The 5-HTT gene (SLC6A4) is regulated by a common polymorphism in the promoter region (5-HTTLPR), which has functional consequences. Two major alleles have been observed and shown to have differential transcriptional activity with the long (L) allele having greater gene expression than the short (S) allele. 5-HTTLPR appears to modulate depression, anxiety and personality traits such as neuroticism. Additionally, a significant influence of 5-HTTLPR genotype on amygdala reactivity in response to fearful stimuli has been reported. Moreover, 5-HTTLPR seems to impact on the role of stressful life events (SLEs) in the development of depression. An elevated risk of depression and suicidal behaviors has been found in carriers of at least one low expressing S allele who had experienced SLEs, suggesting a gene x environment interaction. However, a recent meta-analysis showed that several findings failed to replicate this finding. Since genetic polymorphisms of the dopaminergic and serotonergic neurotransmission interact at the molecular, analyses with another polymorphism of the dopaminergic system, the dopamine D4 receptor (DRD4) was included to consider these likely gene-gene interactions (epistasis). The aim of this series of studies was to investigate the role 5-HTTLPR and SLEs on the endocrine stress response in different age samples. While newborns have been examined by a heel prick, stress responses were provoked in children (8-12 yrs) and younger adults (19-31 yrs) and older adults (54-68 yrs.) with the Trier Social Stress Test (TSST). The Life History Calendar (LHC) and Life Events Questionnaire (LEQ) were used to acquire data on SLEs. While in newborns the S/S genotype showed a significantly higher acute endocrine stress response than L/L or S/L genotypes, no significant difference between genotype groups was found in children. In the younger adult sample, the genotype impacted on cortisol stress responsiveness was reversed. Adults carrying the more active L allele of the 5-HTTLPR polymorphism showed a significantly larger cortisol response to the TSST than individuals carrying at least one of the lower expressing S allele. In older adults, no significant difference between genotype groups was found. However, results point in the same direction with showing highest cortisol response in individuals with L/L genotype. These data suggest that the association between 5-HTTLPR and endocrine stress reactivity seems to alter across lifespan, more specific the effects of genotype turns around. In addition, a significant interaction effect of 5-HTTLPR and SLEs has been found in the sample of younger adults, i.e. that early SLE as well as a severe number SLEs across the entire lifespan seem to modulate the interaction between HPA axis activity and 5-HTTLPR genotype. Additionally, a DRD4 by 5-HTTLPR interaction emerged which point to independent and joint effects of these polymorphisms on stress responsivity with regard to the concept of genegene interaction.

Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

The 5-HTT gene (SLC6A4) is regulated by a common polymorphism in the promoter region (5-HTTLPR), which has functional consequences. Two major alleles have been observed and shown to have differential transcriptional activity with the long (L) allele having greater gene expression than the short (S) allele. 5-HTTLPR appears to modulate depression, anxiety and personality traits such as neuroticism. Additionally, a significant influence of 5-HTTLPR genotype on amygdala reactivity in response to fearful stimuli has been reported. Moreover, 5-HTTLPR seems to impact on the role of stressful life events (SLEs) in the development of depression. An elevated risk of depression and suicidal behaviors has been found in carriers of at least one low expressing S allele who had experienced SLEs, suggesting a gene x environment interaction. However, a recent meta-analysis showed that several findings failed to replicate this finding. Since genetic polymorphisms of the dopaminergic and serotonergic neurotransmission interact at the molecular, analyses with another polymorphism of the dopaminergic system, the dopamine D4 receptor (DRD4) was included to consider these likely gene-gene interactions (epistasis). The aim of this series of studies was to investigate the role 5-HTTLPR and SLEs on the endocrine stress response in different age samples. While newborns have been examined by a heel prick, stress responses were provoked in children (8-12 yrs) and younger adults (19-31 yrs) and older adults (54-68 yrs.) with the Trier Social Stress Test (TSST). The Life History Calendar (LHC) and Life Events Questionnaire (LEQ) were used to acquire data on SLEs. While in newborns the S/S genotype showed a significantly higher acute endocrine stress response than L/L or S/L genotypes, no significant difference between genotype groups was found in children. In the younger adult sample, the genotype impacted on cortisol stress responsiveness was reversed. Adults carrying the more active L allele of the 5-HTTLPR polymorphism showed a significantly larger cortisol response to the TSST than individuals carrying at least one of the lower expressing S allele. In older adults, no significant difference between genotype groups was found. However, results point in the same direction with showing highest cortisol response in individuals with L/L genotype. These data suggest that the association between 5-HTTLPR and endocrine stress reactivity seems to alter across lifespan, more specific the effects of genotype turns around. In addition, a significant interaction effect of 5-HTTLPR and SLEs has been found in the sample of younger adults, i.e. that early SLE as well as a severe number SLEs across the entire lifespan seem to modulate the interaction between HPA axis activity and 5-HTTLPR genotype. Additionally, a DRD4 by 5-HTTLPR interaction emerged which point to independent and joint effects of these polymorphisms on stress responsivity with regard to the concept of genegene interaction.