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.
Appropriate responsiveness to everyday-life stressors is crucial for adequate functioning in a natural environment.1 Conversely, depending on individual's genetic makeup, prolonged stress, coupled with inappropriate responsiveness, may lead to physiological and psychiatric disorders.1, 2, 3 Central to the stress responses are the activation of the cerebral noradrenergic system, the peripheral sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis,4 with corticotrophin-releasing hormone (CRH) being identified as a critical coordinator of these processes.5
Despite the evidence mounting for a major genetic contribution to psychopathology,6, 7, 8 attempts at directly linking genotypes to psychopathological states remain largely unsuccessful.6, 7, 8 At present, results from studies relating psychopathology with the three most tested common monoaminergic polymorphic variations in the serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) have led to inconsistent results.8, 9 One reason for this could be that most studies involve simple associations between ‘genetically complex’ psychiatric or behavioural phenotypes and single genetic variables whose individual roles may be minimal. However, there is a growing body of literature advocating the examination of gene–gene and gene–environment interactions, which are both believed to be additive and epistatic, making their inclusion in single studies relevant.6, 7, 8, 10
A large body of both clinical and preclinical studies supports a role of monoaminergic genes in psychopathology.5, 11 Studies examining functional polymorphic variations relating to monoamine degrading enzymes such as MAOA, COMT or the 5-HTT display alterations in emotional and physiological stress responses.11, 12, 13 The gene coding for MAOA is mapped to the short arm of the X chromosome, with a variable-number-tandem-repeat (VNTR) polymorphism in the promoter region of the MAOA.14 The polymorphism consists of 30-bp repeated sequence present in 2, 3, 3.5, 4, or 5 repeats (R), with the 3.5R or 4R, which together are called MAOA-H (high activity) transcribed 10 times more efficient than those with 2R, 3R or 5R also known as MAOA-L, (low activity) in MAOA functioning.15 On the other hand, a common functional polymorphism in the COMT gene, which is the result of a G to A mutation that translates into a valine (val) to methionine (met) substitution at codon 158, has been shown to account for a four-fold decrease in enzyme activity.8 Furthermore, the 5-HTT gene, located at 17q11.1–q12, plays a central role in the regulation of the serotonin synaptic function and is considered to be a promising candidate gene involved in various psychiatric disorders.16
Even though these monoaminergic genotypes are implicated in emotional regulation and psychopathology,8, 13, 17 there are virtually no reports of functional interactions between these genes and valid intermediate phenotypes of emotional disorders.6, 8, 18, 19 To test the hypothesis that allelic variations of MAOA, COMT and 5-HTT will collectively influence endocrine and behavioural response to psychosocial stress, we exposed 70 individuals with varying degree of susceptibility to major depression (MD) (as determined by their mental health status and familial loading; see also the methods section) to an acute psychological stress challenge in the laboratory.3, 6, 20 We next ask how these genes will affect HPA axis regulation to an endocrine challenge because due to the acute nature of our stress challenge, one can only interpret our findings as relating to the acute psychological stress. Instead of including a placebo day, we tested if these genotypes influence HPA axis reactivity to an endocrine challenge that is known to induce neuroendocrine states similar to stress-related clinical phenotypes; we exposed 64 individuals (most of whom also underwent the stress challenge) to the combined dexamethason and corticotrophin-releasing hormone (dex/CRH) challenge.21, 22, 23
Participants in this study were recruited from local and regional sources (North Netherlands Population Registration) as volunteers for the Neurobiological and Epidemiological cohort-study of Adolescents at Risk of Anxiety and Depression (ARIADNE).23, 24 For the psychological stress challenge, 70 participants took part in the laboratory stress challenge (see Supplementary Table S1). For the dex/CRH challenge, 64 individuals were included, a majority of whom were tested in the stress challenge (see Supplementary Table S2). The healthy controls, healthy high-risk probands (HRP) (i.e., subjects who have at least two first-degree relatives suffering from MD) and patients diagnosed with early onset of MD before the age of 30 years (mean age=20.14 years; ranging from 15 to 32) took part in the study (see Supplementary Table S1).
Psychiatric assessment was performed according to DSM IV revised, with life-time depression being determined with the Composite International Diagnostic Interview (CIDI) WHO-2000 version. The healthy controls and HRP individuals were free of medication and psychiatric/neurological disorders. MD patients were free of neurological disorders and under SSRI medication.
Subjects arrived at 12:30 for experimental sessions after completing the evaluations about 2 weeks before the study. For both the stress experiment and dex/CRH challenge, they were instructed to fast the morning of the experiment, and refrain from intensive physical exercise and use of alcohol 24 h before the experiment. Before the stress test, an intravenous catheter (saline drip) was inserted into an antecubital vein at approximately 1300. Subjects rested in a dental chair (semi-supine) for 45 min (min) watching a documentary film about Antarctica to acclimatise. Subjects were then exposed to the Groningen Acute Stress test (GAST). The GAST is a modified version of psychological stress task used earlier in a similar experimental setting.18, 25 Here we added a computer task in which participants could make financial gains in the first block, but would subsequently lose all their gained money or a substantial part of it in the second block, depending on their task performance.23 Subjective stress-experience scores during exposure to various stressors were acquired immediately after each stress task on a 10-point Likert scale: 1 signifying no stress experience at all and 10, extreme experience of distress. The procedure for the dex/CRH challenge was carried out as reported earlier.21, 22
Adrenocorticotrophin hormone (ACTH) plasma levels were assayed using the Nichols Advantage enzyme immunoassay for the 10 samples collected during different stress and rest conditions http://www.nicholsdiag.com/products. Plasma cortisol levels were assayed using a validated automatic analyser system (Elecsys 2010, Roche, Switzerland) whereby serum cortisol levels were determined by means of a specific and highly sensitive enzyme immunoassay.
Ten millilitres of EDTA anticoagulated blood was collected and centrifuged at 800 g for 10 min at 4°C. The Buffy coat was collected and stored at −20°C until DNA isolation. After thawing, DNA was isolated with the help of the Qiamp Mini Blood Kit (QIAGEN Benelux BV, Venlo, The Netherlands). Genotyping of the COMT val158met polymorphism (1947 G/A; GenBank Z26491; dbSNP: rs4680) was performed with the allelic discrimination technique on an Applied Biosystems 7500 real-time polymerase chain reaction (PCR) system (Applied Biosystems, Nieuwekerk a/d IJssel, The Netherlands) according to the protocol supplied by Applied Biosystems. We used primers COMT-GAF (5′-IndexTermCGAGATCAACCCCGACTGT-3′) and COMT-GAR (5′-IndexTermCAGGCATGCACACCTTGTC-3′), minor grove-binding probes VIC-5′-IndexTermTTTCGCTGGCGTGAAG-3′-NFQ (G) and FAM-5′-IndexTermTCGCTGGCATGAAG-3′-NFQ (A). Additionally, a TaqMan universal PCR master mix, supplied by Applied Biosystems, was also used.
MAOA genotyping was performed using blood samples as described previously.15 Some modifications in the methodological approach were made: we used 100–350 ng of DNA. AmpliTaq Gold polymerase (1 U, instead of 0.5 U) was used during PCR. Separation of PCR products through gel electrophoresis was done with the Spreadex EL-1200 gel, and the acquired base pairs were made visible using GelStar (SYBR-green).
5-HTT genotyping was carried out using anticoagulated blood according to the general procedures described previously.26 We used HTTp2A en HTTp2B primesets for the PCR analysis of 406/450 bp. Instead of 10 μl, we used 50 μl PCR reaction mix using DNA ranging from 100 to 350 ng. For the PCR reaction, an initial step of 12 min instead of 2 min was applied at 95°C, followed by 40 cycles of 30 s at 95°C, 30 s at 61°C, 60 s at 72°C with the end extension being 7 min at 72°C. Detection was performed on a 2% agarose gel containing 0.64 μg/ml ethidium bromide in TBE buffer using 50-bp ladder instead of 100 bp.
A χ2-test was used to associate genetic and demographic variables. Baseline values for each hormonal measure were analysed using the first blood samples for each variable: cortisol and ACTH. Additionally, mean scores for subjective stress experience were used using the reported stress experience after each stressor on a 10-point Likert scale. The Kolmogorov–Smirnov statistic was used to determine normality, allowing us to transform all non-normal measures to the logarithmic scale.
Stress-related hormonal measures are presented as percent of baseline (i.e., the original variable at each sampling point in time divided by the baseline mean and multiplied by 100 using SPSS 12.0.1 (Chicago, IL, USA).25 Out of the 10 blood-sampling points, the two samples collected during speech preparation/anticipation (SP) were averaged. A similar measure was adopted by averaging the last three samples collected during rest/recovery for a measure of the overall percentage change during recovery from stress, adding up to a total amount of six stress conditions (i.e., SP, public speaking (PS), mental arithmetic (MA), financial gain ‘gain’, financial loss ‘loss’ and recovery from stress). For the dex/CRH challenge in experiment 2, peak responses of cortisol and ACTH were assessed (i.e., sample 4 for ACTH and 5 for cortisol). Furthermore, the area under the curve (AUC) was calculated with trapezoidal approximation from logarithmic-transformed values for cortisol and ACTH.27
We included individuals with different degrees of MD susceptibility to test whether these differences will be predictive for any observed Gene by Endocrine response to acute psychological stress. Because our MD patients were all under SSRI treatment, we assessed the effects of positive MD diagnosis on our observed stress response by redefining our groups into two, i.e., those with a presence of MD diagnosis (patients) and those without MD diagnosis/treatment (healthy controls and HRPs). This new variable will be hereafter referred to as Diagnosis. We first tested if the groups differed in behavioural and endocrine responses to the experimental challenges and found no differences between the HRP and MD groups in all of our measured variables. This led to our redefinition of the three groups into a high (HRP and MD individuals)- and low-risk (healthy controls) groups, hereafter referred to as MDRisk.
An allelic variation of MAOA in terms of high expression MAOA variants as compared to the low expression variants was defined as described.15 Main effects of genotypes (5-HTT, COMT and MAOA), MDRisk, Sex and Diagnosis as well as their interactions on mean baseline peripheral endocrine measures, mean subjective stress scores and mean percentage change in endocrine stress response in all hormonal measures were analysed using the analysis of variance. Owing to the limited number of subjects included in our experiments for the purpose of examining gene–gene interactions, we focus our report on interaction between two variables (i.e., without looking at three-way interactions) and only results that survived multiple testing using the Bonferroni correction at P<0.05 are reported.
We tested for the significant association between the genetic and demographic variables and the only association we found was between MAOA and Sex (χ2=5.833, P=0.016, d.f.=1), with a higher frequency of male representation within the group carrying the low-activity MAOA, whereas high-activity allelic carriers were predominantly women (see Supplementary Table S1). Initially, we analysed the baseline measures and found an interaction between 5-HTT and MDRisk in baseline measures of cortisol (F=3.491, d.f.=2, P<0.039, Figure 1a), with the high-risk individuals that are homozygous for the long allele showing the highest levels of baseline plasma cortisol. Regarding the same finding in low-risk individuals, it was the short allelic load of the 5-HTT gene that led to higher baseline cortisol levels. An interaction between MAOA and Sex was found in baseline plasma cortisol measures (F=7.529, d.f.=1, P<0.009, Figure 1b), which shows female dominance in baseline plasma cortisol levels, but only within the group of high-expression MAOA variants. Additionally, an interaction between MAOA allelic variation and MDRisk was found in baseline ACTH measures (F=5.432, d.f.=1, P=0.024 Figure 1c) with the high-risk individuals showing higher baseline ACTH levels but only in individuals with the low-expression MAOA variation.
We rated participants' subjective experience to examine if the stress response during the psychological challenge significantly affected their experience of stress. An interaction between MAOA allelic variation and Sex was found regarding the reported stress experience during MA (F=10.993, d.f.=1, P<0.002, Figure 1d).
Endocrine regulation is central to the maintenance of homeostasis. Here, we tested the role of genes on peripheral cortisol and ACTH response to psychological stress. Most importantly, an interaction between the allelic variations of COMT and MAOA in percentage change in plasma ACTH response to PS (F=3.610, d.f.=2, P=0.035), MA (F=4.155, d.f.=2, P=0.022), gain (F=9.874, d.f.=2, P<0.0001), loss (F=5.692, d.f.=2, P<0.006) and during recovery (F=6.412, d.f.=2, P<0.004) (Figure 2a and 2b) was found. An interaction between 5-HTT and Sex was found in the percentage change in plasma cortisol response during PS and MA (F=3.604, d.f.=2, P=0.036; F=5.759, d.f.=2, P<0.006, respectively, Figure 2c). Additionally, a main effect of 5-HTT regarding percentage change in plasma ACTH response to PS (F=4.214, d.f.=2, P<0.024 and during MA (F=5.704, d.f.=2, P<0.007, Figure 2d) was found.
Regarding the sample of individuals that took part in the dex/CRH challenge, we found no associations between participants' genetic and demographic variables. A significant main effect of MAOA on cortisol peak response to the challenge was found (F=8.151, d.f.=1, P<0.007, Figure 3a). Additionally, a main effect of Sex was found in the ACTH peak response (F=4.850, d.f.=1, P=0.034, Figure 3b). Interestingly, we found a main effect of MAOA on the AUC response of cortisol during the endocrine challenge (F=10.31, d.f.=1, P<0.003, Figure 3c). A main effect of Sex in AUC response of ACTH was also found (F=7.443, d.f.=1, P<0.010, Figure 3d).
The ‘stress-diathesis’ theory of MD predicts the contribution of multiple factors to MD pathophysiology.28 The preclinical and clinical literature posits that adverse early-life experiences trigger MD onset, with the vulnerability or sensitisation playing out differently depending on the genetic constitution of the individual and environmental variables such as duration of the adverse experience and the availability of social buffering.3, 28 Here, we found a main effect of 5-HTT and an interaction between COMT and MAOA on plasma ACTH stress response.
Patients suffering from MD are known to exhibit hypersecretion of CRH, coupled with an elevated CRH concentration in the cerebrospinal fluid and a blunted ACTH response to exogenous CRH administration.1 By further examining the role of these genes in an endocrine challenge, which may be seen as a simulation of the intermediate endophenotypes of prolonged long-term stress experience,20 we found main effects of both Sex and MAOA in ACTH and cortisol responses to the dex/CRH challenge.
Our findings of Sex interactions with MAOA in baseline measures of cortisol and subjective experience during mental arithmetic may suggest a role of this genotype in sex-related differences in the prevalence of disorders like MD. With MAOA being an X-linked gene, however, such findings should be interpreted with caution. Additionally, Sex by 5-HTT interaction in cortisol response to psychosocial stress was made. Given the putative role of the SS-allelic variation of this genotype in MD susceptibility in the face of adversity, our findings of higher endocrine response in SS female individuals may also likely contribute to the sex-related differences in MD prevalence. Indeed, the same 5-HTT genotype also interacted with MD susceptibility in baseline measures of cortisol. Taken together, these findings suggest a role for these genotypes in the susceptibility to stress-related disorders like MD.
Activation of the HPA axis is an important adaptive mechanism that enables the maintenance of homeostasis. Additionally, reciprocal reverberatory neural connections as well as a functional relationship exist between the CRH and noradrenergic neurons of the central stress system.1 It has been shown that both CRH and noradrenergic neurons receive stimulatory innervations from serotonergic and cholinergic systems, inhibitory input from γ-aminobutyric acid-benzodiazepine and opioid peptide neuronal systems of the brain as well as from the end-product of the HPA axis, the glucocorticoids.1 Taken together, our findings of a main effect of 5-HTT, on the one hand, suggest a functionally unique role of the serotonergic system in the HPA axis functioning that might be mediated by CRH. Furthermore, our only observed stress-related gene–gene interaction between these genotypes in HPA axis (i.e., ACTH) response to stress may suggest an important contribution of catecholamines in the regulation of homeostasis and maintenance of health.
Glucocorticoids play an important role in the regulation of basal activity of the HPA axis, as well as in the termination of the stress response, by acting at the extra-hypothalamic centres, the hypothalamus and pituitary gland.1, 28 Thus, the negative feedback of glucocorticoids on the secretion of CRH and ACTH serves to limit the duration of the total tissue exposure of the organism to glucocorticoids, minimizing catabolic, lipogenic, antireproductive and immunosuppressive effects of these hormones.1 Our finding of significant main effects of MAOA, showing that individuals carrying the low-expression variants are less able to achieve adequate negative feedback of the HPA axis response to the endocrine challenges, resulting in lower glucocorticoid response to the dex/CRH challenge, suggests that this allelic variation may play a role in aberrant HPA axis response to environmental challenges. Interestingly, this finding is in line with a recent report showing low-expression variants of the BDNF gene leading to similar HPA axis response to the dex/CRH challenge in severely depressed.22 Earlier, polymorphic variations in the COMT gene have been shown to predict brain response to negative emotional and painful stimuli12, 13 as well as HPA axis response to various endocrine challenges as a function of COMT or GABA polymorphic variations.25
Earlier, it was shown that COMT may mediate HPA axis functioning.23, 29 MAOA allelic variation, on the other hand, specifically the low-expression MAOA variant, has been implicated in complex phenotypic variables such as aggression, impulsivity and violent behaviour,7, 8 and both COMT and MAOA genotypes have been associated with psychiatric samples and treatment response to antidepressants.8 Longitudinal studies showed that patients with persistent HPA axis disturbance responded poorly to treatment and when remitted, still maintain a high risk of relapse.20 Our findings of a main effect of 5-HTT and an interaction between COMT and MAOA in HPA axis-regulated endocrine stress response to psychological stress, whereby COMT-mediated stress response seemed to be determined by individual's MAOA genotype, were in line with our findings of a functional influence of MAOA on endocrine response to the dex/CRH challenge. Together, these findings indicate an involvement of these common monoaminergic genes in the modulation of peripheral endocrine regulation. Such a system may be relevant for the maintenance of homeostasis and, thereby, physical and mental well-being.
The monoamine hypothesis of depression was based upon the postulated deficiency or imbalance in noradrenalin or serotonin.11 However, hyperactivity in the HPA axis in MD patients has been shown to be affected by long-term antidepressant treatment.5, 11 Our current findings of a COMT by MAOA interaction as well as a main effect of 5-HTT on HPA axis response to psychological stress are in line with the evidence that attenuation of HPA axis activity is a direct pharmacological effect of antidepressants.5, 11 Our findings of a strong genetic modulation of ACTH and not cortisol in response to stress may relate to the possibility that ACTH is more sensitive to the stress experience because of the direct influence of the hypothalamus on the secretion of ACTH which, in turn, triggers cortisol secretion.30 One explanation for our not finding a significant interaction between 5-HTT and other genes could be the fact that NE and their metabolising enzymes are present in different cellular compartments. So the catecholamines could be affected by intercellular actions of either MAOA or COMT separately or in combination, whereas serotonin degradation by MAOA is confined to cells expressing 5-HTT.31 In sum, despite the acute nature of our stress challenge, it is likely that a combination of these low-activity variants of COMT and MAOA genes may become a vulnerability trait if stressful experiences persist.
Here, the sample used is rather small given the goals making the need for a replication with a larger sample size highly necessary to further allow the assessment of complex genetic contributions without compromising statistical power.8, 10, 25 In conclusion, we analysed the effects of monoamine-associated genes on endocrine and psychological stress challenges. Our findings successfully demonstrated the potential of investigating complex genetic response to valid disease pathways. If replicated, our findings of significant gene–gene interactions – whereby no marked response related to the COMT genotype in terms of peripheral endocrine response to psychological stress in individuals who are carriers of the high-expression MAOA variation – supported by a stronger role of the MAOA genotype in HPA axis response to an endocrine challenge, may lead to beneficial therapies for stress-related disorders.
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This work is funded by an NWO grant number 904-53-092. We especially thank Christian Keysers for valuable comments on earlier versions of the manuscript. We thank Iteke te Riet, Ruud Delissen and Roelie Nijzing for professional assistance, Magdalena Hubert, Astrid Brugman, Erik Nijboer, Janneke (DAJ) Dijck Brouwer, Henk Breukelman, Jan Koerts and colleagues for genotyping and endocrine analysis, our Ariadne colleagues for the HRP group selection, and Harm Jan Pot, Enno Hebekotte and Ernst Horwitz of the psychiatry department and our colleagues from GGZ Zuid and GGZ Stadskanaal for patient information. We acknowledge the individual participants and their families. We acknowledge Joop Clots, Ben Mulder and colleagues of the social sciences faculty for technical assistance.
MJ, GvdP and IPK designed research. MJ performed research. IPK contributed reagents and performed genotyping. MJ and JK analysed the data. MJ wrote the paper with contributions of JK, IPK, CH, RBM, JO and JAdB.
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Jabbi, M., Korf, J., Kema, I. et al. Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA. Mol Psychiatry 12, 483–490 (2007). https://doi.org/10.1038/sj.mp.4001975
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