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ABSTRACT: Dopamine and norepinephrine are key regulators of cognitive and affective processes. The enzyme catechol-O-methyltransferase (COMT) catabolizes catecholamines and the COMT Val158Met polymorphism has been linked to several neuropsychiatric variables. Additionally, stressful life events (SLEs) contribute substantially to affective processes. We used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the effects of COMT and SLEs on the cortisol response in 119 healthy children (8-12 yr). Saliva cortisol was measured during and after the Trier Social Stress Test for Children. SLEs were assessed with a standardized interview with one of the children's parents. Linear regression analysis revealed a significant effect for COMT, with Met allele carriers showing a higher cortisol response (β=0.300, p=0.001). In turn, more SLEs lead to a less pronounced cortisol increase (β=-0.192, p=0.029) probably indicating increased resilience. Our results further underscore the essential and differential role of genetic variation and environmental factors on stress responsivity.
The International Journal of Neuropsychopharmacology 12/2011; 15(9):1229-39. · 4.58 Impact Factor
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ABSTRACT: Identification of genetic factors that influence stress reactivity is important in order to link environmental demands, particularly adversity to disease outcome. There is ample literature on genetic contribution to the endocrine stress response, while evidence for genetic contribution to individual differences in autonomic nervous system function is sparse and produced conflicting results. Here, we investigated the influence of two polymorphisms in the Catechol-o-methyltransferase (COMT) and serotonin transporter (5-HTT; SCL6A4) gene. We examined the autonomic stress response to the Trier Social Stress Test for Children in 115 children. Salivary α-amylase (sAA) was obtained prior to the stressor and repeatedly during recovery as a marker of autonomic reactivity. Furthermore, heart rate (HR) and heart rate variability (HRV) were monitored continuously. We found differences in ANS stress response associated with each polymorphism (all p<.05). Children with the L variant of 5-HTTLPR showed a higher increase and sharper recovery of sAA in response to stress than those with S variants. For HR, we found differences associated with COMT, i.e. children carrying at least one met allele showed lower mean HR increase and slower HR recovery in response to the stressor compared to those with two val alleles (p<.001) as well as a significant decrease in heart rate variability (p<.05). Our findings indicate that these two polymorphisms do indeed influence the ANS response to stress. This study provides further evidence for the crucial role of genetic factors in the modulation of differences in the acute stress response during childhood.
International journal of psychophysiology: official journal of the International Organization of Psychophysiology 11/2011; 83(3):302-8. · 3.05 Impact Factor
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ABSTRACT: There has been significant controversy whether stressful life events (SLEs) experienced over the lifespan may elevate the risk of depression in individuals who are homozygous for the short (S) allele of the repeat length polymorphism (5-HTTLPR) in the regulatory region of the serotonin transporter gene (SLC6A4), compared with individuals homozygous for the long (L) allele. On the basis of the hypothesis that age may be a critical variable, by which such a gene-by-environment interaction may be present in younger adults, but not in older adults and in children, aim of this study was to investigate the role of 5-HTTLPR and SLEs on the endocrine stress response in multiple age cohorts. A total of 115 children (8-12 years), 106 younger adults (18-31 years), and 99 older adults (54-68 years) were subjected to the Trier Social Stress Test (TSST) and structured interviews on SLEs. The TSST induced significant endocrine stress responses in all groups. There was a main effect of genotype in younger and older adults with individuals homozygous for the more active L allele showing a significantly larger cortisol response to the TSST than individuals carrying at least one of the low-expressing S alleles. As predicted, there was a significant interaction of 5-HTTLPR genotype and SLEs, but this interaction was only significant in younger adults and only when the measured SLEs had occurred during the first 5 years of life, suggesting that both age and the specific type of SLE has a role in whether a significant gene-environment interaction is observed.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2011; 36(7):1332-9. · 6.99 Impact Factor
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ABSTRACT: Considerable variability in the activity of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress has been found in quantitative genetic studies investigating healthy individuals suggesting that at least part of this variance is due to genetic factors. Since the HPA axis is regulated by a neuronal network including amygdala, hippocampus, prefrontal cortex as well as brainstem circuits, the investigation of candidate genes that impact neurotransmitter systems related to these brain regions might further elucidate the genetic underpinnings of the stress response. However, aside from genetic risk factors, past stressful life events might also result in long-term adjustments of HPA axis reactivity. Here, we investigated the effects of the -1019 G/C polymorphism in the HTR1A gene encoding the serotonin (5-HT) receptor 1A (5-HT(1A)) and stressful life events experienced during childhood and adolescence on changes in cortisol levels in response to the Trier Social Stress Test (TSST) in a sample of healthy older adults (N=97). Regression analyses revealed a significant effect of HTR1A genotype with the G allele being associated with a less pronounced stress response. In addition, an inverse relationship between past stressful life events and cortisol release but no gene × environment interaction was detected. The results further underscore the crucial role of functional serotonergic genetic variation as well as stressful events during critical stages of development on the acute stress response later in life.
Hormones and Behavior 03/2011; 60(1):105-11. · 3.87 Impact Factor
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ABSTRACT: The dopamine transporter (DAT) and the enzyme catechol-O-methyltransferase (COMT) both terminate synaptic dopamine action. Here, we investigated the influence of two polymorphisms in the respective genes: DAT1 (SLC6A3) VNTR and COMT val(158)met (rs4680). Startle magnitudes to intense noise bursts as measured with the eye blink response were recorded during the presentation of pictures of three valence conditions (unpleasant, pleasant and neutral) and during baseline without additional pictorial stimulation in a sample of healthy older adults (N = 94). There was a significant Bonferroni corrected main effect of COMT genotype on the overall startle responses, with met/met homozygotes showing the highest and participants with the val/val genotype showing the lowest startle response, while participants with the val/met genotype displayed intermediate reactions. There was also a DAT1 VNTR main effect, which, after Bonferroni correction, still showed a tendency toward significance with carriers of at least one 9-repeat (R) allele showing smaller overall startle responses compared to 10R/10R homozygotes. Thus, older adult carriers of COMT variants, which result in lower enzyme activity and therefore probably enhanced dopamine signaling, showed stronger startle activity. Although the functional significance of DAT1 VNTR is less defined, our results point to a potential influence of SLC6A3 on startle magnitude.
Acta Neurovegetativa 03/2011; 118(9):1281-92. · 2.73 Impact Factor
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ABSTRACT: tract Salivary alpha-amylase (sAA) increases rapidly in response to psychosocial stress in young adults, but no direct comparisons between different age groups across the life span have been made. Secretion of sAA and cortisol was assessed in children, young adults, and older adults after exposure to the Trier Social Stress Test. Additionally, cardiovascular activity was measured in both adult groups. Older adults showed attenuated sAA, heart rate (HR), and heart rate variability (HRV) responses. Furthermore, we found higher sAA but lower cortisol at baseline as well as lower sAA and cortisol responses in children. Age x sex interactions were observed only for cortisol with higher responses in older male participants. No associations between the parameters were found. These results implicate sAA as an alternative or additional sympathetic stress marker throughout the life span, with marked and rapid stress responsiveness in three relevant age groups.
Psychophysiology 05/2010; 47(3):587-95. · 3.29 Impact Factor
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ABSTRACT: Serotonin, a key regulator of emotional behavior, is synthesized by tryptophan hydroxylase (TPH). Allelic variation of TPH2 gene expression influences serotonin synthesis in the brain and therefore may modulate emotional processing. Here, we investigated the influence of the -703 G/T polymorphism in the regulatory promoter region of the TPH2 gene on the startle response in three different age samples: children (N=110), young adults (N=209), and older adults (N=95). Startle magnitudes to intense noise bursts were recorded during baseline and while participants viewed unpleasant, pleasant or neutral pictures. There was a significant TPH2xsex interaction effect in young adults with male T allele carriers showing stronger overall startle responses compared to male G/G homozygotes while in young women this effect appeared to be reversed. The difference between TPH2 genotype groups also reached significance in the female subsample when including menstrual cycle phase. In contrast, there was no effect of TPH2 or a TPH2xsex interaction effect in children or in older adults.
Biological psychology 03/2010; 83(3):214-21. · 4.36 Impact Factor
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ABSTRACT: A functional polymorphism in the 5′flanking region of the serotonin transporter gene (17q11.2, 5-HTTLPR) alters the transcription of the 5-HT transporter gene and seems to be associated with depression and anxiety-related personality traits in humans. This effect appears to be the most pronounced in individuals who are homozygous for the low-expressing “S” allele who have experienced significant critical life events in the past. Animal studies now link this polymorphism to an increased stress reactivity of the hypothalamus–pituitary–adrenal (HPA) axis. In humans, it remains unknown whether this polymorphism by itself affects HPA axis or only in interaction with environmental factors. The aim of the present study was to investigate the role of the 5-HTTLPR polymorphism for the HPA axis in humans early in the development at a time when individuals were exposed to very few or no early adverse experiences so far.We genotyped DNA for the 5-HTTLPR polymorphism including the A/G single-nucleotide polymorphism (SNP) in 126 three-day old newborns. The newborn's stress response was stimulated by a heel prick which is a part of a routine medical procedure. The heel prick induced a significant biological (i.e., cortisol) stress response in all newborns. Newborns with the “S/S” genotype showed a significantly higher endocrine response in comparison to newborns with “L/L” or “S/L” genotype.In this sample of newborn babies, the 5-HTTLPR genotype affected the HPA stress response to painful stimulation irrespective of additional influence of pre- or perinatal environmental factors we measured.
Psychoneuroendocrinology.
