Higher anxiety and larger amygdala volumes in carriers of a TMEM132D risk variant for panic disorder.
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ABSTRACT:
SUBMITTER: Haaker J
PROVIDER: S-EPMC3944634 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
Publications
Higher anxiety and larger amygdala volumes in carriers of a TMEM132D risk variant for panic disorder.
Haaker J J Lonsdorf T B TB Raczka K A KA Mechias M-L ML Gartmann N N Kalisch R R
Translational psychiatry 20140204
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Project description:A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.
| S-EPMC3565207 | biostudies-literature
Project description:BackgroundAnxiety is one of the most common co-occurring conditions in people with autism spectrum disorder. The amygdala has been identified as being associated with anxiety in populations with and without autism, yet associations in autism were based on relatively small or developmentally constrained samples, leaving questions as to whether these results hold at different developmental ages and in a larger, more robust sample.MethodsStructural neuroimaging and parent report of anxiety symptoms of children ages 5-13 years with (n = 123) and without (n = 171) a diagnosis of autism were collected from the University of Maryland and three sites from the Autism Brain Imaging Data Exchange. Standardized residuals for bilateral amygdala volumes were computed adjusting for site, hemispheric volumes, and covariates (age, sex, Full Scale IQ).ResultsClinically significant anxiety symptoms did not differentiate amygdala volumes between groups (i.e., autism and anxiety, autism without anxiety, without autism or anxiety). No significant association between left or right amygdala volumes and anxiety scores was observed among the sample of individuals with autism. Meta-analytic and Bayes factor estimations provided additional support for the null hypothesis. Age, sex, and autism severity did not moderate associations between anxiety and amygdala volumes.ConclusionsNo relation between amygdala volumes and anxiety symptoms in children with autism was observed in the largest sample to investigate this question. We discuss directions for future research to determine whether additional factors including age or method of assessment may contribute to this lack of association.
| S-EPMC9021331 | biostudies-literature
Project description:The role of the amygdala in the experience of emotional states and stress is well established. Connections from the amygdala to the hypothalamus activate the hypothalamic-pituitaryadrenal (HPA) axis and the cortisol response. Previous studies have failed to find consistent whole amygdala volume changes in Major Depressive Disorder (MDD), but differences may exist at the smaller substructural level of the amygdala nuclei. High-resolution T1 and T2-weighted-fluid-attenuated inversion recovery MRIs were compared between 80 patients with MDD and 83 healthy controls (HC) using the automated amygdala substructure module in FreeSurfer 6.0. Volumetric assessments were performed for individual nuclei and three anatomico-functional composite groups of nuclei. Salivary cortisol awakening response (CAR), as a measure of HPA responsivity, was measured in a subset of patients. The right medial nucleus volume was larger in MDD compared to HC (p = 0.002). Increased right-left volume ratios were found in MDD for the whole amygdala (p = 0.004), the laterobasal composite (p = 0.009) and in the central (p = 0.003) and medial (p = 0.014) nuclei. The CAR was not significantly different between MDD and HC. Within the MDD group the left corticoamygdaloid transition area was inversely correlated with the CAR, as measured by area under the curve (AUCg) (p ≤ 0.0001). In conclusion, our study found larger right medial nuclei volumes in MDD compared to HC and relatively increased right compared to left whole and substructure volume ratios in MDD. The results suggest that amygdala substructure volumes may be involved in the pathophysiology of depression.
| S-EPMC8361319 | biostudies-literature
Project description:TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.
| S-EPMC7962252 | biostudies-literature
Project description:BackgroundDespite considerable effort, the neurobiological underpinnings of hyper-responsive threat processing specific to patients suffering from generalized anxiety disorder (GAD) remain poorly understood. The current functional magnetic resonance imaging (fMRI) study aims to delineate GAD-specific brain activity during immediate threat processing by comparing GAD patients to healthy controls (HC), to social anxiety disorder (SAD) and to panic disorder (PD) patients.MethodBrain activation and functional connectivity patterns to threat vs. neutral pictures were investigated using event-related fMRI. The sample consisted of 21 GAD, 21 PD, 21 SAD and 21 HC.ResultsGAD-specific elevated activity to threat vs. neutral pictures was found in cingulate cortex, dorsal anterior insula/frontal operculum (daI/FO) and posterior dorsolateral prefrontal cortex (dlPFC). Defining these effects as seed regions, we detected GAD-specific increased functional connectivity to threat vs. neutral pictures between posterior dlPFC and ventrolateral prefrontal cortex, between cingulate cortex and amygdala, between cingulate cortex and anterior insula, as well as decreased functional connectivity between daI/FO and mid-dlPFC.ConclusionThe findings present the first evidence for GAD-specific neural correlates of hyper-responsive threat processing, possibly reflecting exaggerated threat sensitivity, maladaptive appraisal and attention-allocation processes.
| S-EPMC5065042 | biostudies-literature
Project description:Lead is a ubiquitous neurotoxicant, and adverse cognitive and behavioral effects are well-documented in children and occupationally exposed adults but not in adults with low environmental exposure.To investigate the association of current blood lead levels with 3 common psychiatric disorders-major depression, panic, and generalized anxiety-in young adults.Cross-sectional epidemiologic survey.Nationally representative sample of US adults.A total of 1987 adults aged 20 to 39 years who responded to the National Health and Nutrition Examination Survey (1999-2004).Twelve-month DSM-IV criteria-based diagnoses of major depressive disorder, panic disorder, and generalized anxiety disorder assessed using the Composite International Diagnostic Interview.The mean (SD) blood lead level was 1.61 (1.72) microg/dL (range, 0.3-37.3 microg/dL) (to convert to micromoles per liter, multiply by 0.0483). Increasing blood lead levels were associated with higher odds of major depression (P = .05 for trend) and panic disorder (P = .02 for trend) but not generalized anxiety disorder (P = .78 for trend) after adjustment for sex, age, race/ethnicity, education status, and poverty to income ratio. Persons with blood lead levels in the highest quintile had 2.3 times the odds of major depressive disorder (95% confidence interval [CI], 1.13-4.75) and 4.9 times the odds of panic disorder (1.32-18.48) as those in the lowest quintile. Cigarette smoking was associated with higher blood lead levels and outcome, but models that excluded current smokers also resulted in significantly increased odds of major depression (P = .03 for trend) and panic disorder (P = .01 for trend) with higher blood lead quintiles.In these young adults with low levels of lead exposure, higher blood lead levels were associated with increased odds of major depression and panic disorders. Exposure to lead at levels generally considered safe could result in adverse mental health outcomes.
| S-EPMC2917196 | biostudies-other
Project description:We herein report an association between TMEM132D and panic disorder (PD) in a Japanese population, evaluating the effects of HLA-DRB1*13:02, which we previously reported as a susceptibility genetic factor for PD. SNPs in TMEM132D showed significant associations with PD in subjects without HLA-DRB1*13:02 (rs4759997; P=5.02×10(-6), odds ratio=1.50) but not in those with the HLA allele. TMEM132D might have a role in the development of PD in subjects without HLA-DRB1*13:02.
| S-EPMC4766370 | biostudies-literature
Project description:The results of a genomewide scan for genes conferring susceptibility to anxiety disorders in the Icelandic population are described. The aim of the study was to locate genes that predispose to anxiety by utilizing the extensive genealogical records and the relative homogeneity of the Icelandic population. Participants were recruited in two stages: (1) Initial case-identification by a population screening for anxiety disorders, using the Stamm Screening Questionnaire, was followed by aggregation into extended families, with the help of our genealogy database; and (2) those who fulfilled the diagnostic and family aggregation criteria underwent a more detailed diagnostic workup based on the Composite International Diagnostic Interview. Screening for anxiety in close relatives also identified additional affected members within the families. After genotyping was performed with 976 microsatellite markers, affected-only linkage analysis was done, and allele-sharing LOD scores were calculated using the program Allegro. Linkage analysis of 25 extended families, in each of which at least one affected individual had panic disorder (PD), resulted in a LOD score of 4.18 at D9S271, on chromosome 9q31. The intermarker distance was 4.4 cM on average, whereas it was 1.5 cM in the linked region as additional markers were added to increase the information content. The linkage results may be relevant not only to PD but also to anxiety in general, since our linkage study included patients with other forms of anxiety.
| S-EPMC1180274 | biostudies-literature
Project description:ObjectiveTo test whether red blood cell (RBC) levels of marine omega-3 fatty acids measured in the Women's Health Initiative Memory Study were related to MRI brain volumes measured 8 years later.MethodsRBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes were assessed in 1,111 postmenopausal women from the Women's Health Initiative Memory Study. The endpoints were total brain volume and anatomical regions. Linear mixed models included multiple imputations of fatty acids and were adjusted for hormone therapy, time since randomization, demographics, intracranial volume, and cardiovascular disease risk factors.ResultsIn fully adjusted models, a 1 SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm(3) larger brain volume (p = 0.048). DHA was marginally correlated (p = 0.063) with total brain volume while EPA was less so (p = 0.11). There were no correlations between ischemic lesion volumes and EPA, DHA, or EPA + DHA. A 1 SD greater omega-3 index was correlated with greater hippocampal volume (50 mm(3), p = 0.036) in fully adjusted models. Comparing the fourth quartile vs the first quartile of the omega-3 index confirmed greater hippocampal volume (159 mm(3), p = 0.034).ConclusionA higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured 8 years later. While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy. Future studies should examine whether maintaining higher RBC EPA + DHA levels slows the rate of hippocampal or overall brain atrophy.
| S-EPMC3917688 | biostudies-literature
Project description:Unbiased genome-wide approaches can provide novel insights into the biological pathways that are important for human behavior and psychiatric disorder risk. The association of α-endomannosidase gene (MANEA) variants and cocaine-induced paranoia (CIP) was initially described in a study that used a whole-genome approach. Behavioral effects have been reported for other mannosidase genes, but MANEA function in humans and the clinical potential of the previous findings remain unclear. We hypothesized that MANEA would be associated with psychiatric phenotypes unrelated to cocaine use. We used a multi-stage association study approach starting with four psychiatric disorders to show an association between a MANEA single-nucleotide polymorphism (SNP; rs1133503) and anxiety disorders. In the first study of 2073 European American (EA) and 2459 African American subjects mostly with comorbid drug or alcohol dependence, we observed an association in EAs of rs1133503 with panic disorder (PD) (191 PD cases, odds ratio (OR)=1.7 (95% confidence interval (CI): 1.22-2.41), P=0.002). We replicated this finding in an independent sample of 142 PD cases (OR =1.53 (95% CI: 1.00-2.31), P=0.043) and extended it in an independent sample of 131 generalized social anxiety disorder cases (OR=2.15 (95% CI: 1.27-3.64), P=0.004). MANEA alleles and genotypes were also associated with gene expression differences in whole blood cells. Using publically available data, we observed a consistent effect on expression in brain tissue. We conclude that pathways involving α-endomannosidase warrant further investigation in relation to anxiety disorders.
| S-EPMC3905232 | biostudies-literature