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.

Obsessive-compulsive disorder (OCD) is heterogeneous. Clinical presentation of OCD differs by sex and age-of-onset and evidence supports classification based on these subtypes. The prevalence of OCD in the general population is 2%. However, it has been established that women tend to experience onset and exacerbation of OCD during reproductive milestones. In particular, the prevalence of postpartum OCD is between 4 to 9%. This study seeks to examine the effects of past childhood maltreatment and S/Lg-allele status of the 5-HTTLPR polymorphism on perinatal obsessive-compulsive symptoms and aberrant resting state functional connectivity in the postpartum period. Forty women participated in the first visit and sixteen women have been followed up with in the postpartum period. 5-HTTLPR genotype was determined from whole blood samples via polymerase chain reaction and a restriction fragment length digest. We used the Yale-Brown Obsessive-Compulsive Scale and Perinatal Obsessive-Compulsive scale to measure symptom severity. Resting state functional connectivity was determined from functional magnetic resonance imaging data. Obsessive-compulsive symptoms during late pregnancy are significantly predicted by 5-HTTLPR genotype, past history of total childhood maltreatment or childhood emotional neglect and trait anxiety symptoms. Whereas obsessive-compulsive symptoms during the postpartum period are predicted by poor sleep quality and childhood emotional maltreatment or 5-HTTLPR genotype, childhood emotional maltreatment and trait anxiety symptoms. Seed to region-of-interest analysis was employed to evaluate resting state functional connectivity differences between OCD patients and healthy controls in the postpartum period. Compared to healthy controls, OCD patients show greater connectivity between the caudate nucleus with the orbitofrontal cortex, the pars triangularis and the cingulate area. The insular cortex shows decreased connectivity between the right and left, the dorsal anterior cingulate area and the pars opercularis. The amygdala has increased connectivity with the cingulate area, the calcarine fissure, the supramarginal gyrus and decreased connectivity with the gyrus rectus. The above clinical and neuroimaging findings are in line with past work. However, this is the first study to show both 5-HTTLPR genotype and history of childhood maltreatment predict obsessive-compulsive symptoms in a perinatal population. Further, the resting state data replicates findings in the OCD literature but the study is the first to show this in postpartum women. This study serves as a platform for future work to further investigate both gene-environment interactions and distinct neuroimaging correlates in perinatal OCD. / Thesis / Master of Science (MSc)

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.