects of ADHD behaviour, there is additional rater-specific variance.

Parental concordance and comorbidity for psychiatric disorder and associate risks for current psychiatric symptoms and disorders in a community sample of juvenile twins.

In this report we characterize associations between parental psychiatric disorders and children's psychiatric symptoms and disorders using a population-based sample of 850 twin families. Juvenile twins are aged 8-17 years and are personally interviewed about their current history of DSM-III-R conduct, depression, oppositional-defiant, overanxious, and separation anxiety disorders using the CAPA-C. Mothers and fathers of twins are personally interviewed about their lifetime history of DSM-III-R alcoholism, antisocial personality disorder, generalized anxiety disorder, major depression, panic disorder/agoraphobia, social phobia, and simple phobia using a modified version of the SCID and the DIS. Generalized least squares and logistic regression are used to identify the juvenile symptoms and disorders that are significantly associated with parental psychiatric histories. The specificity of these associations is subsequently explored in a subset of families with maternal plus parental psychiatric histories with a prevalence > 1%. Parental depression that is not comorbid or associated with a different spousal disorder is associated with a significantly elevated level of depression and overanxious disorder symptoms and a significantly increased risk for overanxious disorder. Risks are higher for both symptomatic domains in association with maternal than paternal depression, and highest in association with maternal plus paternal depression. Risks for otherjuvenile symptoms and disorders index the comorbid and spousal histories with which parental depression is commonly associated. Paternal alcoholism that is not comorbid or associated with a maternal disorder is not significantly associated with current psychiatric symptoms or disorders in offspring. Risks for oppositional-defiant or conduct symptoms/disorders in the offspring of alcoholic parents index parental comorbidity and/or other spousal histories.

The Fe/S assembly protein IscU behaves as a substrate for the molecular chaperone Hsc66 from Escherichia coli.

IscU, a NifU-like Fe/S-escort protein, binds to and stimulates the ATPase activity of Hsc66, a hsp70-type molecular chaperone. We present evidence that stimulation arises from interactions of IscU with the substrate-binding site of Hsc66. IscU inhibited the ability of Hsc66 to suppress the aggregation of the denatured model substrate proteins rhodanese and citrate synthase, and calorimetric and surface plasmon resonance measurements showed that ATP destabilizes Hsc66.IscU complexes in a manner expected for hsp70-substrate complexes. Studies on the interaction of IscU with Hsc66 truncation mutants further showed that IscU does not bind the isolated ATPase domain of Hsc66 but does bind and stimulate a mutant containing the ATPase domain and substrate binding beta-sandwich subdomain. These results support a role for IscU as a substrate for Hsc66 and suggest a specialized function for Hsc66 in the assembly, stabilization, or transfer of Fe/S clusters formed on IscU.

Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis.

BACKGROUND: Women who report childhood sexual abuse (CSA) are at increased risk for developing psychiatric disorders in adulthood. What is the diagnostic specificity and cause of this association? METHODS: In a population-based sample of 1411 female adult twins, 3 levels of CSA were assessed by self-report and cotwin report: nongenital, genital, and intercourse. Interviews with twins and parents assessed family background and diagnoses of psychiatric and substance dependence disorders. Odds ratios (ORs) were calculated by logistic regression. RESULTS: By self-report, 30.4% reported any CSA and 8.4% reported intercourse. Self-reported CSA was positively associated with all disorders, the highest ORs being seen with bulimia and alcohol and other drug dependence. The ORs were modest and often nonsignificant with nongenital CSA and increased with genital CSA and especially intercourse, where most ORs exceeded 3.0. A similar pattern of findings was seen with CSA as reported by the cotwin, although many ORs were smaller. Controlling for family background factors and parental psychopathology produced a small to modest reduction in ORs. In twin pairs discordant for CSA, the exposed twin was at consistently higher risk of illness. CONCLUSIONS: Women with CSA have a substantially increased risk for developing a wide range of psychopathology. Most of this association is due to more severe forms of CSA and cannot be explained by background familial factors. Although other biases cannot be ruled out, these results are consistent with the hypothesis that CSA is causally related to an increased risk for psychiatric and substance abuse disorders.

Familial aggregation for conduct disorder symptomatology: the role of genes, marital discord and family adaptability.

BACKGROUND: There is extensive evidence of statistical associations between family discord/ maladaptation and antisocial behaviour in the children, but questions remain on the extent to which the psychopathological risks are genetically or environmentally mediated. METHODS: Twin pairs (N = 1,350), aged 8 to 16 years, in the general population-based Virginia Twin Study of Adolescent Behavioral Development were assessed using the Child and Adolescent Psychiatric Assessment interview administered separately to both twins and both parents. Structured interviews for parental lifetime psychiatric disorders were also administered to the mothers and fathers. Maternal reports on Olsson's Family Adaptability and Cohesiveness questionnaire and the Dyadic Adjustment Scale were used as indices of the family environment. A path analytical model based on an extended twin-family design was used to test hypotheses about parent offspring similarity for conduct disorder symptomatology. RESULTS: Family discord and maladaptation, which intercorrelated at 0.63, were associated with a roughly two-fold increase in risk for conduct disorder symptomatology. When parental conduct disorder was included in the model the environmental mediation effect for family maladaptation remained, but that for family discord was lost. CONCLUSION: It is concluded that there is true environmental mediation from family maladaptation, operating as a shared effect, which accounts for 3.5 % of the phenotypic variance. The assumptions underlying this genetic research strategy are made explicit, together with its strengths and limitations.

An evaluation of different approaches for behavior genetic analyses with psychiatric symptom scores.

We used a simulation study to evaluate six approaches for behavior genetic analyses of psychiatric symptom scores. For the selection of the correct model, the best results were obtained with approaches using transformed scores in combination with a procedure involving p-values. With normalizing transformations, the chi 2 test statistic gave a reasonable impression of the overall fit of the model but was less accurate when used as a difference test. The asymptotic distribution free estimation methods yielded chi 2s that were much too large. All data analysis techniques yielded substantially biased parameter estimates. The most biased results were obtained with normalizing transformations. The least biased results were obtained with tobit correlations, but because of its large standard errors the most precise estimates were obtained with polychoric correlations and optimal scale scores. An empirical study showed that a recognition of the role of methodological factors was helpful to understand part of the differences between assessment instruments, raters, and data analysis techniques that were found in the real data.

Interaction of the iron-sulfur cluster assembly protein IscU with the Hsc66/Hsc20 molecular chaperone system of Escherichia coli.

The iscU gene in bacteria is located in a gene cluster encoding proteins implicated in iron-sulfur cluster assembly and an hsc70-type (heat shock cognate) molecular chaperone system, iscSUA-hscBA. To investigate possible interactions between these systems, we have overproduced and purified the IscU protein from Escherichia coli and have studied its interactions with the hscA and hscB gene products Hsc66 and Hsc20. IscU and its iron-sulfur complex (IscU-Fe/S) stimulated the basal steady-state ATPase activity of Hsc66 weakly in the absence of Hsc20 but, in the presence of Hsc20, increased the ATPase activity up to 480-fold. Hsc20 also decreased the apparent K(m) for IscU stimulation of Hsc66 ATPase activity, and surface plasmon resonance studies revealed that Hsc20 enhances binding of IscU to Hsc66. Surface plasmon resonance and isothermal titration calorimetry further showed that IscU and Hsc20 form a complex, and Hsc20 may thereby aid in the targeting of IscU to Hsc66. These results establish a direct and specific role for the Hsc66/Hsc20 chaperone system in functioning with isc gene components for the assembly of iron-sulfur cluster proteins.

Kinetic characterization of the ATPase cycle of the molecular chaperone Hsc66 from Escherichia coli.

Hsc66 from Escherichia coli is a constitutively expressed hsp70 class molecular chaperone whose activity is coupled to ATP binding and hydrolysis. To better understand the mechanism and regulation of Hsc66, we investigated the kinetics of ATP hydrolysis and the interactions of Hsc66 with nucleotides. Steady-state experiments revealed that Hsc66 has a low affinity for ATP (K(m)(ATP) = 12.7 microM) compared with other hsp70 chaperones. The kinetics of nucleotide binding were determined by analyzing changes in the Hsc66 absorbance spectrum using stopped-flow methods at 23 degrees C. ATP binding results in a rapid, biphasic increase of Hsc66 absorbance at 280 nm; this is interpreted as arising from a two-step process in which ATP binding (k(a)(ATP) = 4.2 x 10(4) M(-1) s(-1), k(d)(ATP) = 1.1 s(-1)) is followed by a slow conformational change (k(conf) = 0. 1 s(-1)). Under single turnover conditions, the ATP-induced transition decays exponentially with a rate (k(decay) = 0.0013 s(-1)) similar to that observed in both steady-state and single turnover ATP hydrolysis experiments (k(hyd) = 0.0014 s(-1)). ADP binding to Hsc66 results in a monophasic transition in the absence (k(a)(ADP) = 7 x 10(5) M(-1) s(-1), k(d)(ADP) = 60 s(-1)) and presence of physiological levels of inorganic phosphate (k(a)(ADP(P(i)) = 0.28 x 10(5) M(-1) s(-1), k(d)(ADP(P(i)) = 9.1 s(-1)). These results indicate that ATP hydrolysis is the rate-limiting step under steady-state conditions and is >10(3)-fold slower than the rate of ADP/ATP exchange. Thus, in contrast to DnaK and eukaryotic forms of hsp70 that have been characterized to date, the R if T equilibrium balance for Hsc66 is shifted in favor of the low peptide affinity T state, and regulation of the reaction cycle is expected to occur at the ATP hydrolysis step rather than at nucleotide exchange.