John M. Hettema

Ion channels are involved in a wide range of central nervous system functions and have been implicated in several neuropsychiatric disorders. Rodent studies suggest that the acid-sensing ion channel, ASIC1, may play a role in fear conditioning, a model for human anxiety disorders. In this study, we examined, for the first time, the human analog of ASIC1, the amiloride-sensitive cation channel 2 (ACCN2) gene, for its association with genetic risk across a range of anxiety spectrum phenotypes. Using multivariate structural equation modeling, we selected twin pairs scoring at the extremes of a latent genetic risk factor that underlies susceptibility to neuroticism, major depression, generalized anxiety disorder, panic disorder, agoraphobia, and social phobia, from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each selected pair for whom DNA was available was entered into a 2-stage, case–control association study for the ACCN2 gene. In the resulting sample of 589 cases and 539 controls, a total of seven single nucleotide polymorphisms that represented the major allelic variation across the ACCN2 locus were screened in stage 1, the positive results of which were tested for replication in stage 2. Although several markers or haplotypic combinations met threshold significance criteria in stage 1, their association was not replicated in stage 2. Post hoc analyses did not reveal significant association to the specific psychiatric phenotypes. Although the ACCN2 gene may play a role in rodent fear conditioning, we could not detect association with genetic risk shared among human anxiety spectrum disorders.

Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.

Background. Both generalized anxiety disorder (GAD) and stressful life events (SLEs) are established risk factors for major depressive disorder, but no studies exist that examine the interrelationship of their impact on depressive onsets. In this study, we sought to analyze the joint effects of prior history of GAD and recent SLEs on risk for major depressive episodes, comparing these in men and women.Method. In a population-based sample of 8068 adult twins, Cox proportional hazard models were used to predict onsets of major depression from reported prior GAD and last-year SLEs rated on long-term contextual threat.Results. For all levels of threat, prior GAD increases risk for depression, with a monotonic relationship between threat level and risk. While females without prior GAD consistently show higher depressive risk than males, this is no longer the case in subjects with prior GAD who have experienced SLEs. Rather, males appear to be more vulnerable to the depressogenic effects of both prior GAD and SLEs.Conclusion. The effects of prior GAD and SLEs jointly increase the risk of depression in both sexes, but disproportionately so in males.

Comorbidity among the anxiety disorders has proved to be the rule rather than the exception,^1-3 such that it is unlikely for an individual to experience a single anxiety disorder in isolation.⁴ The etiology of comorbidity can be loosely divided into origins of causation (disorder A causes disorder B) or shared risk factors (both disorders are etiologically related to the same underlying causes).⁵ It is the latter that this study seeks to elucidate regarding the underlying risk factors that increase comorbidity among the anxiety disorders.

OBJECTIVE: The authors examined the sources of covariation between generalized anxiety disorder and the personality trait of neuroticism. Because women have higher levels of neuroticism and twice the risk of lifetime generalized anxiety disorder of men, gender-specific effects were also explored. METHOD: Lifetime generalized anxiety disorder and neuroticism were assessed in more than 8,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Sex-limited Cholesky structural equation models were used to decompose the correlations between generalized anxiety disorder and neuroticism into genetic and environmental components, including sex-specific factors. RESULTS: Genetic correlations between generalized anxiety disorder and neuroticism were high and differed (nonsignificantly) between men and women (1.00 and 0.58, respectively). When nonsignificant gender differences were removed from the models, correlations between generalized anxiety disorder and neurotic...

FEAR CONDITIONING, a basic form of associative learning, is a traditional model for the acquisition of fears and phobias.¹ Also, fear conditioning has long been an important experimental method for the study of etiologic processes related to fear and anxiety.² Behavioral treatment paradigms for anxiety disorders, such as exposure and response prevention, are based on the related processes of habituation and extinction. Habituation allows individuals to ignore innocuous events by producing a progressive decline in response to repeated presentations of a neutral stimulus via nonassociative learning. Fear conditioning occurs when fear is associated with a neutral (conditioned) stimulus (CS) after pairing with a fear-provoking (unconditioned) stimulus (UCS), eg, electric shock. The CS acquires the fear-provoking response attributes of the UCS. Extinction is the decremental response to further presentations of the CS after its pairing with the UCS is eliminated. Interestingly, fear conditioning is more easily acquired and less readily extinguished with evolutionarily fear-relevant (snakes and spiders) than fear-irrelevant (circles and triangles) stimuli.³