NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors
2020-09-01, Vukojevic, Vanja, Coynel, David, Ghaffari, Navid R., Freytag, Virginie, Elbert, Thomas, Kolassa, Iris-Tatjana, Wilker, Sarah, McGaugh, James L., Papassotiropoulos, Andreas, de Quervain, Dominique J.-F.
Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations.
The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder
2014, Wilker, Sarah, Pfeiffer, Anett, Kolassa, Stephan, Elbert, Thomas, Lingenfelder, Birke, Ovuga, Emilio, Papassotiropoulos, Andreas, de Quervain, Dominique, Kolassa, Iris-Tatjana
Exposure-based therapies are considered the state-of-the-art treatment for Posttraumatic Stress Disorder (PTSD). Yet, a substantial number of PTSD patients do not recover after therapy. In the light of the well-known gene × environment interactions on the risk for PTSD, research on individual genetic factors that influence treatment success is warranted. The gene encoding FK506-binding protein 51 (FKBP5), a co-chaperone of the glucocorticoid receptor (GR), has been associated with stress reactivity and PTSD risk. As FKBP5 single-nucleotide polymorphism rs1360780 has a putative functional role in the regulation of FKBP5 expression and GR sensitivity, we hypothesized that this polymorphism influences PTSD treatment success. We investigated the effects of FKBP5 rs1360780 genotype on Narrative Exposure Therapy (NET) outcome, an exposure-based short-term therapy, in a sample of 43 survivors of the rebel war in Northern Uganda. PTSD symptom severity was assessed before and 4 and 10 months after treatment completion. At the 4-month follow-up, there were no genotype-dependent differences in therapy outcome. However, the FKBP5 genotype significantly moderated the long-term effectiveness of exposure-based psychotherapy. At the 10-month follow-up, carriers of the rs1360780 risk (T) allele were at increased risk of symptom relapse, whereas non-carriers showed continuous symptom reduction. This effect was reflected in a weaker treatment effect size (Cohen's D=1.23) in risk allele carriers compared with non-carriers (Cohen's D=3.72). Genetic factors involved in stress response regulation seem to not only influence PTSD risk but also responsiveness to psychotherapy and could hence represent valuable targets for accompanying medication.
Human genome-guided identification of memory-modulating drugs
2013, Papassotiropoulos, Andreas, Gerhards, Christiane, Heck, Angela, Ackermann, Sandra, Aerni, Amanda, Schicktanz, Nathalie, Auschra, Bianca, Demougin, Philippe, Mumme, Eva, Elbert, Thomas, Ertl, Verena, Gschwind, Leo, Hanser, Edveena, Huynh, Kim-Dung, Jessen, Frank, Kolassa, Iris-Tatjana, Milnik, Annette, Paganetti, Paolo, Spalek, Klara, Vogler, Christian, Muhs, Andreas, Pfeifer, Andrea, de Quervain, Dominique J.-F.
In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory—a trait central to posttraumatic stress disorder—and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand–receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand–receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.
Microarray-based maps of copy-number variant regions in european and sub-saharan populations
2010, Vogler, Christian, Gschwind, Leo, Röthlisberger, Benno, Huber, Andreas, Filges, Isabel, Miny, Peter, Auschra, Bianca, Stetak, Attila, Demougin, Philippe, Vukojevic, Vanja, Kolassa, Iris-Tatjana, Elbert, Thomas, Quervain, Dominique J.-F. de, Papassotiropoulos, Andreas
The genetic basis of phenotypic variation can be partially explained by the presence of copy-number variations (CNVs). Currently available methods for CNV assessment include high-density single-nucleotide polymorphism (SNP) microarrays that have become an indispensable tool in genome-wide association studies (GWAS). However, insufficient concordance rates between different CNV assessment methods call for cautious interpretation of results from CNV-based genetic association studies. Here we provide a cross-population, microarray-based map of copy-number variant regions (CNVRs) to enable reliable interpretation of CNV association findings. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to scan the genomes of 1167 individuals from two ethnically distinct populations (Europe, N = 717; Rwanda, N = 450). Three different CNV-finding algorithms were tested and compared for sensitivity, specificity, and feasibility. Two algorithms were subsequently used to construct CNVR maps, which were also validated by processing subsamples with additional microarray platforms (Illumina 1M-Duo BeadChip, Nimblegen 385K aCGH array) and by comparing our data with publicly available information. Both algorithms detected a total of 42669 CNVs, 74% of which clustered in 385 CNVRs of a crosspopulation map. These CNVRs overlap with 862 annotated genes and account for approximately 3.3% of the haploid human genome. We created comprehensive cross-populational CNVR-maps. They represent an extendable framework that can leverage the detection of common CNVs and additionally assist in interpreting CNV-based association studies.
Exome sequencing of healthy phenotypic extremes links TROVE2 to emotional memory and PTSD
2017-03-27, Heck, Angela, Milnik, Annette, Vukojevic, Vanja, Petrovska, Jana, Egli, Tobias, Singer, Jochen, Escobar, Pablo, Kolassa, Iris-Tatjana, Elbert, Thomas, Papassotiropoulos, Andreas
Many mental disorders represent the extremes of the normal distribution of traits, which are related to multiple cognitive and emotional dimensions. By performing whole-exome sequencing of healthy, young subjects with extremely high versus extremely low aversive memory performance, we identified TROVE2 as a gene implicated in emotional memory in health and disease. TROVE2 encodes Ro60, a broadly expressed RNA-binding protein implicated in the regulation of inflammatory gene expression and autoimmunity. A regulatory TROVE2 variant was linked to higher emotional memory capacity and higher emotional memory-related brain activation in healthy subjects. In addition, TROVE2 was associated with traumatic memory and the frequency of post-traumatic stress disorder in genocide survivors.
Response to: Further Support for an Association between the Memory-Related Gene WWC1 and Posttraumatic Stress Disorder : Results from the Detroit Neighborhood Health Study
2014, Wilker, Sarah, Elbert, Thomas, Papassotiropoulos, Andreas, de Quervain, Dominique J.-F., Kolassa, Iris-Tatjana
Posttraumatic stress disorder (PTSD) is characterized by pathologic, intrusive memories of the experienced traumata. The risk to develop PTSD depends on the cumulative exposure to traumatic experience (traumatic load), on the extent of childhood adversities, and on genetic factors. The latter account for about one third of interindividual variability (1). Despite this pronounced genetic influence, little is known about the underlying genetic factors and molecular processes. Considering the strong role of fear memory development in PTSD, we recently argued for the investigation of memory-related genes in PTSD (2,3).
PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors
2012-05-29, Quervain, Dominique J. F. de, Kolassa, Iris-Tatjana, Ackermann, Sandra, Aerni, Amanda, Boesiger, Peter, Demougin, Philippe, Elbert, Thomas, Ertl, Verena, Gschwind, Leo, Hadziselimovic, Nils, Hanser, Edveena, Heck, Angela, Hieber, Petra, Huynh, Kim-Dung, Klarhöfer, Markus, Luechinger, Roger, Rasch, Björn, Scheffler, Klaus, Spalek, Klara, Stippich, Christoph, Vogler, Christian, Vukojevic, Vanja, Stetak, Attila, Papassotiropoulos, Andreas
Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity--including aversive memory--in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.
Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors
2014, Vukojevic, Vanja, Kolassa, Iris-Tatjana, Fastenrath, Matthias, Gschwind, Leo, Spalek, Klara, Milnik, Annette, Heck, Angela, Vogler, Christian, Wilker, Sarah, Demougin, Philippe, Peter, Fabian, Atucha, Erika, Stetak, Attila, Roozendaal, Benno, Elbert, Thomas, Papassotiropoulos, Andreas, de Quervain, Dominique J.-F.
Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation–which was associated with lower NR3C1 expression–was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.
The Role of Memory-related Gene WWC1 (KIBRA) in Lifetime Posttraumatic Stress Disorder : Evidence from Two Independent Samples from African Conflict Regions
2013-11-01, Wilker, Sarah, Kolassa, Stephan, Vogler, Christian, Lingenfelder, Birke, Elbert, Thomas, Papassotiropoulos, Andreas, de Quervain, Dominique, Kolassa, Iris-Tatjana
Background: Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common
WWC1 alleles influence the risk for a lifetime diagnosis of PTSD.
Methods: Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n ¼ 392, Rwanda, and n ¼ 399, Northern Uganda, espectively). Array-based single nucleotide polymorphism (SNP) genotyping was performed. The influence of WWC1 tagging SNPs and traumatic load on lifetime PTSD
was estimated by means of logistic regression models with correction for multiple comparisons in the Rwandan sample. Replication analysis was performed in the independent Ugandan sample.
Results: An association of two neighboring SNPs in almost complete linkage disequilibrium, rs10038727 and rs4576167, with lifetime PTSD was discovered in the Rwandan sample. Although each traumatic event added to the probability of lifetime PTSD in a dosedependent manner in both genotype groups, carriers of the minor allele of both SNPs displayed a diminished risk (p ¼ .007, odds
ratio ¼ .29 [95% confidence interval ¼ .15–.54]). This effect was confirmed in the independent Ugandan sample.
Conclusions: This study reveals an association between two WWC1 SNPs and the likelihood of PTSD development, indicating that this memory-related gene might be involved in processes that occur in response to traumatic stress and influence the strengthening of fear memories.
Association Study of Trauma Load and SLC6A4 Promoter Polymorphism in Posttraumatic Stress Disorder : Evidence From Survivors of the Rwandan Genocide
2010, Kolassa, Iris-Tatjana, Ertl, Verena, Eckart, Cindy, Thurm, Franka, Kolassa, Stephan, Papassotiropoulos, Andreas, Quervain, Dominique J.-F. de, Elbert, Thomas
Objective: As exposure to different types of traumatic stressors increases, the occurrence of posttraumatic stress disorder (PTSD) increases. However, because some people exhibit either surprising resilience or high vulnerability, further influencing factors have been conjectured, such as gene-environment interactions. The SLC6A4 gene, which encodes serotonin transporter, has been identified as predisposing toward differential emotional processing between genotypes of its promoter polymorphism.
Method: We investigated 408 refugees from the Rwandan genocide and assessed lifetime exposure to traumatic events, PTSD (according to DSM-IV) status, and genotype of the SLC6A4 promoter polymorphism. The study was conducted from March 2006 to February 2007.
Results: The prevalence of PTSD approached
100% when traumatic exposure reached extreme levels. However, persons homozygous for the short allele of the SLC6A4 promoter polymorphism showed no dose-response relationship but were at high risk for developing PTSD after very few traumatic events. This genotype influence vanished with increasing exposure to traumatic stressors. Conclusion: We find evidence for a geneenvironment interplay for PTSD and show that genetic influences lose importance when environmental factors cause an extremely high trauma burden to an individual. In the future, it may be important to determine whether the effectiveness of therapeutic interventions in PTSD is also modulated by the SLC6A4 genotype.