Do the genetic or environmental determinants of anxiety and depression change with age? A longitudinal study of Australian twins.

Because the determinants of anxiety and depression in late adolescence and early adulthood may differ from those in later life, we investigated the temporal stability and magnitude of genetic and environmental correlates of symptoms of anxiety and depression across the life span. Data were collected from a population-based Australian sample of 4364 complete twin pairs and 777 singletons aged 20 to 96 years who were followed-up over three studies between 1980 and 1996. Each study contained the 14-item self-report DSSI/sAD scale which was used to measure recently experienced symptoms of anxiety and depression. Symptom scores were then divided and assigned to age intervals according to each subject's age at time of participation. We fitted genetic simplex models to take into account the longitudinal nature of the data. For male anxiety and depression, the best fitting simplex models comprised a single genetic innovation at age 20 which was transmitted, and explained genetic variation in anxiety and depression at ages 30, 40, 50 and 60. Most of the lifetime genetic variation in female anxiety and depression could also be explained by innovations at age 20 which were transmitted to all other ages; however, there were also smaller age-dependent genetic innovations at 30 for anxiety and at 40 and 70 for depression. Although the genetic determinants of anxiety and depression appear relatively stable across the lifespan for males and females, there is some evidence to support additional mid-life and late age gene action in females for depression. The fact that midlife onset for anxiety occurs one decade before depression is also consistent with a causal relationship (anxiety leading to depression) between these conditions. These findings have significance for large scale depression prevention projects.     

Shared Genetic Factors of Anxiety and Depression Symptoms in a Brazilian Family-Based Cohort,the Baependi Heart Study

To investigate the phenotypic and genetic overlap between anxiety and depression symptoms in an admixed population from extended family pedigrees. Participants (n = 1,375) were recruited from a cohort of 93 families (mean age±SD 42±16.3, 57% female) in the rural town of Baependi, Brazil. The Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety symptoms. Heritability estimates were obtained by an adjusted variance component model. Bivariate analyses were performed to obtain the partition of the covariance of anxiety and depression into genetic and environmental components, and to calculate the genetic contribution modulating both sets of symptoms. Anxiety and depression scores were 7.49±4.01 and 5.70±3.82, respectively. Mean scores were affected by age and were significantly higher in women. Heritability for depression and anxiety, corrected for age and sex, were 0.30 and 0.32, respectively. Significant genetic correlations (ρ_g = 0.81) were found between anxiety and depression scores; thus, nearly 66% of the total genetic variance in one set of symptoms was shared with the other set. Our results provided strong evidence for a genetic overlap between anxiety and depression symptoms, which has relevance for our understanding of the biological basis of these constructs and could be exploited in genome-wide association studies.     

Association of polyaminergic loci with anxiety, mood disorders, and attempted suicide

Background

The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression.

Methodology/Principal Findings

We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes.

Conclusions/Significance

These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.     

Genetic Markers of a Munc13 Protein Family Member,BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I–associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders.     

Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles.

BACKGROUND: Unrelated individuals (n = 242) were interviewed directly for the presence of migraine, anxiety disorders, and major depression. MATERIALS AND METHODS: The data described in this study are derived from a clinical genetic relational database that was developed initially for the genetic analysis of migraine. Genotyping of the DRD2 NcoI C to T polymorphism located in exon 6 (His313His) was performed using previously described primers. RESULTS: A significantly increased incidence of migraine with aura (MWA), major depression, generalized anxiety disorder (GAD), panic attacks, and phobia was observed in individuals with the DRD2 NcoI C/C genotype compared with individuals with an DRD2 NcoI T allele. Specifically, 69% (91/131) of DRD2 NcoI C/C individuals in the present study met criteria for at least one of these neuropsychiatric disorders versus only 22% (4/18) of the DRD2 NcoI T/T individuals (Chi-square = 15.29; p < 0.00005). The DRD2 NcoI C allele frequency is significantly higher (Chi-square = 17.13; p < 0.00002) in individuals with MWA, anxiety disorders, and/or major depression (C allele frequency = 0.80) than in individuals who have none of these disorders (C allele frequency = 0.67). CONCLUSIONS: These data indicate that MWA, anxiety disorders, and major depression can be components of a distinct clinical syndrome associated with allelic variations within the DRD2 gene. Clinical recognition of this genetically based syndrome has significant diagnostic and therapeutic implications.     

Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population-based sample of postpartum Taiwanese women

Depression and anxiety disorders often coexist clinically and both are known to have a genetic basis, but the mode of inheritance is too complicated to be determined so far. Serotonin is the biogenic amine neurotransmitter most commonly associated with depression and anxiety. Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied. In this study, we examined whether polymorphism of the TPH1 gene is related to the etiology of major depression, anxiety and comorbid depression and anxiety. Five single nucleoside polymorphisms of the TPH1 gene were studied in a population-based sample of postpartum Taiwanese women consisting of 120 subjects with depression or/and anxiety and 86 matched normal controls. A significant difference (P = 0.0107) in genotype frequency for the T27224C polymorphism was found between the comorbid and normal groups, and risk analysis showed that the C allele conferred a strong protective effect (odds ratio = 0.27; 95% confident interval = 0.11-0.7). Three-allele haplotypes involving T27224C polymorphism were constructed and haplotype associations between particular haplotype combinations and various diseases identified. However, the associations were weak and the overall haplotype frequency profiles in all groups were similar. The results suggest that depression, anxiety, and comorbid depression and anxiety disorders may have related etiologies. In addition, this study suggests that the TPH1 gene might play a role in the pathogenesis of these closely related disorders.     

Little epistasis for anxiety-related measures in the DeFries strains of laboratory mice

Recent advances in methodologies for testing epistatic interactions, combined with several successes in demonstrating genetic interaction effects in animal and human genetics, have rekindled interest in the role of epistatic influences on complex traits. It has even been suggested that the unacknowledged presence of epistasis vitiates the genetic dissection of human and animal behavior. Here we report a genome-wide interaction analysis of 1636 F₂ mice to show that epistasis is of minimal importance in an animal model of anxiety. By using a sufficiently large sample of F₂ animals, we provide evidence that interaction effects between any two loci contribute less than 5% to the total phenotypic variance in multiple tests of anxiety. We conclude that interactions between loci do not necessarily vitiate the genetic analysis of behavior in at least one animal model of anxiety.     

Behavioral genetics: anxiety under interrogation.

Recent genetic mapping experiments in the mouse have made significant inroads into understanding the complex genetics of behavior and, in particular, anxiety.     

Direct-to-consumer testing: if consumers are not anxious,why are policymakers?

Direct-to-consumer genetic testing continues to receive significant attention from both the popular press and policymakers. While the demand for these services has not, to date, been significant, it nevertheless seems likely that more and more individuals will be accessing DTC services. As a result, commentators have suggested that the DTC industry requires more oversight. A common rationale for policy action is that DTC services might cause undue anxiety. However, emerging evidence suggests that this is not the case. Indeed, it appears that genetic risk information has little impact on individual behavior or anxiety levels. Though more research is clearly needed, this type of research should inform the regulatory response to DTC services.     

Muscle tension and physiologic hyperarousal,performance, and state affectivity: assessing the independence of effects in frequent headache and depression

Anxiety, depression, and frequent headache are closely associated. The comorbidity may be due to selection bias (such as inherent in treatment seeking), shared environmental or genetic factors, or a common underlying process. In this study, comorbidity is considered an alternative explanation for correlates of frequent headache found in earlier work. This study addressed whether EMG, peripheral temperature, performance measures, and measures of affect were independently attributable to depression or headache proneness, after control of trait anxiety. Headache state was evaluated in parallel analysis. Seventy-two participants, comprising four groups, were tested: depressedt/ptheadache-prone, depressed/headache-resistant, not depressed/headache-prone, and not depressed/headache-resistant. Participants completed a performance task that allowed assessment of ambition and performance accuracy while measures of affect, headache state, EMG, and peripheral temperature were obtained. Headache proneness, independently of depression and trait anxiety, was related to heightened EMG. Depression was related to EMG, ambition, and performance accuracy independently of headache proneness and trait anxiety. Headache state was associated only with negative affect, independently of depression and anxiety. These results suggest that headache states during assessment, as well as comorbid depression and anxiety, are not primarily responsible for the heightened EMG found in headache-prone individuals. Negative affect often reported in the headache prone, however, may be due to concommitant anxiety. Other analyses address a variety of issues surrounding distinctions among these variables raised in previous research.     

Animal models of anxiety and their molecular dissection

Genetic approaches to psychiatric illness need appropriate animal models both for investigating how genetic variants give rise to behavioural disorder and for identifying genes that may be important in human conditions. Yet the relevance of many animal models to psychiatric illness is often not clear. Here I discuss how genetic approaches can be used to validate animal models of anxiety, an approach which is applicable to other animal models. One drawback of genetic validation is the difficulty inherent in identifying the molecular variants that influence the phenotype. I review genetic approaches that have the potential to overcome this problem.     

Performance of Polygenic Scores for Predicting Phobic Anxiety

Context

Anxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits.

Objective

To investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes.

Design

Longitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort.

Setting and Participants

Study participants (n = 11,127) were individuals from the Nurses'' Health Study and Health Professionals Follow-up Study.

Main Outcome Measure

Anxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived.

Results

We found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety.

Conclusion

There is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20–40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety.     

Genetic effects on an animal model of anxiety

Genetic effects on behavioural measures thought to model anxiety have been reported on 15 mouse chromosomes. In general the individual effect from each locus is small, contributing to 10% or less of the total variation, but through use of crosses between inbred rodents the power to detect such effects is high: 39 loci have been reported at stringent levels of significance. Novel multivariate analyses of these data go some way to characterizing the genetic architecture of anxiety and also to validating the tests that are used for its measurement. However, we are still some way from finding the molecular variants that explain the heritability of the trait.     

Serotonin transporter gene variation, infant abuse, and responsiveness to stress in rhesus macaque mothers and infants

A functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene has been associated with variation in anxiety and hypothalamus-pituitary-adrenal (HPA) axis function in humans and rhesus macaques. Individuals carrying the short allele are at a higher risk for developmental psychopathology, and this risk is magnified in short allele carriers who have experienced early life stress. This study investigated the relationship between 5-HTTLPR allelic variation, infant abuse, and behavioral and hormonal responses to stress in rhesus macaques. Subjects were 10 abusive mothers and their infants, and 10 nonabusive mother-infant pairs. Mothers and infants were genotyped for the rh5-HTTLPR, and studied in the first 6 months of infant life. For mothers and infants, we measured social group behavior, behavioral responses to handling procedures, and plasma concentrations of ACTH and cortisol under basal conditions and in response to stress tests. The proportion of individuals carrying the short rh5-HTTLPR allele was significantly higher among abusive mothers than controls. Among mothers and infants, the short allele was associated with higher basal cortisol levels and greater hormonal stress responses in the infants. In addition, infants who carried the short rh5-HTTLPR allele had higher anxiety scores than infants homozygous for the long allele. The rh5-HTTLPR genotype also interacted with early adverse experience to impact HPA axis function in the infants. These results are consistent with those of previous studies which demonstrate associations between serotonergic activity and anxiety and stress reactivity, and add additional evidence suggesting that genetic variation in serotonergic function may contribute to the occurrence of abusive parenting in rhesus macaques and modulate emotional behavior and HPA axis function.     

Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior

The identification of genetic variants responsible for behavioral variation is an enduring goal in biology, with wide-scale ramifications, ranging from medical research to evolutionary theory on personality syndromes. Here, we use for the first time a large-scale genetical genomics analysis in the brains of chickens to identify genes affecting anxiety as measured by an open field test. We combine quantitative trait locus (QTL) analysis in 572 individuals and expression QTL (eQTL) analysis in 129 individuals from an advanced intercross between domestic chickens and Red Junglefowl. We identify 10 putative quantitative trait genes affecting anxiety behavior. These genes were tested for an association in the mouse Heterogeneous Stock anxiety (open field) data set and human GWAS data sets for bipolar disorder, major depressive disorder, and schizophrenia. Although comparisons between species are complex, associations were observed for four of the candidate genes in mice and three of the candidate genes in humans. Using a multimodel approach we have therefore identified a number of putative quantitative trait genes affecting anxiety behavior, principally in chickens but also with some potentially translational effects as well. This study demonstrates that chickens are an excellent model organism for the genetic dissection of behavior.     

COMT Val(158)Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence: results from the Victorian Adolescent Health Cohort Study

We investigated whether a composite genetic factor, based on the combined actions of catechol-O-methyltransferase (COMT) (Val(158)Met) and serotonin transporter (5HTTLPR) (Long-Short) functional loci, has a greater capacity to predict persistence of anxiety across adolescence than either locus in isolation. Analyses were performed on DNA collected from 962 young Australians participating in an eight-wave longitudinal study of mental health and well-being (Victorian Adolescent Health Cohort Study). When the effects of each locus were examined separately, small dose-response reductions in the odds of reporting persisting generalized (free-floating) anxiety across adolescence were observed for the COMT Met(158) [odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76-0.95, P = 0.004] and 5HTTLPR Short alleles (OR = 0.88, CI = 0.79-0.99, P = 0.033). There was no evidence for a dose-response interaction effect between loci. However, there was a double-recessive interaction effect in which the odds of reporting persisting generalized anxiety were more than twofold reduced (OR = 0.45, CI = 0.29-0.70, P < 0.001) among carriers homozygous for both the COMT Met(158) and the 5HTTLPR Short alleles (Met(158)Met + Short-Short) compared with the remaining cohort. The double-recessive effect remained after multivariate adjustment for a range of psychosocial predictors of anxiety. Exploratory stratified analyses suggested that genetic protection may be more pronounced under conditions of high stress (insecure attachments and sexual abuse), although strata differences did not reach statistical significance. By describing the interaction between genetic loci, it may be possible to describe composite genetic factors that have a more substantial impact on psychosocial development than individual loci alone, and in doing so, enhance understanding of the contribution of constitutional processes in mental health outcomes.     

First Genome-Wide Association Study on Anxiety-Related Behaviours in Childhood

Background

Twin studies have shown that anxiety in a general population sample of children involves both domain-general and trait-specific genetic effects. For this reason, in an attempt to identify genes responsible for these effects, we investigated domain-general and trait-specific genetic associations in the first genome-wide association (GWA) study on anxiety-related behaviours (ARBs) in childhood.

Methods

The sample included 2810 7-year-olds drawn from the Twins Early Development Study (TEDS) with data available for parent-rated anxiety and genome-wide DNA markers. The measure was the Anxiety-Related Behaviours Questionnaire (ARBQ), which assesses four anxiety traits and also yields a general anxiety composite. Affymetrix GeneChip 6.0 DNA arrays were used to genotype nearly 700,000 single-nucleotide polymorphisms (SNPs), and IMPUTE v2 was used to impute more than 1 million SNPs. Several GWA associations from this discovery sample were followed up in another TEDS sample of 4804 children. In addition, Genome-wide Complex Trait Analysis (GCTA) was used on the discovery sample, to estimate the total amount of variance in ARBs that can be accounted for by SNPs on the array.

Results

No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome (p<5×10⁻⁸). Attempts to replicate the top associations did not yield significant results. In contrast to the substantial twin study estimates of heritability which ranged from 0.50 (0.03) to 0.61 (0.01), the GCTA estimates of phenotypic variance accounted for by the SNPs were much lower 0.01 (0.11) to 0.19 (0.12).

Conclusions

Taken together, these GWAS and GCTA results suggest that anxiety – similar to height, weight and intelligence − is affected by many genetic variants of small effect, but unlike these other prototypical polygenic traits, genetic influence on anxiety is not well tagged by common SNPs.     

Anxiolytic effect of motilin and reversal with GM-109, a motilin antagonist, in mice

There have been few reports on the effects of the brain-gut peptide motilin on the central nervous system (CNS). We administered motilin intracerebroventricularly to mice and investigated the effect of motilin on anxiety using an elevated plus-maze. Motilin produced a significant decrease in anxiety with an inverted U-shaped dose response. To determine whether the anxiolytic effect of motilin was mediated via motilin receptors in the brain, the effect of GM-109, a novel motilin receptor antagonist, was investigated. GM-109 showed a significant and dose-dependent antagonism on the motilin-induced anxiolytic effect. GM-109 administered alone had no effect on anxiety. These results suggest that motilin receptors are present in the brain and may have a role in anxiety and emotion.     

A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice

Whole-genome genetic association studies in outbred mouse populations represent a novel approach to identifying the molecular basis of naturally occurring genetic variants, the major source of quantitative variation between inbred strains of mice. Measuring multiple phenotypes in parallel on each mouse would make the approach cost effective, but protocols for phenotyping on a large enough scale have not been developed. In this article we describe the development and deployment of a protocol to collect measures on three models of human disease (anxiety, type II diabetes, and asthma) as well as measures of mouse blood biochemistry, immunology, and hematology. We report that the protocol delivers highly significant differences among the eight inbred strains (A/J, AKR/J, BALBc/J, CBA/J, C3H/HeJ, C57BL/6 J, DBA/2 J, and LP/J), the progenitors of a genetically heterogeneous stock (HS) of mice. We report the successful collection of multiple phenotypes from 2000 outbred HS animals. The phenotypes measured in the protocol form the basis of a large-scale investigation into the genetic basis of complex traits in mice designed to examine interactions between genes and between genes and environment, as well as the main effects of genetic variants on phenotypes.     

Early Life Experiences and Exercise Associate with Canine Anxieties

Personality and anxiety disorders across species are affected by genetic and environmental factors. Shyness-boldness personality continuum exists across species, including the domestic dog, with a large within- and across-breed variation. Domestic dogs are also diagnosed for several anxiety-related behavioral conditions, such as generalized anxiety disorders, phobias, and separation anxiety. Genetic and environmental factors contributing to personality and anxiety are largely unknown. We collected questionnaire data from a Finnish family dog population (N = 3264) in order to study the associating environmental factors for canine fearfulness, noise sensitivity, and separation anxiety. Early life experiences and exercise were found to associate with anxiety prevalence. We found that fearful dogs had less socialization experiences (p = 0.002) and lower quality of maternal care (p < 0.0001) during puppyhood. Surprisingly, the largest environmental factor associating with noise sensitivity (p < 0.0001) and separation anxiety (p = 0.007) was the amount of daily exercise; dogs with noise sensitivity and separation anxiety had less daily exercise. Our findings suggest that dogs share many of the same environmental factors that contribute to anxiety in other species as well, such as humans and rodents. Our study highlights the importance of early life experiences, especially the quality of maternal care and daily exercise for the welfare and management of the dogs, and reveals important confounding factors to be considered in the genetic characterization of canine anxiety.