Publications by authors named "Heike Weber"

68 Publications

The role of pharmacogenetics in the treatment of anxiety disorders and the future potential for targeted therapeutics.

Expert Opin Drug Metab Toxicol 2021 Oct 15:1-12. Epub 2021 Oct 15.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Introduction: Anxiety disorders (AD) are among the most common mental disorders worldwide. Pharmacotherapy, including benzodiazepines, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants is currently based on 'trial-and-error,' and is effective in a subset of patients or produces partial response only. Recent research proposes that treatment response and tolerability of the drugs are associated with genetic factors.

Areas Covered: In the present review, we provide information on pharmacogenetics (PGx) in AD, including pharmacokinetic and pharmacodynamic genes. Moreover, we discuss the future potential of PGx for personalized treatment.

Expert Opinion: In psychiatry, PGx testing is still in its infancy, especially in the treatment of AD. As of today, implementation in clinical routine is recommended only for CYP2D6 and CYP2C19, mainly in terms of safety of treatment and potentially of treatment outcome in general. However, the evidence for PGx testing addressing pharmacodynamics for specific AD is limited to date. Nevertheless, PGx may develop into a valuable and promising tool to improve therapy in AD, but there is a need for more research to fully exploit its possibilities. Future perspectives include research into single genes, polygenic risk scores, and pharmacoepigenetics to provide targeted therapy.
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http://dx.doi.org/10.1080/17425255.2021.1991912DOI Listing
October 2021

A Common Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD.

Genes (Basel) 2021 Aug 29;12(9). Epub 2021 Aug 29.

Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, 97080 Würzburg, Germany.

The cell-cell signaling gene is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the gene in humans is sparse. Therefore, we tested for association of a functional intronic SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of is associated with personality traits and impacts neural processing during working memory tasks. Thus, might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
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http://dx.doi.org/10.3390/genes12091356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471784PMC
August 2021

Genetic contributions to anxiety disorders: where we are and where we are heading.

Psychol Med 2021 Oct 9;51(13):2231-2246. Epub 2021 Feb 9.

Department of Psychology, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

Anxiety disorders are among the most common psychiatric disorders worldwide. They often onset early in life, with symptoms and consequences that can persist for decades. This makes anxiety disorders some of the most debilitating and costly disorders of our time. Although much is known about the synaptic and circuit mechanisms of fear and anxiety, research on the underlying genetics has lagged behind that of other psychiatric disorders. However, alongside the formation of the Psychiatric Genomic Consortium Anxiety workgroup, progress is rapidly advancing, offering opportunities for future research.Here we review current knowledge about the genetics of anxiety across the lifespan from genetically informative designs (i.e. twin studies and molecular genetics). We include studies of specific anxiety disorders (e.g. panic disorder, generalised anxiety disorder) as well as those using dimensional measures of trait anxiety. We particularly address findings from large-scale genome-wide association studies and show how such discoveries may provide opportunities for translation into improved or new therapeutics for affected individuals. Finally, we describe how discoveries in anxiety genetics open the door to numerous new research possibilities, such as the investigation of specific gene-environment interactions and the disentangling of causal associations with related traits and disorders.We discuss how the field of anxiety genetics is expected to move forward. In addition to the obvious need for larger sample sizes in genome-wide studies, we highlight the need for studies among young people, focusing on specific underlying dimensional traits or components of anxiety.
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http://dx.doi.org/10.1017/S0033291720005486DOI Listing
October 2021

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

Eur Neuropsychopharmacol 2021 Mar 20;44:105-120. Epub 2021 Jan 20.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany; Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.
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http://dx.doi.org/10.1016/j.euroneuro.2021.01.004DOI Listing
March 2021

Stress impairs response to antidepressants via HPA axis and immune system activation.

Brain Behav Immun 2021 03 8;93:132-140. Epub 2021 Jan 8.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080 Würzburg, Germany.

Childhood trauma as well as severe events occurring later in life have been associated with the development of major depressive disorder (MDD). However, the interaction of early and later occurring adverse events in patients with MDD is understudied. This study aims to disentangle this interaction by investigating the effects on two of the main stress-response systems of the body, the hypothalamic-pituitaryadrenal (HPA-) axis and the immune system in depressed patients. The function of the HPA-axis was assessed by measuring FKBP5, SGK1 and NR3C1 mRNA-expression in peripheral blood after an in vivo glucocorticoid receptor (GR) challenge with 1.5 mg dexamethasone in 150 depressed in-patients (47.4% females). Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ), severe life events occurring one year prior to hospital admission were assessed with the List of Threatening Experiences (LTE). Multiple childhood traumata, i.e. ≥ 3, were present in 68 (45.5%) patients, 59 (39.3%) experienced ≥ 3 severe recent life events. The history of ≥ 3 severe recent life events was associated with an impaired GR-induction of SGK1 (F = 10.455; df = 1; p = 0.002) and FKBP5 mRNA expression (F = 8.720; df = 1; p = 0.004), and with elevated measures of the immune system such as CRP and lymphocyte count. In addition, severe recent life events were associated with a substantially impaired treatment response to antidepressants (F = 7.456; df = 1; p = 0.008). These effects could not be observed in relation to childhood trauma. Severe life events occurring prior to MDD development substantially impaired the stress-response systems and the response to treatment with antidepressants. This finding may indicate the need to employ additional treatment options such as psychotherapy right at the beginning of treatment or immune-modulating approaches.
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http://dx.doi.org/10.1016/j.bbi.2020.12.033DOI Listing
March 2021

Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk.

Front Psychiatry 2020 14;11:557160. Epub 2020 Dec 14.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany.

While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive-neurotic type, an adventurous-hyperactive type with a stronger genetic component, and an anxious-inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.
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http://dx.doi.org/10.3389/fpsyt.2020.557160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768074PMC
December 2020

An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes.

J Neural Transm (Vienna) 2020 11 29;127(11):1527-1537. Epub 2020 May 29.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel Platz 1, 97080, Würzburg, Germany.

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.
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http://dx.doi.org/10.1007/s00702-020-02206-xDOI Listing
November 2020

Neural correlates of NOS1 ex1f-VNTR allelic variation in panic disorder and agoraphobia during fear conditioning and extinction in fMRI.

Neuroimage Clin 2020 23;27:102268. Epub 2020 Apr 23.

Department of Psychiatry and Psychotherapy & Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany.

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.
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http://dx.doi.org/10.1016/j.nicl.2020.102268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200443PMC
March 2021

Shared genetic background between children and adults with attention deficit/hyperactivity disorder.

Neuropsychopharmacology 2020 09 12;45(10):1617-1626. Epub 2020 Apr 12.

Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.
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http://dx.doi.org/10.1038/s41386-020-0664-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419307PMC
September 2020

Anxiety risk SNPs on chromosome 2 modulate arousal in children in a fear generalization paradigm.

Eur Child Adolesc Psychiatry 2020 Sep 21;29(9):1301-1310. Epub 2019 Dec 21.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Alterations in fear learning/generalization are considered to be relevant mechanisms engendering the development of anxiety disorders being the most prevalent mental disorders. Although anxiety disorders almost exclusively have their first onset in childhood and adolescence, etiological research focuses on adult individuals. In this study, we evaluated findings of a recent meta-analysis of genome-wide association studies in adult anxiety disorders with significant associations of four single nucleotide polymorphisms (SNPs) in a large cohort of 347 healthy children (8-12 years) characterized for dimensional anxiety. We investigated the modulation of anxiety parameters by these SNPs in a discriminative fear conditioning and generalization paradigm in the to-date largest sample of children. Results extended findings of the meta-analysis showing a genomic locus on 2p21 to modulate anxious personality traits and arousal ratings. These SNPs might, thus, serve as susceptibility markers for a shared risk across pathological anxiety, presumably mediated by alterations in arousal.
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http://dx.doi.org/10.1007/s00787-019-01458-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497385PMC
September 2020

Is brain arousal regulation a predictor of response to psychostimulant therapy in adult ADHD patients?

Eur Arch Psychiatry Clin Neurosci 2020 Dec 26;270(8):1073-1076. Epub 2019 Nov 26.

Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

We investigated whether baseline brain arousal instability during resting state EEG, using the Vigilance Algorithm Leipzig (VIGALL 2.1), can predict response to methylphenidate therapy in adult ADHD patients. An arousal stability score of the EEGs of 28 adult ADHD patients was calculated quantifying the extent of arousal decline. In logistic regression analysis, arousal stability score predicted response to MPH [odds ratio 1.28 (95% CI 1.0-1.65); p = 0.027]. In this pilot study, we demonstrated that arousal stability at baseline predicted methylphenidate treatment response, indicating that less stable arousal regulation during a 15-min EEG at rest increases the chance of treatment response.
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http://dx.doi.org/10.1007/s00406-019-01085-yDOI Listing
December 2020

From Stable to Lab-Investigating Key Factors for Sudden Deaths Caused by .

Pathogens 2019 Nov 20;8(4). Epub 2019 Nov 20.

Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.

Swine stocks are endemically infected with the major porcine pathogen () . The factors governing the transition from colonizing residing in the tonsils and the exacerbation of disease have not yet been elucidated. We analyzed the sudden death of fattening pigs kept under extensive husbandry conditions in a zoo. The animals died suddenly of septic shock and showed disseminated intravascular coagulopathy. Genotypic and phenotypic characterizations of the isolated strains, a tonsillar isolate and an invasive type 2 strain, were conducted. Isolated from dead pigs belonged to type 2 strain ST28, whereas one tonsillar isolate harvested from a healthy animal belonged to ST1173. Neither growth, induction of neutrophil extracellular traps, nor survival in blood could explain the sudden deaths. Reconstituted blood assays with serum samples from pigs of different age groups from the zoo stock suggested varying protection of individuals against pathogenic type 2 strains especially in younger pigs. These findings highlight the benefit of further characterization of the causative strains in each case by sequence typing before autologous vaccine candidate selection.
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http://dx.doi.org/10.3390/pathogens8040249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963698PMC
November 2019

Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls.

Neuroimage Clin 2019 21;24:102029. Epub 2019 Oct 21.

Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.

Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli.

Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety.

Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC).

Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.
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http://dx.doi.org/10.1016/j.nicl.2019.102029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854061PMC
September 2020

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Mol Psychiatry 2019 Nov 11. Epub 2019 Nov 11.

Department of Psychology, Humboldt-University Berlin, Berlin, Germany.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10  × 10). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
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http://dx.doi.org/10.1038/s41380-019-0590-2DOI Listing
November 2019

Association of rs7688285 allelic variation coding for GLRB with fear reactivity and exposure-based therapy in patients with panic disorder and agoraphobia.

Eur Neuropsychopharmacol 2019 10 20;29(10):1138-1151. Epub 2019 Aug 20.

Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Germany.

The gene coding for glycine receptor β subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk») in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.
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http://dx.doi.org/10.1016/j.euroneuro.2019.07.133DOI Listing
October 2019

Roadmap for Routine Pharmacogenetic Testing in a Psychiatric University Hospital.

Pharmacopsychiatry 2020 Jul 11;53(4):179-183. Epub 2019 Jun 11.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Major depressive disorder (MDD) implicates a huge burden for patients and society. Although currently available antidepressants are effective treatment options, more than 50% of the patients do not respond to the first administered antidepressant. In addition, in more than 25% with antidepressants-treated patients, adverse effects occur. Currently, the selection of treatment does not reflect objectively measurable data from neurobiological and behavioral systems. However, in the last decades, the understanding of the impact of genetic variants on clinical features such as drug metabolism has grown and can be used to develop tests that enable a patient-tailored individual treatment. In fact, robust evidence was found that genetic variants of CYP450 enzymes such as CYP2D6 and CYP2C19 can be surrogate markers for the metabolism of certain drugs. This article describes a pilot study design aimed to combine clinical variables such as therapeutic drug monitoring, inflammatory and stress markers with static and variable genetic information of depressed patients to develop an algorithm that predicts treatment response, and tolerability using machine learning algorithms. Psychometric evaluation covers the Hamilton Depression Rating Scale, the Childhood Trauma Questionnaire, and adverse drug reactions. An in-depth (epi-)genetic assessment combines genome-wide gene association data with DNA methylation patterns of genes coding CYP enzymes along with a pharmacogenetic battery focusing on CYP enzymes. Using these measures to stratify depressed patients, this approach should contribute to a data-driven assessment and management of MDD, which can be referred to as precision medicine or high-definition medicine.
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http://dx.doi.org/10.1055/a-0914-3234DOI Listing
July 2020

A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders.

Transl Psychiatry 2019 05 23;9(1):150. Epub 2019 May 23.

Neurogenetics Unit, Center for Molecular Medicine, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
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http://dx.doi.org/10.1038/s41398-019-0481-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533285PMC
May 2019

KCNJ6 variants modulate reward-related brain processes and impact executive functions in attention-deficit/hyperactivity disorder.

Am J Med Genet B Neuropsychiatr Genet 2020 07 17;183(5):247-257. Epub 2019 May 17.

Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.

KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)-relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, on reporter gene expression was explored in cultured cells. The KCNJ6 variants were then tested for association with ADHD and personality traits in a family-based sample (165 affected children) and an adult case-control sample (450 patients, 426 controls). Furthermore, the genotypic influence on performance in an n-back task and a cued continuous performance test (cCPT) was investigated by electroencephalography recordings. Finally, rs6517442 function was assessed by a reward anticipation paradigm using functional magnetic resonance imaging. Different haplotypes of rs7275707 and rs6517442 significantly influenced KCNJ6 gene expression proving their functional relevance on the molecular level. In the family-based children sample rs7275707 was associated with ADHD (p = .038). Moreover, rs7275707 showed association with the personality trait of Reward Dependence (p = .031). In the ADHD group, both rs7275707 and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopamine-related brain processes in ADHD risk.
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http://dx.doi.org/10.1002/ajmg.b.32734DOI Listing
July 2020

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Transl Psychiatry 2019 02 4;9(1):75. Epub 2019 Feb 4.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Preclinical studies point to a pivotal role of the orexin 1 (OX) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10), particularly in the female subsample (p = 9.8 × 10). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
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http://dx.doi.org/10.1038/s41398-019-0415-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361931PMC
February 2019

Knockdown of the ADHD Candidate Gene in Murine Hippocampal Primary Cells.

J Atten Disord 2021 02 9;25(4):572-583. Epub 2019 Jan 9.

University Hospital, Goethe University Frankfurt, Germany.

The gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by . Using short hairpin RNAs, we downregulated in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Our findings show that affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that is linked to etiological processes underlying ADHD.
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http://dx.doi.org/10.1177/1087054718822129DOI Listing
February 2021

Zukunftsfelder der Wissenschaftsgeschichte – aus technikhistorischer Gegenwartsperspektive.

Authors:
Heike Weber

Ber Wiss 2018 Dec;41(4):439-443

Karlsruher Institut für Technologie, Institut für Geschichte, Institut für Technikzukünfte, Douglasstr. 24, DE-76133, Karlsruhe.

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http://dx.doi.org/10.1002/bewi.201801946DOI Listing
December 2018

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

Mol Psychiatry 2020 09 16;25(9):2047-2057. Epub 2018 Aug 16.

Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Center of Mental Health, University of Würzburg, Würzburg, Germany.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.
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http://dx.doi.org/10.1038/s41380-018-0210-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473839PMC
September 2020

Childhood trauma dependent anxious depression sensitizes HPA axis function.

Psychoneuroendocrinology 2018 12 26;98:22-29. Epub 2018 Jul 26.

Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 5, 79104, Freiburg, Germany.

Anxious depression is a common subtype of major depressive disorder (MDD) and is associated with greater severity and poorer outcome. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis, especially of the glucocorticoid receptor (GR) function, are often observed in MDD, but evidence lacks for anxious depression. Childhood adversity is known to influence both the HPA axis and risk of MDD. Therefore, we investigated GR-function in anxious depression dependent on childhood adversity. We enrolled 144 depressed in-patients (49.3% females). Anxious depression was defined using the Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score ≥7. Blood draws were performed at 6 pm before and 3 h after 1.5 mg dexamethasone ingestion for measurement of cortisol, ACTH and blood count to assess GR-function and the immune system. In a subgroup of n = 60 FKBP5 mRNA controlled for FKBP5 genotype was measured before and after dexamethasone. Childhood adversity was evaluated using the Childhood Trauma Questionnaire (CTQ). We identified 78 patients (54.2%) with anxious depression who showed a greater severity and worse outcome. These patients were more often exposed to sexual abuse (30% vs. 16%/p = 0.04) and emotional neglect (76% vs. 58%/p = 0.02) than patients with non-anxious depression. Anxious depressed patients showed an enhanced GR-induced FKBP5 mRNA expression (F = 5.128; p = 0.03) and reduced cortisol levels, partly dependent on sexual abuse (F = 7.730; p = 0.006). Additionally, the GR-induced leukocyte response was enhanced in patients with sexual abuse (F = 7.176; p = 0.008). Anxious depression in dependence of childhood trauma is associated with heightened sensitivity of the HPA axis and the immune system which should be considered for treatment algorithms and targets.
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http://dx.doi.org/10.1016/j.psyneuen.2018.07.025DOI Listing
December 2018

RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior.

Eur Neuropsychopharmacol 2020 01 23;30:44-55. Epub 2017 Nov 23.

Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain; Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain. Electronic address:

The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.
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http://dx.doi.org/10.1016/j.euroneuro.2017.11.012DOI Listing
January 2020

Lithium-induced gene expression alterations in two peripheral cell models of bipolar disorder.

World J Biol Psychiatry 2019 07 27;20(6):462-475. Epub 2017 Nov 27.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University of Frankfurt , Frankfurt , Germany.

The aim of our study was to investigate molecular mechanisms of lithium action by studying the gene expression profile of peripheral cell models generated from bipolar patients (BD) and healthy controls (HC). EBV-immortalised lymphoblastoid cells (LCLs) and fibroblast cells from BD and HC were incubated with either lithium chloride or plain medium for 3 weeks. We first conducted a microarray gene expression study. The most promising differentially regulated genes in terms of lithium-associated or disorder-associated pathways were then replicated by quantitative real-time PCR (qRT-PCR). The pooled microarray analysis showed 459 genes to be differentially regulated in BD compared to HC and 58 due to lithium treatment in LCLs, and 295 genes to be differentially regulated in BD compared to HC and five due to lithium treatment in fibroblasts. After correction for multiple comparison, disorder × treatment interactions remained significant in LCLs validated by qRT-PCR. In the control group, lithium influenced the expression of , , , , and . In bipolar and control fibroblast cells lithium treatment decreased expression. The differentially regulated genes in our study add evidence for the relevance of inflammation, neuronal/glial development, phosphatidylinositol second-messenger pathway and ion channels in the mode of action of lithium.
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http://dx.doi.org/10.1080/15622975.2017.1396357DOI Listing
July 2019

Explorative results from multistep screening for potential genetic risk loci of Alzheimer's disease in the longitudinal VITA study cohort.

J Neural Transm (Vienna) 2018 01 12;125(1):77-87. Epub 2017 Oct 12.

Center of Mental Health, Clinic and Policlinic of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

Alzheimer's disease (AD) is a neurodegenerative disorder that preferentially affects individuals of advanced age. Heritability estimates for AD range between 60 and 80%, but only few genetic risk factors have been identified so far. In the present explorative study, we aimed at characterizing the genetic contribution to late-onset AD in participants of the Vienna Transdanube Aging (VITA) longitudinal birth cohort study in a two-step approach. First, we performed a genome-wide screen of pooled DNA samples (n = 588) to identify allele frequency differences between AD patients and non-AD individuals using life-time diagnoses made at the age of 80 (t = 60 months). This analysis suggested a high proportion of brain-expressed genes required for cell adhesion, cell signaling and cell morphogenesis, and also scored in known AD risk genes. In a second step, we confirmed associations using individual genotypes of top-ranked markers examining AD diagnoses as well as the dimensional scores: FULD and MMSE determined up to the age of 82.5 (t = 90 months). Taken together, our study proposes genes ANKS1B, ENST00000414107, LOC100505811, SLC22A14, QRFPR, ZDHHC8P1, ADAMTS3 and PPFIA1 as possible new candidates involved in the etiology of late-onset AD, with further research being needed to clarify their exact roles.
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http://dx.doi.org/10.1007/s00702-017-1796-6DOI Listing
January 2018

UROLITHIASIS IN FREE-RANGING AND CAPTIVE OTTERS (LUTRA LUTRA AND AONYX CINEREA) IN EUROPE.

J Zoo Wildl Med 2017 09;48(3):725-731

Between 1996 and 1998, 477 dead otters from different Central European countries were examined for urolithiasis, including 449 free-ranging Eurasian otters (Lutra lutra) as well as 17 Eurasian otters and 11 Asian small-clawed otters (Aonyx cinerea) from captivity. In the free-ranging specimens, uroliths (sand or stones) were found in 105 animals (23.4%), with no significant difference (P = 0.77) between the sexes. Uroliths were not present in any juveniles (n = 26) and urolithiasis was not considered the main cause of death in any individual. In captive specimens, uroliths were found in 11 out of 17 Eurasian otters (64.7%; four males and seven females), and in 3 out of 11 Asian small-clawed otters (27.3%). Histology could not find any signs of inflammation in examined kidneys (n = 179) or urinary bladders (n = 66). Analyzed stones of free-ranging and captive Eurasian otters were composed mainly of ammonium acid urate. The stones of three captive Asian small-clawed otters consisted mainly of calcium oxalate. The difference in prevalence of uroliths between free-ranging and captive Eurasian otters was significant (P < 0.001). Nevertheless, the prevalence in free-ranging specimens of this study is higher than reported before. Differences between various habitats, environmental changes, and genetic predisposition all represent potential hypothetical explanations for these findings.
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http://dx.doi.org/10.1638/2016-0223.1DOI Listing
September 2017

The regulation of tetraspanin 8 gene expression-A potential new mechanism in the pathogenesis of bipolar disorder.

Am J Med Genet B Neuropsychiatr Genet 2017 Oct 4;174(7):740-750. Epub 2017 Aug 4.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.

In a previous study, we identified the single nucleotide polymorphism (SNP) rs4500567, located in the upstream region of tetraspanin 8 (TSPAN8), to be associated with bipolar disorder (BD). Due to its proximal position, the SNP might have an impact on promoter activity, thus on TSPAN8 gene expression. We investigated the impact of rs4500567 on TSPAN8 expression in vitro with luciferase-based promoter assays in human embryonic kidney (HEK293) and neuroblastoma cells (SH-SY5Y), and its effect on expression of downstream associated genes by microarray-based transcriptome analyses. Immunohistochemical localization studies on murine brain slices served to identify possible target regions of altered TSPAN8 expression in the brain. Promoter assays revealed decreased TSPAN8 expression in presence of the minor allele. Transcriptome analyses of TSPAN8-knockdown cells, mirroring the effects of putatively reduced TSPAN8 expression in minor allele carriers, resulted in 231 differentially expressed genes with enrichments of relevant signaling pathways for psychiatric disorders and neuronal development. Finally, we demonstrate Tspan8 abundance in mouse cerebellum and hippocampus. These findings point to a role of TSPAN8 in neuronal function or development. Considering a rather protective effect of the minor allele of rs4500567, our findings reveal a possible novel mechanism that contributes to the development of BD.
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http://dx.doi.org/10.1002/ajmg.b.32571DOI Listing
October 2017

Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms.

Eur Arch Psychiatry Clin Neurosci 2019 Mar 15;269(2):161-170. Epub 2017 Jul 15.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University Frankfurt, Frankfurt, Germany.

Although cognitive behavioral therapy (CBT) is highly effective in the treatment of anxiety disorders, many patients still do not benefit. This study investigates whether a history of traumatic event experience is negatively associated with outcomes of CBT for panic disorder. The moderating role of the monoamine oxidase A (MAOA) gene and depression symptoms as well as the association between trauma history and fear reactivity as a potential mechanism are further analyzed. We conducted a post-hoc analysis of 172 male and 60 female patients with panic disorder treated with CBT in a multi-center study. Treatment outcome was assessed at post-treatment using self-report and clinician rating scales. Fear reactivity before treatment was assessed via heart rate and self-reported anxiety during a behavioral avoidance test. Among females, we did not find any differences in treatment response between traumatized and non-traumatized individuals or any two-way interaction trauma history × MAOA genotype. There was a significant three-way interaction trauma history × MAOA genotype × depression symptoms on all treatment outcomes indicating that in traumatized female patients carrying the low-activity allele, treatment effect sizes decreased with increasing depression symptoms at baseline. No such effects were observed for males. In conclusion, we found no evidence for a differential treatment response in traumatized and non-traumatized individuals. There is preliminary evidence for poorer treatment outcomes in a subgroup of female traumatized individuals carrying the low-active variant of the MAOA gene. These patients also report more symptoms of depression symptomatology and exhibit a dampened fear response before treatment which warrants further investigation.
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http://dx.doi.org/10.1007/s00406-017-0823-9DOI Listing
March 2019

Requirement of a Functional Flavin Mononucleotide Prenyltransferase for the Activity of a Bacterial Decarboxylase in a Heterologous Muconic Acid Pathway in Saccharomyces cerevisiae.

Appl Environ Microbiol 2017 05 1;83(10). Epub 2017 May 1.

Institute of Molecular Biosciences, Goethe University, Frankfurt am Main, Germany

Biotechnological production of ,-muconic acid from renewable feedstocks is an environmentally sustainable alternative to conventional, petroleum-based methods. Even though a heterologous production pathway for ,-muconic acid has already been established in the host organism , the generation of industrially relevant amounts of ,-muconic acid is hampered by the low activity of the bacterial protocatechuic acid (PCA) decarboxylase AroY isomeric subunit C (AroY-C), leading to secretion of large amounts of the intermediate PCA into the medium. In the present study, we show that the activity of AroY-C in strongly depends on the strain background. We could demonstrate that the strain dependency is caused by the presence or absence of an intact genomic copy of , which encodes a mitochondrial enzyme responsible for the biosynthesis of a prenylated form of the cofactor flavin mononucleotide (prFMN). The inactivity of AroY-C in strain CEN.PK2-1 could be overcome by plasmid-borne expression of Pad1 or its bacterial homologue AroY subunit B (AroY-B). Our data reveal that the two enzymes perform the same function in decarboxylation of PCA by AroY-C, although coexpression of Pad1 led to higher decarboxylase activity. Conversely, AroY-B can replace Pad1 in its function in decarboxylation of phenylacrylic acids by ferulic acid decarboxylase Fdc1. Targeting of the majority of AroY-B to mitochondria by fusion to a heterologous mitochondrial targeting signal did not improve decarboxylase activity of AroY-C, suggesting that mitochondrial localization has no major impact on cofactor biosynthesis. In , the decarboxylation of protocatechuic acid (PCA) to catechol is the bottleneck reaction in the heterologous biosynthetic pathway for production of ,-muconic acid, a valuable precursor for the production of bulk chemicals. In our work, we demonstrate the importance of the strain background for the activity of a bacterial PCA decarboxylase in Inactivity of the decarboxylase is due to a nonsense mutation in a gene encoding a mitochondrial enzyme involved in the biosynthesis of a cofactor required for decarboxylase function. Our study reveals functional interchangeability of Pad1 and a bacterial homologue, irrespective of their intracellular localization. Our results open up new possibilities to improve muconic acid production by engineering cofactor supply. Furthermore, the results have important implications for the choice of the production strain.
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http://dx.doi.org/10.1128/AEM.03472-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411507PMC
May 2017
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