Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA

Abstract

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-Omethyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

“…These include polymorphisms or expression of BDNF (Krishnan et al, 2007), GABRA2 (Nelson et al, 2009), 5-HT1A receptors, dopamine or serotonin transporters (Segman et al, 2002;Kilpatrick et al, 2007;Stein et al, 2009;Wald et al, 2013), catechol-O-methyl transferase (COMT; Jabbi et al, 2007;Kolassa et al, 2010), glucocorticoid receptors and factors that modulate them such as FK506-binding protein (FKBP5;Binder et al, 2008;Derijk and de Kloet, 2008;McGowan et al, 2009;Sarapas et al, 2011), and methylation of corticotrophin-releasing factor (CRF) receptor DNA (Elliott et al, 2010). Several genetically distinct rodent lines are differentially resistant/vulnerable to the effects of stress (Razzoli et al, 2011;Savignac et al, 2011;Camp et al, 2012;Fuchsl et al, 2014).…”

Differential effects of COMT on gait and executive control in aging

“…Relevant to this investigation are studies that have begun to shed light on the epitasis between COMT and other genes in the context of phenotypes such as novelty seeking (Benjamin et al, 2000), extraversion (Golimbet, Alfimova, Gritsenko, & Ebstein, 2007) and the stress response (Jabbi et al, 2007). Moreover, a recent functional magnetic resonance imaging study of working memory revealed that the COMT Met homozygous genotype mediated against inefficient task related brain activations observed in the combined presence of glutamate receptor mgluR3 (GRM3) and the homozygous COMT Val genotype (Tan et al, 2007).…”

Interaction of Serotonin Transporter Gene-Linked Polymorphic Region and Stressful Life Events Predicts Cortisol Stress Response

“…For example, Jabbi et al (2007) and Gotlib et al (2008) found larger cortisol responses to a stressor in homozygous carriers of the S allele (Gotlib et al, 2008;Jabbi et al, 2007). We recently reported that newborns with two S alleles exhibit the highest cortisol response after a physical stressor (Mueller et al, 2010).…”