DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early-life stress and adult ethanol exposure-an explorative study.

DNA methylation and gene expression can be altered by early life stress (ELS) and/or ethanol consumption. The present study aimed to investigate whether DNA methylation of the Vesicular Glutamate Transporters (Vglut)1-3 is related to previously observed Vglut1-3 transcriptional differences in the ventral tegmental area (VTA), nucleus accumbens (Acb), dorsal striatum (dStr) and medial prefrontal cortex (mPFC) of adult rats exposed to ELS, modelled by maternal separation, and voluntary ethanol consumption. Targeted next-generation bisulfite sequencing was performed to identify the methylation levels on 61 5'-cytosine-phosphate-guanosine-3' sites (CpGs) in potential regulatory regions of Vglut1, 53 for Vglut2, and 51 for Vglut3. In the VTA, ELS in ethanol-drinking rats was associated with Vglut1-2 CpG-specific hypomethylation, whereas bidirectional Vglut2 methylation differences at single CpGs were associated with ELS alone. Exposure to both ELS and ethanol, in the Acb, was associated with lower promoter and higher intronic Vglut3 methylation; and in the dStr, with higher and lower methylation in 26% and 43% of the analyzed Vglut1 CpGs, respectively. In the mPFC, lower Vglut2 methylation was observed upon exposure to ELS or ethanol. The present findings suggest Vglut1-3 CpG-specific methylation signatures of ELS and ethanol drinking, underlying previously reported Vglut1-3 transcriptional differences in the mesocorticolimbic brain.

A neurobiological framework of separation anxiety and related phenotypes.

In the DSM-5, separation anxiety disorder (SAD) is newly classified in the chapter on anxiety, renewing research efforts into its etiology. In this narrative review, we summarize the current literature on the genetic, endocrine, physiological, neural and neuropsychological underpinnings of SAD per se, SAD in the context of panic disorder, separation anxiety symptoms, and related intermediate phenotypes. SAD aggregates in families and has a heritability of ~43%. Variants in the oxytocin receptor, serotonin transporter, opioid receptor µ1, dopamine D4 receptor and translocator protein genes have all been associated with SAD. Dysregulation of the hypothalamus-pituitary-adrenal axis, dysfunctional cortico-limbic interaction and biased cognitive processing seem to constitute further neurobiological markers of separation anxiety. Hypersensitivity to carbon dioxide appears to be an endophenotype shared by SAD, panic disorder and anxiety sensitivity. The identification of biological risk markers and its multi-level integration hold great promise regarding the prediction of SAD risk, maintenance and course, and in the future may allow for the selection of indicated preventive and innovative, personalized therapeutic interventions.

Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation.

Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40 µg/kg ip) in mouse pups, 8-9 days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3 h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.

Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice.

Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.

Progressive habituation to separation alleviates the negative effects of weaning in the mother and foal.

Early and definitive separation between offspring and their mothers has negative consequences on behavioral and physiological responses. This study compared sudden and definitive weaning (Sudd group, N = 16) and weaning involving progressive habituation to separation using a fence line during the month preceding definitive separation (Prog group, N = 18). The impact of these two methods was assessed in both foals and their mothers through behavioral and biological parameters, including salivary cortisol, telomere length and blood transcriptomes. On the day of definitive separation, Prog foals neighed and trotted less and presented lower cortisol levels than Sudd foals. The weaning type also acted on the foals' personality development; Prog foals became more curious, less fearful and less gregarious than Sudd foals, and the effects remained visible for at least 3 months. In principal component analysis, the Sudd and Prog groups were well separated along a factor where fear, reactivity and gregariousness correlated with high cortisol levels, but curiosity was associated with an increased telomere length and higher expression of genes involved in mitochondrial functions. Progressive weaning was also beneficial in mares. Principal component analysis showed that most Sudd group mares had higher cortisol levels and displayed more alert postures, neighs and activity on the day of weaning, indicating higher stress levels, while Prog mares had profiles that were characterized by more time spent resting on the day of weaning and longer telomere lengths. In conclusion, this study shows that progressive habituation to separation alleviates the negative effect of definitive weaning on both the mother and her young compared to sudden separation.

Interaction between the Opioid Receptor OPRM1 Gene and Mother-Child Language Style Matching Prospectively Predicts Children's Separation Anxiety Disorder Symptoms.

Recent research suggests that lower mother-child language style matching (LSM) is associated with greater physiological reactivity and insecure attachment in school-aged children, but to date no studies have explored this measure of parent-child behavioral matching for its association with children's anxiety symptoms, a well-known correlate of attachment insecurity and heightened physiological reactivity. There is also considerable evidence of genetic risk for anxiety, including possession of the OPRM1 minor allele, 118G. In the current study (N = 44), we expand upon what is known about children's genetic and environmental risk for anxiety by examining the unique and interactive effects of mother-child LSM and the OPRM1 polymorphism A118G on school-aged children's separation anxiety disorder (SAD) symptoms. SAD symptoms were measured both concurrently with LSM and OPRM1 genotype and two years later through self-report. No significant associations emerged between LSM or OPRM1 and concurrent Time 1 SAD symptoms. However, lower LSM and 118G minor allele possession were both associated with greater SAD symptoms at Time 2; further, the interaction between LSM and OPRM1 genotype significantly predicted SAD symptoms beyond the main effects of the two variables. Possession of the minor allele was only associated with greater SAD symptoms among children in low LSM dyads, whereas children with the minor allele in high LSM dyads showed non-significantly lower SAD symptoms. These findings and a proportion affected analysis provide support for a differential susceptibility model of gene by environment interactions for the OPRM1 gene. We discuss the implications for predicting children's separation anxiety across development.

Oxytocin receptor gene variation, behavioural inhibition, and adult separation anxiety: Role in complicated grief.

OBJECTIVES: Complicated grief (CG) following bereavement significantly increases the risk for mood and anxiety disorders. The severity of grief reactions may be interactively influenced by temperamental and psychological factors such as behavioural inhibition (BI) and separation anxiety (SA) as well as biological factors. Given its central role in attachment and stress processing, a genetic variant in the oxytocin receptor (OXTR) gene was thus investigated in order to elucidate the direction of association as well as its interaction with BI and SA in the moderation of CG severity. METHODS: Ninety-three patients with mood and anxiety disorders were evaluated for CG by means of the Inventory of Complicated Grief (ICG), for BI using the Retrospective Self-Report of Inhibition (RSRI), and for symptoms of SA during adulthood using the Adult Separation Anxiety Scale (ASA-27). All patients were genotyped for OXTR rs2254298. RESULTS: OXTR genotype interacted with BI and, on a trend-level, with adult SA, to increase CG. Specifically, higher levels on the RSRI and ASA-27 scales, respectively, were related to higher ICG scores in GG genotype carriers. CONCLUSIONS: The present study for the first time suggests a gene-environment interaction effect of an OXTR gene variant with BI and possibly also symptoms of adult SA in the moderation of vulnerability for CG.

Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques.

Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.

Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety.

BACKGROUND: The impact of combined variants of Oxytocin Receptor (OXTR) and G protein ß3 subunit genes was investigated in relation to retrospective reports of childhood as well as contemporary adult separation anxiety (SA), based on evidence of a ß/γ dimer-mediated signaling for OXTR. METHODS: A case-control association study (225 healthy adults and 188 outpatients with depression) was performed to establish Risk-Combined Genotype (RCG) of the studied variants (OXTR rs53576 and the functional Gß3 subunit rs5443). Current SA was evaluated by the ASA-27 and retrospective childhood symptoms by the SASI. GG genotype of OXTR rs53576 combined with T-carrier genotype of Gß3 rs5443 represented the RCG. RESULTS: Compared to non-RCG, those with RCG had significantly higher levels of childhood and adult SA. The RCG was significantly associated with childhood SA threshold score (OR=2.85, 90%CI: 1.08-7.50). Childhood SA was, in turn, strongly associated with a threshold SA score in adulthood (OR=15.58; 95% CI: 4.62-52.59). LIMITATIONS: Although the overall sample size is sizable, comparisons among subgroups with specific combination of alleles are based on relatively small numbers. CONCLUSIONS: Our study indicates that variations in OXTR and Gß3 genes are specifically associated with presence and severity of SA in childhood and adulthood, but not with depression or anxiety in general. Because there is increasing interest in oxytocin in social behavior, the gene-SA associations identified have potential translational and clinical relevance.

Genetic Regulation of Maternal Oxytocin Response and Its Influences on Maternal Behavior.

We interrogated the genetic modulation of maternal oxytocin response and its association with maternal behavior using genetic risk scores within the oxytocin receptor (OXTR) gene. We identified a novel SNP, rs968389, to be significantly associated with maternal oxytocin response after a challenging mother-infant interaction task (Still Face Paradigm) and maternal separation anxiety from the infant. Performing a multiallelic analysis across OXTR by calculating a cumulative genetic risk score revealed a significant gene-by-environment (G × E) interaction, with OXTR genetic risk score interacting with adult separation anxiety to modulate levels of maternal sensitivity. Mothers with higher OXTR genetic risk score and adult separation anxiety showed significantly reduced levels of maternal sensitivity during free play with the infant. The same G × E interaction was also observed for the extended OXTR cumulative genetic risk score that included rs968389. Moreover, the extended cumulative OXTR genetic risk score itself was found to be significantly associated with maternal separation anxiety as it specifically relates to the infant. Our results suggest a complex montage of individual and synergistic genetic mediators of maternal behavior. These findings add to specific knowledge about genetic regulation of maternal oxytocin response in relation to maternal adjustment and infant bonding through the first few months of life.

Perinatal Brain Injury is Accompanied by Disturbances in Expression of SLC Protein Superfamily in Endotheliocytes of Hippocampal Microvessels.

The peculiarities in expression of transport proteins and the proteins implicated in the control of glycolysis by the cellular components of neurovascular units were examined in animals of different age under normal conditions and after modeled perinatal stress or hypoxic brain injury. In both cases, the specialties in expression of transport proteins in ontogenesis were revealed. The perinatal hypoxic brain injury resulted in up-regulation of MCT1, MCT4, and GLUT4 expression in endotheliocytes of hippocampal microvessels accompanied by transient elevation of HIF-1α and GSK3 expression.

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.

The stability and change of etiological influences on depression, anxiety symptoms and their co-occurrence across adolescence and young adulthood.

BACKGROUND: Depression and anxiety persist within and across diagnostic boundaries. The manner in which common v. disorder-specific genetic and environmental influences operate across development to maintain internalizing disorders and their co-morbidity is unclear. This paper investigates the stability and change of etiological influences on depression, panic, generalized, separation and social anxiety symptoms, and their co-occurrence, across adolescence and young adulthood. METHOD: A total of 2619 twins/siblings prospectively reported symptoms of depression and anxiety at mean ages 15, 17 and 20 years. RESULTS: Each symptom scale showed a similar pattern of moderate continuity across development, largely underpinned by genetic stability. New genetic influences contributing to change in the developmental course of the symptoms emerged at each time point. All symptom scales correlated moderately with one another over time. Genetic influences, both stable and time-specific, overlapped considerably between the scales. Non-shared environmental influences were largely time- and symptom-specific, but some contributed moderately to the stability of depression and anxiety symptom scales. These stable, longitudinal environmental influences were highly correlated between the symptoms. CONCLUSIONS: The results highlight both stable and dynamic etiology of depression and anxiety symptom scales. They provide preliminary evidence that stable as well as newly emerging genes contribute to the co-morbidity between depression and anxiety across adolescence and young adulthood. Conversely, environmental influences are largely time-specific and contribute to change in symptoms over time. The results inform molecular genetics research and transdiagnostic treatment and prevention approaches.

Shared genetic and environmental influences on early temperament and preschool psychiatric disorders in Hispanic twins.

OBJECTIVE: Despite an increasing recognition that psychiatric disorders can be diagnosed as early as preschool, little is known how early genetic and environmental risk factors contribute to the development of psychiatric disorders during this very early period of development. METHOD: We assessed infant temperament at age 1, and attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and separation anxiety disorder (SAD) at ages 3 through 5 years in a sample of Hispanic twins. Genetic, shared, and non-shared environmental effects were estimated for each temperamental construct and psychiatric disorder using the statistical program MX. Multivariate genetic models were fitted to determine whether the same or different sets of genes and environments account for the co-occurrence between early temperament and preschool psychiatric disorders. RESULTS: Additive genetic factors accounted for 61% of the variance in ADHD, 21% in ODD, and 28% in SAD. Shared environmental factors accounted for 34% of the variance in ODD and 15% of SAD. The genetic influence on difficult temperament was significantly associated with preschool ADHD, SAD, and ODD. The association between ODD and SAD was due to both genetic and family environmental factors. The temperamental trait of resistance to control was entirely accounted for by the shared family environment. CONCLUSIONS: There are different genetic and family environmental pathways between infant temperament and psychiatric diagnoses in this sample of Puerto Rican preschool age children.

Exposure to early life stress regulates Bdnf expression in SERT mutant rats in an anatomically selective fashion.

Although the causes of psychiatric disorders are not fully understood, it is well established that mental illness originates from the interaction between genetic and environmental factors. In this regard, compelling evidence demonstrates that depression can be the consequence of altered, and often maladaptive, response to adversities during pre- and early post-natal life. In this study, we investigated the impact of chronic maternal separation (MS) on the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in serotonin transporter (SERT) knockout rats in the ventral and dorsal hippocampus as well as the ventromedial and dorsomedial prefrontal cortex (PFC). We found that both SERT deletion and the MS led to an overall reduction in Bdnf expression in the ventral hippocampus and the ventromedial PFC, whereas in the dorsal hippocampus and in the dorsomedial PFC, we observed a significant increase in the neurotrophin gene expression after MS exposure, specifically in the heterozygous SERT rats. In summary, we show that the modulation of Bdnf expression in SERT mutant rats exposed to MS reflects the complex functional consequences of this gene-environment interaction with a clear distinction between the ventral and the dorsal subfields of the hippocampus and of the PFC. Early life stress differently affects the expression of Bdnf in an anatomically distinct manner as a function of SERT genotype. Specifically, both SERT deletion and the maternal separation (MS) led to an overall reduction in Bdnf expression in the ventral hippocampus and in the ventromedial prefrontal cortex, whereas in the dorsal hippocampus and in the dorsomedial prefrontal cortex, we observed a significant increase in the neurotrophin gene expression after MS exposure specifically in the heterozygous SERT rats. We think that these findings may provide novel cues for modulating neurotrophin function, which is dys-regulated in several psychiatric conditions.

Early-life risk factors for panic and separation anxiety disorder: insights and outstanding questions arising from human and animal studies of CO2 sensitivity.

Genetically informative studies showed that genetic and environmental risk factors act and interact to influence liability to (a) panic disorder, (b) its childhood precursor separation anxiety disorder, and (c) heightened sensitivity to CO2, an endophenotype common to both disorders. Childhood adversities including parental loss influence both panic disorder and CO2 hypersensitivity. However, childhood parental loss and separation anxiety disorder are weakly correlated in humans, suggesting the presence of alternative pathways of risk. The transferability of tests that assess CO2 sensitivity - an interspecific quantitative trait common to all mammals - to the animal laboratory setting allowed for environmentally controlled studies of early parental separation. Animal findings paralleled those of human studies, in that different forms of early maternal separation in mice and rats evoked heightened CO2 sensitivity; in mice, this could be explained by gene-by-environment interactional mechanisms. While several questions and issues (including obvious divergences between humans and rodents) remain open, parallel investigations by contemporary molecular genetic tools of (1) human longitudinal cohorts and (2) animals in controlled laboratory settings, can help elucidate the mechanisms beyond these phenomena.

Personality dimensions as common and broadband-specific features for internalizing and externalizing disorders.

Several researchers have suggested that the nature of the covariation between internalizing and externalizing disorders may be understood better by examining the associations between temperament or personality and these disorders. The present study examined neuroticism as a potential common feature underlying both internalizing and externalizing disorders and novelty seeking as a potential broad-band specific feature influencing externalizing disorders alone. Participants were 12- to 18-year-old twin pairs (635 monozygotic twin pairs and 691 dizygotic twin pairs; 48 % male and 52 % female) recruited from the Colorado Center for Antisocial Drug Dependence. Genetic and nonshared environmental influences shared in common with neuroticism influenced the covariation among distinct internalizing disorders, the covariation among distinct externalizing disorders, and the covariation between internalizing and externalizing disorders. Genetic influences shared in common with novelty seeking influenced the covariation among externalizing disorders and the covariation between major depressive disorder and externalizing disorders, but not the covariation among internalizing disorders or between anxiety disorders and externalizing disorders. Also, after accounting for genetic and environmental influences shared in common with neuroticism and novelty seeking, there were no significant common genetic or environmental influences among the disorders examined, suggesting that the covariance among the disorders is sufficiently explained by neuroticism and novelty seeking. We conclude that neuroticism is a heritable common feature of both internalizing disorders and externalizing disorders, and that novelty seeking is a heritable broad-band specific factor that distinguishes anxiety disorders from externalizing disorders.

The impact of voluntary exercise on relative telomere length in a rat model of developmental stress.

BACKGROUND: Exposure to early adverse events can result in the development of later psychopathology, and is often associated with cognitive impairment. This may be due to accelerated cell aging, which can be catalogued by attritioned telomeres. Exercise enhances neurogenesis and has been proposed to buffer the effect of psychological stress on telomere length. This study aimed to investigate the impact of early developmental stress and voluntary exercise on telomere length in the ventral hippocampus (VH) and prefrontal cortex (PFC) of the rat. Forty-five male Sprague-Dawley rats were categorised into four groups: maternally separated runners (MSR), maternally separated non-runners (MSnR), non-maternally separated runners (nMSR) and non-maternally separated non-runners (nMSnR). Behavioural analyses were conducted to assess anxiety-like behaviour and memory performance in the rats, after which relative telomere length was measured using qPCR. RESULTS: Maternally separated (MS) rats exhibited no significant differences in either anxiety levels or memory performance on the elevated-plus maze and the open field compared to non-maternally separated rats at 49 days of age. Exercised rats displayed increased levels of anxiety on the day that they were removed from the cages with attached running wheels, as well as improved spatial learning and temporal recognition memory compared to non-exercised rats. Exploratory post-hoc analyses revealed that maternally separated non-exercised rats exhibited significantly longer telomere length in the VH compared to those who were not maternally separated; however, exercise appeared to cancel this effect since there was no difference in VH telomere length between maternally separated and non-maternally separated runners. CONCLUSIONS: The increased telomere length in the VH of maternally separated non-exercised rats may be indicative of reduced cellular proliferation, which could, in turn, indicate hippocampal dysfunction. This effect on telomere length was not observed in exercised rats, indicating that voluntary exercise may buffer against the progressive changes in telomere length caused by alterations in maternal care early in life. In future, larger sample sizes will be needed to validate results obtained in the present study and obtain a more accurate representation of the effect that psychological stress and voluntary exercise have on telomere length.

Duplication of GTF2I results in separation anxiety in mice and humans.

Duplication (dup7q11.23) and deletion (Williams syndrome) of chromosomal region 7q11.23 cause neurodevelopmental disorders with contrasting anxiety phenotypes. We found that 30% of 4- to 12-year-olds with dup7q11.23 but fewer than 5% of children with WS or in the general population met diagnostic criteria for a separation-anxiety disorder. To address the role of one commonly duplicated or deleted gene in separation anxiety, we compared mice that had varying numbers of Gtf2i copies. Relative to mouse pups with one or two Gtf2i copies, pups with additional Gtf2i copies showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. This study links the copy number of a single gene from 7q11.23 to separation anxiety in both mice and humans, highlighting the utility of mouse models in dissecting specific gene functions for genomic disorders that span many genes. This study also offers insight into molecular separation-anxiety pathways that might enable the development of targeted therapeutics.

Childhood separation anxiety disorder and adult onset panic attacks share a common genetic diathesis.

BACKGROUND: Childhood separation anxiety disorder (SAD) is hypothesized to share etiologic roots with panic disorder. The aim of this study was to estimate the genetic and environmental sources of covariance between childhood SAD and adult onset panic attacks (AOPA), with the primary goal to determine whether these two phenotypes share a common genetic diathesis. METHODS: Participants included parents and their monozygotic or dizygotic twins (n = 1,437 twin pairs) participating in the Virginia Twin Study of Adolescent Behavioral Development and those twins who later completed the Young Adult Follow-Up (YAFU). The Child and Adolescent Psychiatric Assessment was completed at three waves during childhood/adolescence followed by the Structured Clinical Interview for DSM-III-R at the YAFU. Two separate, bivariate Cholesky models were fit to childhood diagnoses of SAD and overanxious disorder (OAD), respectively, and their relation with AOPA; a trivariate Cholesky model also examined the collective influence of childhood SAD and OAD on AOPA. RESULTS: In the best-fitting bivariate model, the covariation between SAD and AOPA was accounted for by genetic and unique environmental factors only, with the genetic factor associated with childhood SAD explaining significant variance in AOPA. Environmental risk factors were not significantly shared between SAD and AOPA. By contrast, the genetic factor associated with childhood OAD did not contribute significantly to AOPA. Results of the trivariate Cholesky reaffirmed outcomes of bivariate models. CONCLUSIONS: These data indicate that childhood SAD and AOPA share a common genetic diathesis that is not observed for childhood OAD, strongly supporting the hypothesis of a specific genetic etiologic link between the two phenotypes.