met/met genoptye seem to profit less from exposure-based CBT treatment than val-carriers.
It is possible, that patients with the met/met genotype may be generally less responsive to treatment as compared to non-carriers irrespective of the underlying disease.
while no differences in constitutive secretion have been observed 250, 251. The region of the pro-domain containing the BDNFval66met SNP seems to be of importance for the regulated secretion of BDNF (see also 1.7.1) and the met-variant likely leads to inefficient trafficking of BDNF to secretory granules for a review see e.g., 249. It has been suggested that the met-variant leads to impaired binding to sortilin (see also 1.7.1) which may be the underlying mechanism 250.
The met allele is the minor allele with a frequency of approximately 20-30% in caucasians, with pronounced differences between ethnic groups 252. Homozygous met-carriers comprise as little as 4% of the caucasian population and therefore most studies so far have a priori combined carriers of one or two met-alleles to a met-carrier group.
As this group commonly contains only very few homozygous individuals, little data exist on a possible allele load or heterosis effect. Even though the literature may suggest a specific effect in met-carriers, only conclusions about a difference between heterozygous and those homozygous for the val-allele can be drawn.
In the following sections, the relevant literature on behavioral, imaging and psychiatric genetics will be summarized, focusing on human data.
1.7.3 Associations studies of the BDNFval66met
Alterations in brain maturation and development, in concert with plastic changes induced by environmental events may contribute to altered processing of emotional information and learning. BNDF is a regulatory factor that affects these neuronal processes in an activity-dependent manner and thus, genetic variation in the BDNF gene including its pro-domain has the potential to significantly affect these processes.
Behavioral Genetics
The involvement of BDNF in hippocampus-dependent cognitive learning and memory has been known from studies in both rodents 253 and humans 251, 254. More recently, a similar role for BDNF in amygdala-dependent learning processes like Pavlovian fear conditioning has been shown in rodents using pharmacological and genetic approaches
255-257
. Furthermore, it has been shown that prelimbic cortical BDNF is required for the memory of learned fear but not innate fear or extinction 258.
Due to its critical involvement in the molecular processes underlying amygdala-dependent learning, BDNF has been suggested to e a critical modulator of emotional memory formation.
In humans, an association has been reported, between the met-allele of the BDNFval66met and deficient as FPS in a conditioned fear generalization paradigm 259. Furthermore, we report deficient fear conditioning as measured by FPS but not SCR (Study II). However, a third study found deficient fear extinction in animals and humans to be associated with the met-allele but did not find an effect on the acquisition of fear as measured by SCR and fMRI 260.
Furthermore, several studies have been published on an association of the BDNFval66met polymorphism with anxiety-related personality traits (e.g. neuroticism or harm avoidance). In sum, findings in personality genetics are inconclusive and contradictory. Still, a recent metaanalysis supports an association of the BDNF met-allele with lower neuroticism scores 261.
Psychiatric Genetics
The human BDNF gene has been suggested to be a candidate gene for a variety of neuropsychiatric disorders including mood disorders 262, 263, schizophrenia 264 and eating disorders 265. A recent metaanalyis yields support from case-control studies for an association of the BDNFval66met polymorphism with substance-related disorders (met-carriers), eating disorders (val/val) and schizophrenia (met/met) 266 while no association was found with anxiety disorders 261.
Furthermore, evidence from both human and animal studies has suggested a critical involvement of BNDF in the therapeutic mechanisms of antidepressive treatments for a review see e.g., 267, but a recent study did not find supporting evidence for this in depressive patients 268.
Imaging Genetics
Few imaging genetics studies have investigated the BDNFval66met polymorphism as compared to the wealth of data available for the 5-HTTLPR or the COMTval158met polymorphism.
One of the most reliable effects observed in morphometric studies is smaller hippocampal volumes in carriers of the BDNF met-allele 269-271, extending into the parahippocampal gyrus and the amygdala 272. In line with this, functional imaging studies have shown that carriers of the BDNF met-allele perform more poorly and display less hippocampus activation than homozygous val/val individuals in memory tasks relying on the hippocampus 251, 254. Recently also differential amygdala reactivity to affective pictures has been shown with met-carriers displaying enhanced amygdala reactivity 273.
Very recently, an fMRI study on the role of the BDNFval66met polymorphism in fear conditioning and extinction was published 260. This study resports deficits in fear extinction on the psychophysiological level as well as the neural level (lower vmPFC activation during extinction in met-carriers as well as atypical frontal-amygdala activity).
2 AIMS
The work presented in this thesis focused on translational studies and tried to bring together insights from molecular genetics, psychophysiology as well as functional neuroimaging. The ultimate aim of the studies presented was to help unravelling the genetic underpinnings of anxiety related traits (e.g. fear conditioning and extinction, amygdala reactivity to angry faces) and anxiety disorders (e.g. panic disorder, PD).
Both healthy research volunteers and patients suffering from PD were studied for this purpose.
The specific objectives were to investigate:
if and which impact the 5-HTTLPR and COMTval158met polymorphisms have on human fear conditioning and extinction using psychophysiological methods (Study I).
if and which impact the BDNFval66met polymorphism has on human fear conditioning and extinction using psychophysiological methods (Study II).
if the 5-HTTLPR/rs25531 mini-haplotype affects the symptomatic profile in PD patients (Study III) and thereby trying to translate the experimental findings from Study I into the clinical setting.
if the COMTval158met polymorphism affects outcome of (exposure-based) CBT treatment in PD patients (Study IV) and thereby trying to translate the experimental findings from Study I into the clinical setting.
if and which impact the 5-HTTLPR and COMTval158met polymorphisms have on amygdala reactivity and habituation during the passive viewing of angry faces using fMRI (Study V).