By rodent studies it has been shown that the mineralocorticoid receptor (MR) is a candidate gene for the investigation of cognitive functions comparable to human executive function. The present work addresses the question if polymorphisms in the MR gene can act as a "probe" to explain a part of the interindividual variance of human executive functions. For this purpose, 72 healthy young participants were assigned to four equally sized groups, concerning their particular MR genotype for two common MR polymorphisms. They were investigated in an electroencephalogram (EEG) test session, accomplishing two cognitive tests while delivering saliva samples for subsequent cortisol measures. The two tests chosen for the assessment of executive functions were the Attention Network Task (ANT) and a modified version of the Wisconsin Card Sorting Test (WCST).Chapter 1 of the present work reports of the rational bases for the empirical approach, which were built up on a broad theoretical background presented in Chapter 2. In the third chapter, the investigation and results of the statistical analysis for behavioral data (i.e. reaction times, accuracy/error rates) are presented. No association with MR polymorphisms was found for the reaction times of both tests. For the accuracy rate, differences between genotype groups were found for ANT and WCST, indicating an association of MR polymorphisms and accuracy in the Alertness and Executive Control network of the ANT and during the detection of an intradimensional shift in the WCST. Data acquisition and the results for EEG data analyses are presented in Chapter 4. The results show that groups differing for MR genotype show different activity over prefrontal motor areas during the process of answering to the ANT. Those group differences again were prominent for the Alertness and Executive Control network. A tendency for further significant group differences was found for activity on frontopolar positions in extradimensional rule switching. Chapter 5 summarizes the findings for the analysis of salivary free cortisol, showing a tendency for an association between MR polymorphisms and a mildly stimulated Hypothalamus-pituitary-adrenal (HPA) axis during the test situation. The results of the different measures are integrated and discussed in Chapter 6 within the scope of novel findings in investigating the functionality of the chosen MR polymorphisms. Finally, Chapter 7 gives an outlook on the methodology and constraints of future research strategies to further describe the role of the MR in human cognitive function.
Hypothalamic-pituitary-adrenal (HPA) axis-related genetic variants influence the stress response
(2019)
The physiological stress system includes the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary system (SAM). Parameters representing these systems such as cortisol, blood pressure or heart rate define the physiological reaction in response to a stressor. The main objective of the studies described in this thesis was to understand the role of the HPA-related genetic factors in these two systems. Genetic factors represent one of the components causing individual variations in physiological stress parameters. Five genes involved in the functioning of the HPA axis regarding stress responses are examined in this thesis. They are: corticotropin-releasing hormone (CRH), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the 5-hydroxytryptamine-transporter-linked polymorphic region (5-HTTLPR) in the serotonin transporter (5-HTT) and the brain-derived neurotrophic factor (BDNF) gene. Two hundred thirty-two healthy participants were genotyped. The influence of genetic factors on physiological parameters, such as post-awakening cortisol and blood pressure was assessed, as well as the influence of genetic factors on stress reactivity in response to a socially evaluated cold pressor test (SeCPT). Three studies tested the HPA-related genes each on three different levels. The first study examined the influences of genotypes and haplotypes of these five genes on physiological as well as psychological stress indicators (Chapter 2). The second study examined the effects of GR variants (genotypes and haplotypes) and promoter methylation level on both the SAM system and the HPA axis stress reactivity (Chapter 3). The third study comprised the characterization of CRH promoter haplotypes in an in-vitro study and the association of the CRH promoter with stress indicators in vivo (Chapter 4).
Psychiatric/Behavioral disorders/traits are usually polygenic in nature, where a particular phenotype is the manifestation of multiple genes. However, the existence of large families with numerous members who are affected by these disorders/traits steers us towards a Mendelian (or monogenic) possibility, where the phenotype is caused by a single gene. In order to better understand the genetic architecture of general psychiatric/behavioral disorders/traits, this thesis investigates large pedigrees that display a Mendelian pattern for attention-deficit/hyperactivity disorder, schizophrenia and bipolar disorder. Numerous challenges in the field of psychiatric and behavioral sciences have impeded the genetic investigation of such disorders/traits. Examples include frequent cross-disorders, genetic heterogeneity across subjects as well as the use of diagnostic tools that can be subjective at times. To overcome these challenges, this thesis investigates large multi-generational pedigrees, which comprise a significant number of members who exhibit specific psychiatric/behavioral phenotypes. These pedigrees provide high-resolution experimental setups that can dissect the genetic complexities of psychiatric/behavioral disorders/traits. This thesis adopts a classical two-stage genetic approach to investigate the various psychiatric/behavioral disorders/traits in large pedigrees. The classical two-stage genetic approach is commonly used by many human geneticists to study a wide spectrum of human physiological disorders but is only being applied to the field of psychiatric and behavioral genetics recently. Through the study of large pedigrees, this thesis discovers the genomic regions that may play a causative role in the expression of certain psychiatric/behavioral disorders/traits within the vast genome.