Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders

Abstract

Anxiety sensitivity (AS) is a dispositional characteristic that predisposes to the development of anxiety disorders (eg, panic and posttraumatic stress disorder) and major depression. AS is subject to genetic and environmental influences, the former as yet unidentified and the latter known to include childhood maltreatment. The serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) has been associated with depression, but most consistently in the context of environmental stress. We tested the hypothesis that 5-HTTLPR genotype and childhood maltreatment would interact to increase susceptibility to AS in young adults. Subjects were European-American college undergraduates (N ¼ 150, median age 18 years) characterized on a measures of AS (Anxiety Sensitivity Index) and retrospective childhood maltreatment (Childhood Trauma Questionnaire [CTQ]). 5-HTTLPR genotypes were obtained from blood-derived DNA. Linear regression was used to model relationships between 5-HTTLPR, childhood emotional abuse, and AS; covariates such as sex, neuroticism, and ancestral proportion scores were incorporated into some models in a larger, ethnically heterogenous sample (N ¼ 247) to evaluate robustness of the findings to model assumptions. A statistically signficant interaction was observed between levels of childhood emotional (or physical) maltreatment and 5-HTTLPR genotype. Specifically, S/S individuals with higher levels of maltreatment had significantly higher levels of AS than subjects in other groups. No such relationship was found for neuroticism, attesting to the possible specificity of the findings for AS. Findings were consistently robust to the inclusion of covariates, and were not confounded by population stratification. In conclusion, these results provide evidence of a specific genetic influence on anxiety sensitivityFan intermediate phenotype for anxiety (and depressive) disorders; this effect is modified by severity of childhood maltreatment. These findings are consistent with the notion that 5-HTTLPR operates broadly to moderate emotional responsivity to stress.

Longitudinal genetic analysis of anxiety sensitivity.

“…Interestingly, previous research has found evidence to suggest that geneenvironment interactions are present in the development of anxiety sensitivity (Stein, Schork and Gelernter, 2008). Specifically, the effect of childhood maltreatment on anxiety sensitivity was found to be moderated by variation in the serotonin transporter gene (5HTTLPR).…”

Future Directions in Emotion Dysregulation and Youth Psychopathology

“…For example, although impulsive male individuals who are reared in protective environments are likely to exhibit only ADHD (Beauchaine, Hinshaw, & Pang, 2010;Beauchaine & McNulty, 2013), their impulsivity often progresses to more serious externalizing conduct if they are reared in high-risk environments characterized by coercive parenting (e.g., Patterson, DeGarmo, & Knutson, 2000), coercive and deviant peer group affiliations (e.g., Dishion & Hiatt Racer, 2013;Snyder et al, 2008), and neighborhood violence and criminality (e.g., Meier, Slutske, Arndt, & Cadoret, 2008). Similarly, environmental risk, including child maltreatment and exposure to protracted stress, increase the likelihood of emerging anxiety and depressive disorders among those with specific genetic vulnerabilities, such as the short allele of the serotonin transporter and certain glucocorticoid polymorphisms (see, e.g., Beauchaine, Crowell, & Hsiao, 2015;Nugent, Tyrka, Carpenter, & Price, 2011;Stein, Schork, & Gelernter, 2008). 2 …”

Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats.

“…A comparable gene by environment interaction involving the SLC6A4 gene that codes for the 5-HTT is apparent in the effects of childhood maltreatment on the risk for depression in humans (Caspi et al, 2003;Stein, Schork, & Gelernter, 2008).…”