1. ¹Department of Psychiatry, University Medical Centre Groningen (UMCG), Groningen, The Netherlands
2. ²UMCG Groningen, BCN NeuroImaging Centre, Antonius Deusinglaan 2, Groningen, The Netherlands
3. ³Department of Pathology and Laboratory Medicine, University Medical Centre Groningen (UMCG), Groningen, The Netherlands
4. ⁴Department of Adolescent and Child psychiatry, University Medical Centre Groningen (UMCG), Groningen, The Netherlands

Correspondence: Dr M Jabbi, Department of Psychiatry, University Medical Centre Groningen (UMCG), Hanzeplein 1, Postbus, 30.001, 9700 RB Groningen, The Netherlands. E-mail: m.jabbi@med.umcg.nl

Received 27 November 2006; Accepted 17 December 2006; Published online 6 March 2007.

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-O-methyl 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.