A major role for common genetic variation in anxiety disorders.
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ABSTRACT:
SUBMITTER: Purves KL
PROVIDER: S-EPMC7237282 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose of the reviewSample size increases have resulted in novel and replicable loci for substance use disorders (SUDs). We summarize some of the latest insights into SUD genetics and discuss some next steps in addiction genetics.Recent findingsGenome-wide association studies have substantiated the role of previously known variants (e.g., rs1229984 in ADH1B for alcohol) and identified several novel loci for alcohol, tobacco, cannabis, opioid and cocaine use disorders. SUDs are genetically correlated with psychiatric outcomes, while liability to substance use is inconsistently associated with these outcomes and more closely associated with lifestyle factors. Specific variant associations appear to differ somewhat across populations, although similar genes and systems are implicated.SummaryThe next decade of human genetic studies of addiction should focus on expanding to non-European populations, consider pleiotropy across SUD and with other psychiatric disorders, and leverage human and cross-species functional data to elucidate the biological mechanisms underlying SUDs.
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Project description:Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.
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Project description:In this paper we examine the nature of automatic cognitive processing in anxiety disorders and Major Depressive Disorder (MDD). Rather than viewing automaticity as a unitary construct, we follow a social cognition perspective (Bargh, 1994) that argues for four theoretically independent features of automaticity: unconscious (processing of emotional stimuli occurs outside awareness), efficient (processing emotional meaning uses minimal attentional resources), unintentional (no goal is needed to engage in processing emotional meaning), and uncontrollable (limited ability to avoid, alter or terminate processing emotional stimuli). Our review of the literature suggests that most anxiety disorders are characterized by uncontrollable, and likely also unconscious and unintentional, biased processing of threat-relevant information. In contrast, MDD is most clearly typified by uncontrollable, but not unconscious or unintentional, processing of negative information. For the anxiety disorders and for MDD, there is no sufficient evidence to draw firm conclusions about efficiency of processing, though early indications are that neither anxiety disorders nor MDD are characterized by this feature. Clinical and theoretical implications of these findings are discussed and directions for future research are offered. In particular, it is clear that paradigms that more directly delineate the different features of automaticity are required to gain a more comprehensive and systematic understanding of the importance of automatic processing in emotion dysregulation.
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Project description:The resting EEG is a dynamic index of cortical activation, cognitive function and consciousness and is therefore an intermediate phenotype for many behaviors in which arousal is implicated such as anxiety and alcoholism. We performed a dense whole genome linkage scan using 3878 unlinked SNPs in a large pedigree derived from a population isolate sample of 328 Plains American Indians. Alpha (8-13 Hz), theta (4-8 Hz) and beta (13-30 Hz) EEG power was heritable (0.58-0.27) and stable over a 2 year period (r = 0.82-0.53). Genetic correlations between frequency bands were high (0.75). Linkage peaks for EEG power in all three frequency bands converged on chromosome 5q13-14 with genome-wide significant LOD scores of 3.5 (empirical p<0.0001) for alpha and beta power. A logical candidate gene, corticotropin releasing hormone-binding protein (CRH-BP), was located at the apex of these convergent linkage peaks. CRH-BP was significantly associated with alpha power in the Plains Indians and also in a replication sample of 188 Caucasians. Moreover, the same SNPs and haplotypes, located within the CRH-BP haplotype block, were also associated with anxiety disorders in the Plains Indians and alcohol use disorders in the Caucasians. CRH-BP modulates CRH which influences cortical and hippocampal EEG activity and is the primary mediator of the neuroendocrine stress response. Our results suggest a likely role for CRH-BP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction.
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Project description:BACKGROUND:There have been considerable recent advances in understanding the genetic architecture of anxiety disorders and posttraumatic stress disorder (PTSD), as well as the underlying neurocircuitry of these disorders. However, there is little work on the concordance of genetic variations that increase risk for these conditions, and that influence subcortical brain structures. We undertook a genome-wide investigation of the overlap between the genetic influences from single nucleotide polymorphisms (SNPs) on volumes of subcortical brain structures and genetic risk for anxiety disorders and PTSD. METHOD:We obtained summary statistics of genome-wide association studies (GWAS) of anxiety disorders (Ncases = 7016, Ncontrols = 14,745), PTSD (European sample; Ncases = 2424, Ncontrols = 7113) and of subcortical brain structures (N = 13,171). SNP Effect Concordance Analysis (SECA) and Linkage Disequilibrium (LD) Score Regression were used to examine genetic pleiotropy, concordance, and genome-wide correlations respectively. SECAs conditional false discovery was used to identify specific risk variants associated with anxiety disorders or PTSD when conditioning on brain related traits. RESULTS:For anxiety disorders, we found evidence of significant concordance between increased anxiety risk variants and variants associated with smaller amygdala volume. Further, by conditioning on brain volume GWAS, we identified novel variants that associate with smaller brain volumes and increase risk for disorders: rs56242606 was found to increase risk for anxiety disorders, while two variants (rs6470292 and rs683250) increase risk for PTSD, when conditioning on the GWAS of putamen volume. LIMITATIONS:Despite using the largest available GWAS summary statistics, the analyses were limited by sample size. CONCLUSIONS:These preliminary data indicate that there is genome wide concordance between genetic risk factors for anxiety disorders and those for smaller amygdala volume, which is consistent with research that supports the involvement of the amygdala in anxiety disorders. It is notable that a genetic variant that contributes to both reduced putamen volume and PTSD plays a key role in the glutamatergic system. Further work with GWAS summary statistics from larger samples, and a more extensive look at the genetics underlying brain circuits, is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.
| S-EPMC6519055 | biostudies-literature
Project description:Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N?=?1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P?<?0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P?<?0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
| S-EPMC5324578 | biostudies-literature
Project description:With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.
| S-EPMC4605546 | biostudies-other
Project description:A cohort of adolescents and young adults took part in this longitudinal 5-year follow-up study. We selected four groups of subjects from the same community sample carefully paired by age and gender: (1) Typically Developing Adolescent (n=14); (2) Incident Anxiety Disorder (n=11); (3) Persistent Anxiety Disorder (n=14); (4) Remittent Anxiety Disorder (n=8).
2016-03-08 | GSE78975 | GEO
Project description:BACKGROUND:It has been shown in the past two decades that anxiety disorders are the most common mental disorders in general population across the world. This study sought to assess the prevalence of major anxiety disorders, their sociodemographic correlates and mental health service utilization as part of the Iranian Mental Health Survey (IranMHS). METHODS:A national household face-to-face survey was carried out on a representative sample of Iranian adults from January to June 2011 using Composite International Diagnostic Interview (CIDI 2.1). A total of 7886 subjects between 15 and 64 years who can understand Persian language were included. The 12-month prevalence of anxiety disorders according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), their socio-demographic correlates, health service use and days out of role were measured in this study. RESULTS:The 12-month prevalence of anxiety disorders (not including specific phobias) was 15.6%. The prevalence was 12.0% in males and 19.4% in females. The three most prevalent anxiety disorders were generalized anxiety disorder (5.2%), obsessive-compulsive disorder (5.1%) and social phobia (3.2%), respectively. Factors found to be significantly associated with anxiety disorders were: female gender (OR?=?1.16, 95% CI: 1.09-1.23), middle (OR?=?1.23, 95%CI: 1.01-1.50) or low (OR?=?1.66, 95%CI: 1.31-2.10) socioeconomic status, unemployment (OR?=?1.98, 95%CI: 1.49-2.62), and urban residence (OR?=?1.31, 95%CI: 1.10-1.57). Comorbidity with non-anxiety disorders significantly increased service utilization. In all subgroups, service utilization was higher among females while the number of days out of role was higher among males. CONCLUSIONS:Anxiety disorders are common conditions with a higher prevalence among the female gender, unemployed individuals, and people with low socioeconomic conditions living in urban areas. Comorbidity of anxiety disorders with other psychological disorders aggravates the disability and significantly increases the number of days out of role.
| S-EPMC6102821 | biostudies-literature
Project description:SignificanceMajor depressive, anxiety, and stress-related disorders are highly comorbid and may affect similar neurocircuitry and cognitive processes. However, the neurocircuitry underlying shared dimensions of cognitive impairment is unclear and holds the promise of reimagining psychiatric nosology. Here we leverage population imaging data (n = 27,132) to show that while major depressive and anxiety disorders share functional and structural neural signatures, stress-related disorders are distinct from these two conditions. We report that better cognitive function is associated with lower connectivity of specific nodes of the default mode and frontoparietal networks. These findings provide population benchmarks for brain-cognition associations in healthy participants and those with lifetime major depressive and anxiety disorders, advancing our understanding of intrinsic brain networks underlying cognitive dysfunction.
| S-EPMC9191681 | biostudies-literature