Neurophysiological and genetic distinctions between pure and comorbid anxiety disorders

Abstract

Anxiety disorders are often comorbid with major depression (MD) and alcohol use disorders (AUD). Two common functional polymorphisms in catechol-O-methyltransferase (COMT Val158Met) and brain-derived neurotrophic factor (BDNF Val66Met) genes have been implicated in the neurobiology of anxiety and depression. We hypothesized that attentional response and working memory (auditory P300 event-related potential and Weschler Adult Intelligence Scale, Revised digit symbol scores) as well as genetic vulnerability would differ between pure anxiety disorders and comorbid anxiety. Our study sample comprised 249 community-ascertained men and women with lifetime DSM-III-R diagnoses. We analyzed groups of participants with pure anxiety disorders, pure MD, pure AUD, comorbid anxiety, and no psychiatric disorder. Participants were well at the time of testing; state anxiety and depressed mood measures were at most only mildly elevated. Individuals with pure anxiety disorders had elevated P300 amplitudes (P=0.0004) and higher digit symbol scores (P<0.0001) compared with all the other groups. Individuals with comorbid anxiety had the greatest proportion of COMT Met158 and BDNF Met66 alleles (P=0.009) as well as higher harm avoidance-neuroticism (P<0.0005) than all other groups. Our results suggest that there may be two vulnerability factors for anxiety disorders with differing genetic susceptibility: (a) heightened attention and better working memory with mildly elevated anxiety-neuroticism, a constellation that may be protective against other psychopathology; and (b) poorer attention and working memory with greater anxiety-neuroticism, a constellation that may also increase vulnerability to AUD and MD. This refinement of the anxiety phenotype may have implications for therapeutic interventions.

Possible Association of the GSK3β Gene with the Anxiety Symptoms of Major Depressive Disorder and P300 Waveform

“…To our knowledge, this is the first report of evidence that the GSK3b gene is associated with the risk of anxiety symptoms in MDD in a Chinese population sample. However, in recent years, many studies have shown that a brain-derived neurotrophic factor (BDNF) gene polymorphism (rs6265) is associated with the anxiety symptoms of MDD ( Jiang et al, 2005;Lang et al, 2005;Chen et al, 2006;Hunnerkopf et al, 2007;Enoch et al, 2008). BDNF regulates neuronal survival in the central nervous system via the phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (PKB) pathway, and activated PKB regulates a number of cell survival-related proteins, such as GSK3b (Huang and Reichardt, 2001).…”

Meta-Analysis of the Brain-Derived Neurotrophic Factor Gene <i>(BDNF)</i> Val66Met Polymorphism in Anxiety Disorders and Anxiety-Related Personality Traits

“…Three articles were split into separate studies [22][23][24] , thus a total of 16 studies were available for the analyses. To avoid misclassification of the genotype exposure, studies whose allele frequency in the control population deviated from the Hardy-Weinberg equilibrium (p ^ 0.01) were excluded, as was the case for 1 study [25] .…”

“…Since the genetic association of the BDNF 66Met allele and anxiety was investigated for both clinically diagnosed AD and ARPT [2,[22][23][24][25][26][27][28][29][30][31][32][33][34][35] , we carried out a meta-analysis of the published literature in order to clarify the relationship between the BDNF Val66Met polymorphism and anxiety in humans.…”

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

“…Nominally significant associations with social anxiety or SAD have been reported for several candidate loci including COMT (Hettema et al, 2015), catenin-δ2 (CTNND2) (Nivard et al, 2014), and CNTNAP2 (Stein et al, 2011) and several loci involved in circadian rhythm function (Sipila et al, 2010). Given the strong genetic correlations among anxiety disorders, several studies have examined broad phenotypes including multiple anxiety disorders with nominal associations reported for glutamic acid decarboxylase 1 (GAD1) (Donner et al, 2012;Hettema et al, 2006a), DRD2 (Sipila et al, 2010), COMT, BDNF (Enoch et al, 2008), and PPARGC1A (Hettema et al, 2011).…”