SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive.

SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.

Using Alternative Definitions of Controls to Increase Statistical Power in GWAS.

Genome-wide association studies (GWAS) are often underpowered due to small effect sizes of common single nucleotide polymorphisms (SNPs) on phenotypes and extreme multiple testing thresholds. The most common approach for increasing statistical power is to increase sample size. We propose an alternative strategy of redefining case-control outcomes into ordinal case-subthreshold-asymptomatic variables. While maintaining the clinical case threshold, we subdivide controls into two groups: individuals who are symptomatic but do not meet the clinical criteria for diagnosis (subthreshold) and individuals who are effectively asymptomatic. We conducted a simulation study to examine the impact of effect size, minor allele frequency, population prevalence, and the prevalence of the subthreshold group on statistical power to detect genetic associations in three scenarios: a standard case-control, an ordinal, and a case-asymptomatic control analysis. Our results suggest the ordinal model consistently provides the greatest statistical power while the case-control model the least. Power in the case-asymptomatic control model reflects the case-control or ordinal model depending on the population prevalence and size of the subthreshold category. We then analyzed a major depression phenotype from the UK Biobank to corroborate our simulation results. Overall, the ordinal model improves statistical power in GWAS consistent with increasing the sample size by approximately 10%.

Methylome-wide association study of anxiety disorders.

Anxiety Disorders (ANX) such as panic disorder, generalized anxiety disorder, and phobias, are highly prevalent conditions that are moderately heritable. Evidence suggests that DNA methylation may play a role, as it is involved in critical adaptations to changing environments. Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety. Using epigenomic deconvolution, we performed MWAS for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Cell-type specific analyses identified 280 and 82 methylome-wide significant associations (q-value < 0.1) in monocytes and granulocytes, respectively. Our top finding in monocytes was located in ZNF823 on chromosome 19 (p = 1.38 × 10-10) previously associated with schizophrenia. We observed significant overlap (p < 1 × 10-06) with the same direction of effect in monocytes (210 sites), T-cells (135 sites), and B-cells (727 sites) between this Discovery MWAS signal and a comparable replication dataset from the Great Smoky Mountains Study (N = 433). Overlapping Discovery-Replication MWAS signal was enriched for findings from published GWAS of ANX, major depression, and post-traumatic stress disorder. In monocytes, two specific sites in the FZR1 gene showed significant replication after Bonferroni correction with an additional 15 nominally replicated sites in monocytes and 4 in T-cells. FZR1 regulates neurogenesis in the hippocampus, and its knockout leads to impairments in associative fear memory and long-term potentiation in mice. In the largest and most extensive methylome-wide study of ANX, we identified replicable methylation sites located in genes of potential relevance for brain mechanisms of psychiatric conditions.

Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies.

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Differential Associations of Distress Tolerance and Anxiety Sensitivity With Adolescent Internalizing Psychopathology.

Distress tolerance and anxiety sensitivity may differentiate among internalizing disorders, though few studies have examined differential associations of distress tolerance and anxiety sensitivity with depression and anxiety symptoms while adjusting for their intercorrelation. In an adolescent genetic epidemiological sample (ages 15-21), the present study (N = 848, 56.97% female) examined concurrent associations of distress tolerance and anxiety sensitivity with internalizing psychopathology (i.e., symptoms of depression, anxiety, and general stress) at baseline and prospective, predictive associations of baseline distress tolerance and anxiety sensitivity with internalizing psychopathology at 2-year follow-up. In addition, the present study assessed distress tolerance with two laboratory-based tasks, a carbon dioxide challenge and the mirror-tracing task, to distinguish between tolerance of physiological and cognitive distress, respectively. Elevated anxiety sensitivity was broadly associated with elevated symptoms of internalizing psychopathology at baseline and prospectively predicted elevated depression, anxiety, and stress symptoms at 2-year follow-up. Higher tolerance of cognitive distress was associated with lower concurrent anxiety symptoms but not with anxiety symptoms at follow-up. The present results clarify previously mixed findings; during adolescence, anxiety sensitivity showed broad concurrent and prospective associations with internalizing disorder risk whereas distress tolerance, specifically regarding cognitive distress, was associated with only elevated concurrent anxiety symptoms.

Assessing Stakeholder Perceptions of the Utility of Genetic Information for the Clinical Care of Mental Health Disorders: We Have a Will but Need to See the Way.

Academic stakeholders' (primarily mental health researchers and clinicians) practices and attitudes related to the translation of genetic information into mental health care were assessed. A three-part survey was administered at two large, urban universities. Response frequencies were calculated. Participants (N = 64) reported moderate levels of translational practice, adequate levels of genetic knowledge, and variable levels of genetic competence. They held positive attitudes toward translating genetic information about mental health broadly but negative attitudes about the impact that such information would have on specific aspects of care. The current study lays the groundwork for further inquiry into translating genetic information to mental health care.

Genetic and environmental risk structure of internalizing psychopathology in youth.

BACKGROUND: Internalizing disorders (IDs), consisting of syndromes of anxiety and depression, are common, debilitating conditions often beginning early in life. Various trait-like psychological constructs are associated with IDs. Our prior analysis identified a tripartite model of Fear/Anxiety, Dysphoria, and Positive Affect among symptoms of anxiety and depression and the following constructs in youth: anxiety sensitivity, fearfulness, behavioral activation and inhibition, irritability, neuroticism, and extraversion. The current study sought to elucidate their overarching latent genetic and environmental risk structure. METHODS: The sample consisted of 768 juvenile twin subjects ages 9-14 assessed for the nine, abovementioned measures. We compared two multivariate twin models of this broad array of phenotypes. RESULTS: A hypothesis-driven, common pathway twin model reflecting the tripartite structure of the measures were fit to these data. However, an alternative independent pathway model provided both a better fit and more nuanced insights into their underlying genetic and environmental risk factors. CONCLUSIONS: Our findings suggest a complex latent genetic and environmental structure to ID phenotypes in youth. This structure, which incorporates both clinical symptoms and various psychological traits, informs future phenotypic approaches for identifying specific genetic and pathophysiological mechanisms underlying ID risk.

A Population-Based Twin Study of Childhood Irritability and Internalizing Syndromes.

Childhood irritability exhibits significant theoretical and empirical associations with depression and anxiety syndromes. The current study used the twin design to parse genetic and environmental contributions to these relationships. Children ages 9-14 from 374 twin pairs were assessed for irritability and symptoms of depression, generalized anxiety, panic, social phobia, and separation anxiety using dimensional self-report instruments. Multivariate structural equation modeling decomposed the correlations between these syndromes into genetic and environmental components to examine shared and specific risk domains. Irritability had significant associations with each internalizing symptom domain. Genetic contributions to irritability are moderately correlated with genetic risk for symptoms of depression, generalized anxiety, and separation anxiety with weaker overlap with the other anxiety syndromes. Familial and specific environmental risk factors explained covariation among syndromes and indicated potential syndrome-specific risk. There is substantial overlap among the genetic and environmental factors that influence individual differences in irritability and those that increase liability for depression and anxiety symptoms in children. These findings deepen the current understanding of childhood internalizing risk factors and provide important implications for syndrome prediction and susceptibility gene discovery efforts.

Genome-wide association study of shared liability to anxiety disorders in Army STARRS.

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome-wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM-based ANX diagnoses. We factor-analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta-analyzed across ancestries (NTotal = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta-analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome-wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10-11 ). Gene-based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.

Genetic underpinnings of callous-unemotional traits and emotion recognition in children, adolescents, and emerging adults.

BACKGROUND: Callous-Unemotional (CU) and psychopathic traits are consistently associated with impaired recognition of others' emotions, specifically fear and sadness. However, no studies have examined whether the association between CU traits and emotion recognition deficits is due primarily to genetic or environmental factors. METHODS: The current study used data from 607 Caucasian twin pairs (N = 1,214 twins) to examine the phenotypic and genetic relationship between the Inventory of Callous-Unemotional Traits (ICU) and facial emotion recognition assessed via the laboratory-based Facial Expression Labeling Task (FELT). RESULTS: The uncaring/callous dimension of the ICU was significantly associated with impaired recognition of happiness, sadness, fear, surprise, and disgust. The unemotional ICU dimension was significantly associated with improved recognition of surprise and disgust. Total ICU score was significantly associated with impaired recognition of sadness. Significant genetic correlations were found for uncaring/callous traits and distress cue recognition (i.e. fear and sadness). The observed relationship between uncaring/callous traits and deficits in distress cue recognition was accounted for entirely by shared genetic influences. CONCLUSIONS: The results of the current study replicate previous findings demonstrating impaired emotion recognition among youth with elevated CU traits. We extend these findings by replicating them in an epidemiological sample not selected or enriched for pathological levels of CU traits. Furthermore, the current study is the first to investigate the genetic and environmental etiology of CU traits and emotion recognition, and results suggest genetic influences underlie the specific relationship between uncaring/callous traits and distress cue (fear/sadness) recognition in others.

Heritability, stability, and prevalence of tonic and phasic irritability as indicators of disruptive mood dysregulation disorder.

BACKGROUND: Little is known about genetic and environmental influences on the components of disruptive mood dysregulation disorder (DMDD), tonic irritability (i.e., irritable mood) and phasic irritability (i.e., temper outbursts). This study examined prevalence, stability, and heritability of tonic irritability, phasic irritability, and a DMDD proxy (pDMDD) based on DSM-5 criteria. METHODS: pDMDD was derived using data from clinical interviews of parents and their twins (N = 1,431 twin pairs), ages 8-17, participating in Waves 1 and 2 of the Virginia Twin Study of Adolescent Behavioral Development. Biometrical modeling was used to compare a common pathway model (CPM) and an independent pathway model (IPM), and heritability estimates were obtained for pDMDD using the symptoms of irritable mood (tonic irritability; DMDD Criterion D), intense temper outbursts (phasic irritability; DMDD Criterion A), and frequent temper outbursts (phasic irritability; DMDD Criterion C). RESULTS: Lifetime prevalence of pDMDD was 7.46%. The stability of DMDD symptoms and the pDMDD phenotype across approximately one year were moderate (.30-.69). A CPM was a better fit to the data than an IPM. Phasic irritability loaded strongly onto the pDMDD latent factor (.89-.96) whereas tonic irritability did not (.28). Genetic influences accounted for approximately 59% of the variance in the latent pDMDD phenotype, with the remaining 41% of the variance due to unique environmental effects. The heritability of tonic irritability (54%) was slightly lower than that of frequent and intense temper (components of phasic irritability; 61% and 63%, respectively). CONCLUSIONS: Compared to tonic irritability, phasic irritability appears to be slightly more stable and heritable, as well as a stronger indicator of the latent factor. Furthermore, environmental experiences appear to play a substantial role in the development of irritability and DMDD, and researchers should seek to elucidate these mechanisms in future work.

The Genetic and Environmental Relationship Between Childhood Behavioral Inhibition and Preadolescent Anxiety.

This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9-13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.

The genetic and environmental structure of fear and anxiety in juvenile twins.

Fear and anxiety are conceptualized as responses to acute or potential threat, respectively. Adult twin studies found substantial interplay between genetic and environmental factors influencing fear disorders (phobias) and anxiety disorders. Research in children, however, has largely examined these factors independently. Thus, there exists a substantial knowledge gap regarding the underlying etiologic structure of these closely-related constructs during development. Symptom counts for five fear (criticism, the unknown, death, animal, medical) and four anxiety (generalized, panic, separation, social) dimensions were obtained for 373 twin pairs ages 9-14. Multivariate twin modeling was performed to elucidate the genetic and environmental influences distributed amongst these dimensions. The best fitting model contained one genetic, two familial environmental, and two unique environmental factors shared between fear and anxiety symptoms plus dimension-specific genetic and unique environmental factors. Although several environmental factors were shared between fear and anxiety dimensions, one latent factor accounted for genetic influences across both domains. While adult studies find somewhat distinct etiological differences between anxiety and phobic disorders, the current results suggest that their relative genetic and environmental influences are not as clearly demarcated in children. These etiological distinctions are more nuanced, likely contributing to the highly diffuse symptom patterns seen during development.

Resting Heart Rate Variability (HRV) in Adolescents and Young Adults from a Genetically-Informed Perspective.

Reduced heart rate variability (HRV) is associated with cardiac morbidity, mortality, and negative psychopathology. Most research concerning genetic influences on HRV has focused on adult populations, with fewer studies investigating the developmental period of adolescence and emerging adulthood. The current study estimated the genetic and environmental contributions to resting HRV in a sample of twins using various HRV time domain metrics to assess autonomic function across two different time measurement intervals (2.5- and 10-min). Five metrics of resting HRV [mean interbeat interval (IBI), the standard deviation of normal IBIs (SDNN), root square mean of successive differences between IBIs (RMSSD), cardiac vagal index (CVI), and cardiac sympathetic index (CSI)] were assessed in 421 twin pairs aged 14-20 during a baseline electrocardiogram. This was done for four successive 2.5-min intervals as well as the overall 10-min interval. Heritability (h2) appeared consistent across intervals within each metric with the following estimates (collapsed across time intervals): mean IBI (h2 = 0.36-0.46), SDNN (h2 = 0.23-0.30), RMSSD (h2 = 0.36-0.39), CVI (h2 = 0.37-0.42), CSI (h2 = 0.33-0.46). Beyond additive genetic contributions, unique environment also was an important influence on HRV. Within each metric, a multivariate Cholesky decomposition further revealed evidence of genetic stability across the four successive 2.5-min intervals. The same models showed evidence for both genetic and environmental stability with some environmental attenuation and innovation. All measures of HRV were moderately heritable across time, with further analyses revealing consistent patterns of genetic and environmental influences over time. This study confirms that in an adolescent sample, the time interval used (2.5- vs. 10-min) to measure HRV time domain metrics does not affect the relative proportions of genetic and environmental influences.

Age-Related Differences in the Structure of Genetic and Environmental Contributions to Types of Peer Victimization.

The goal of the present investigation was to clarify and compare the structure of genetic and environmental influences on different types (e.g., physical, verbal) of peer victimization experienced by youth in pre-/early adolescence and mid-/late adolescence. Physical, verbal, social, and property-related peer victimization experiences were assessed in two twin samples (306 pairs, ages 9-14 and 294 pairs, ages 15-20). Cholesky decompositions of individual differences in victimization were conducted, and independent pathway (IP) and common pathway (CP) twin models were tested in each sample. In the younger sample, a Cholesky decomposition best described the structure of genetic and environmental contributors to peer victimization, with no evidence that common additive genetic or environmental factors influence different types of peer victimization. In the older sample, common environmental factors influenced peer victimization types via a general latent liability for peer victimization (i.e., a CP model). Whereas the pre-/early adolescent sample demonstrated no evidence of a shared genetic and environmental structure for different types of peer victimization, the mid-/late adolescent sample demonstrates the emergence of an environmentally-driven latent liability for peer victimization across peer victimization types.

Genetic and Environmental Contributions of Negative Valence Systems to Internalizing Pathways.

The genetic and environmental contributions of negative valence systems (NVS) to internalizing pathways study (also referred to as the Adolescent and Young Adult Twin Study) was designed to examine varying constructs of the NVS as they relate to the development of internalizing disorders from a genetically informed perspective. The goal of this study was to evaluate genetic and environmental contributions to potential psychiatric endophenotypes that contribute to internalizing psychopathology by studying adolescent and young adult twins longitudinally over a 2-year period. This report details the sample characteristics, study design, and methodology of this study. The first wave of data collection (i.e., time 1) is complete; the 2-year follow-up (i.e., time 2) is currently underway. A total of 430 twin pairs (N = 860 individual twins; 166 monozygotic pairs; 57.2% female) and 422 parents or legal guardians participated at time 1. Twin participants completed self-report surveys and participated in experimental paradigms to assess processes within the NVS. Additionally, parents completed surveys to report on themselves and their twin children. Findings from this study will help clarify the genetic and environmental influences of the NVS and their association with internalizing risk. The goal of this line of research is to develop methods for early internalizing disorder risk detection.

The Inventory of Callous-Unemotional Traits (ICU) in Children: Reliability and Heritability.

Callous-unemotional (CU) traits comprise the core symptoms of psychopathy, yet no study has estimated the heritability of CU traits in a community sample of children using an instrument designed solely to assess CU traits. The current study uses data from 339 twin pairs aged 9-14 to examine the reliability and heritability of the parent-report Inventory of Callous-unemotional Traits (ICU) at two assessments approximately 3 weeks apart. Time-specific measurement error was taken into account to obtain a more accurate estimate of the heritability reflecting the latent liability to CU traits. Test-retest reliability was 0.84 and heritability at visit 1 was 39%. The heritability of the latent liability to CU traits was 47%. This latent liability contributed 79% of the variance in ICU score at visit 1 and visit 2. This is the first study to account for measurement error while examining the heritability of CU traits, furthering our understanding of psychopathy in children.

Anxiety symptoms and children's eye gaze during fear learning.

BACKGROUND: The eye region of the face is particularly relevant for decoding threat-related signals, such as fear. However, it is unclear if gaze patterns to the eyes can be influenced by fear learning. Previous studies examining gaze patterns in adults find an association between anxiety and eye gaze avoidance, although no studies to date examine how associations between anxiety symptoms and eye-viewing patterns manifest in children. The current study examined the effects of learning and trait anxiety on eye gaze using a face-based fear conditioning task developed for use in children. METHODS: Participants were 82 youth from a general population sample of twins (aged 9-13 years), exhibiting a range of anxiety symptoms. Participants underwent a fear conditioning paradigm where the conditioned stimuli (CS+) were two neutral faces, one of which was randomly selected to be paired with an aversive scream. Eye tracking, physiological, and subjective data were acquired. Children and parents reported their child's anxiety using the Screen for Child Anxiety Related Emotional Disorders. RESULTS: Conditioning influenced eye gaze patterns in that children looked longer and more frequently to the eye region of the CS+ than CS- face; this effect was present only during fear acquisition, not at baseline or extinction. Furthermore, consistent with past work in adults, anxiety symptoms were associated with eye gaze avoidance. Finally, gaze duration to the eye region mediated the effect of anxious traits on self-reported fear during acquisition. CONCLUSIONS: Anxiety symptoms in children relate to face-viewing strategies deployed in the context of a fear learning experiment. This relationship may inform attempts to understand the relationship between pediatric anxiety symptoms and learning.

Latent structure of negative valence measures in childhood.

BACKGROUND: Internalizing disorders (IDs), consisting of the syndromes of anxiety and depression, are common, debilitating conditions often having onsets in adolescence. Scientists have developed dimensional self-report instruments that assess putative negative valence system (NVS) trait-like constructs as complimentary phenotypes to clinical symptoms. These include various measures that index temperamental predispositions to IDs and correlate with neural substrates of fear, anxiety, and affective regulation. This study sought to elucidate the overarching structure of putative NVS traits and their relationship to early manifestations of ID symptomatology. METHODS: The sample consisted of 768 juvenile twin subjects ages 9-13. Together with ID symptoms, extant validated instruments were chosen to assess a broad spectrum of NVS traits: anxiety sensitivity, irritability, fearfulness, behavioral activation and inhibition, and neuroticism and extraversion. Exploratory and confirmatory factor analyses (EFA/CFA) were used to investigate the latent structure of the associations among these different constructs and ID symptoms. Bifactor modeling in addition to standard correlated-factor analytic approaches were applied. RESULTS: Factor analyses produced a primary tripartite solution comprising anxiety/fear, dysphoria, and positive affect among all these measures. Competing DSM-like correlated factors and an RDoC-like NVS bifactor structure provided similar fit to these data. CONCLUSIONS: Our findings support the conceptual organization of a tripartite latent internalizing domain in developing children. This structure includes both clinical symptoms and a variety of self-report dimensional traits currently in use by investigators. These various constructs are, therefore, most informatively investigated using an inclusive, integrated approach.