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Comparison of gene expression profiles in the blood, hippocampus and prefrontal cortex of rats

Stephanie H Witt, Wolfgang H Sommer, Anita C Hansson, Carsten Sticht, Marcella Rietschel, Christian C Witt
2013 In Silico Pharmacology  
Construction and content Blood and tissue sampling, and RNA preparation Four male 6-week old Wistar rats (Charles River, Sulzfeld, Germany), were housed for 1 week under standard conditions (2 per cage, 12-h  ... 
doi:10.1186/2193-9616-1-15 pmid:25505659 pmcid:PMC4230692 fatcat:dntsbsdo65glznxrxqnnexqbz4

Cooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2

Christian C Witt, Stephanie H Witt, Stefanie Lerche, Dietmar Labeit, Walter Back, Siegfried Labeit
2007 EMBO Journal  
(C) In dKO quadriceps muscles, hyperactive stretch signaling was suggested by the effect of 72 h immobilization on the stretch marker MLP: abnormally high levels of MLP/Crsp3 are maintained after 72 h  ...  Antibodies: CARP specific antibodies have been described previously (Miller et al, 2003; Witt et al, 2004) .  ... 
doi:10.1038/sj.emboj.7601952 pmid:18157088 pmcid:PMC2168395 fatcat:oxx5wm33zrfs3cytov3ogxk4pi

Hyperfunctioning of the right posterior superior temporal sulcus in response to neutral facial expressions presents an endophenotype of schizophrenia

Zhimin Yan, Stephanie N. L. Schmidt, Josef Frank, Stephanie H. Witt, Joachim Hass, Peter Kirsch, Daniela Mier
2020 Neuropsychopharmacology  
Deficits in social cognition have been proposed as a marker of schizophrenia. Growing evidence suggests especially hyperfunctioning of the right posterior superior temporal sulcus (pSTS) in response to neutral social stimuli reflecting the neural correlates of social-cognitive impairments in schizophrenia. We characterized healthy participants according to schizotypy (n = 74) and the single-nucleotide polymorphism rs1344706 in ZNF804A (n = 73), as they represent risk variants for schizophrenia
more » ... rom the perspectives of personality traits and genetics, respectively. A social-cognitive fMRI task was applied to investigate the association of right pSTS hyperfunctioning in response to neutral face stimuli with schizotypy and rs1344706. Higher right pSTS activation in response to neutral facial expressions was found in individuals with increased positive (trend) and disorganization symptoms, as well as in carriers of the risk allele of rs1344706. In addition, a positive association between right-left pSTS connectivity and disorganization symptoms during neutral face processing was revealed. Although these findings warrant replication, we suggest that right pSTS hyperfunctioning in response to neutral facial expressions presents an endophenotype of schizophrenia. We assume that right pSTS hyperfunctioning is a vulnerability to perceive neutral social stimuli as emotionally or intentionally salient, probably contributing to the emergence of symptoms of schizophrenia.
doi:10.1038/s41386-020-0637-8 pmid:32059228 fatcat:dcwiyusianehpcdlbmpeda35uq

Prospects of Genetics and Epigenetics of Alcohol Use Disorder

Friederike Wedemeyer, Jakob A. Kaminski, Lea Zillich, Alisha S. M. Hall, Eva Friedel, Stephanie H. Witt
2020 Current Addiction Report  
Purpose of Review In this study, we illustrate recent findings regarding the genetics and epigenetics of alcohol use disorder (AUD). We further outline the future direction of genetic and epigenetic research in AUD. Recent Findings Recent genome- and epigenome-wide studies allow new insight into genetic and epigenetic variation associated with AUD. The largest EWAS of AUD so far/to date found evidence for altered glucocorticoid receptor regulation. Longitudinal studies provide insight into the
more » ... ynamics of the disease. Analyses of postmortem brain tissue reveal the impact of chronic alcohol consumption on DNA methylation in the brain. Summary Genetic and environmental factors—mediated via epigenetic mechanisms—play an important role in AUD. Although knowledge of the biological underpinnings of AUD is still limited, ongoing research will ultimately lead to the development of biomarkers for disease classification, course of disease, and treatment response to support personalized medicine in the future.
doi:10.1007/s40429-020-00331-x fatcat:c5g2t5h6jja63giztkfafcmg6a

Association between a Serotonin Transporter Length Polymorphism and Primary Insomnia

Michael Deuschle, Michael Schredl, Claudia Schilling, Stefan Wüst, Josef Frank, Stephanie H. Witt, Marcella Rietschel, Magdalena Buckert, Andreas Meyer-Lindenberg, Thomas G. Schulze
2010 Sleep  
343 5-HTTLPR and Primary Insomnia-Deuschle et al Primary insomnia, according to dsm-iV, is one of the most frequent sleeP disorders, with a PreValence of 3% 1,2 and is characterized by difficulties initiating or maintaining sleep or nonrestorative sleep causing distress or impairment. The presence of learned, sleep-preventing associations, such as conditioned arousal to sleep-related cues and evidence for increased somatized tension are additional criteria for psychophysiological insomnia in
more » ... International Classification of Sleep Disorders (ICSD). Large family and twin studies have consistently shown that insomnia is under strong genetic influence: first-degree relatives of patients with primary insomnia are at a 6.65-fold increased risk to develop insomnia themselves. 3,4 Among other factors, anxious-ruminative personality traits 5 and occurrence of stressful life events contribute to the onset and perpetuation of insomnia. 6 Thus, primary insomnia may be regarded as a potential consequence of gene-environment interaction. Primary insomnia and other insomnia diagnoses show an association with mood disorders, with insomnia typically appearing before the onset of depression. 1 Therefore, insomnia could either be a risk factor for depression, or insomnia and affective disorders could share a common background, e.g., as a spectrum of stress-related disorders. There is a longstanding discussion on the role of serotonin (5-HT) in the regulation of sleep. 7,8 In rodents and cats, it has been shown that typical, but not all 9 serotonergic raphe neurons discharge regularly during waking, at slower rates during slow wave sleep, and cease firing during paradoxical sleep, 10 which indicates serotonergic activity being related to wakefulness. In addition to this possible REM sleep inhibitory action, sleep facilitatory effects have also been reported, 11 likely due to the multitude of postsynaptic receptors, which mediate different responses. In particular, studies in humans support the 5HT 2 -receptor to be involved in slow wave sleep regulation. 12,13 Accordingly, several 5-HT 2a receptor antagonists or inverse agonists are currently being tested in randomized controlled trials for treatment of primary insomnia, 14 which underscores 5-HT's role in the regulation of sleep. The key regulator of serotonin in the synapse, and therefore of overall serotonergic activity, is the 5-HT transporter (5-HTT). The presynaptic 5-HTT is the target of most antidepressants. A frequent variant of the 5-HTT gene (SLC6A4,17q11.2) is a 44 basepair insertion/deletion polymorphism in the 5' regulatory region of the 5-HTT gene; and it affects gene transcription and transporter density in transfected cells. SLC6A4 genotype, usually grouped into "short" (s)-and "long" (l)-alleles, has been studied extensively with regard to psychiatric phenotypes and has been found to be associated with a variety of stress-related psychiatric conditions, such as trait anxiety 15,16 and risk for affective disorders, 17 especially in interaction with environmental adversity. 18,19 Moreover, the 5-HTTLPR s-allele has also been found associated with poor sleep quality in chronic stress 20 and worsened insomnia in depressed patients being treated with fluoxetine. 21 Based on these findings and on the role of psychosocial stress in pathophysiological concepts of primary insomnia, 22 we hypothesized that s-allele of 5-HTTLPR would be associated with primary insomnia. METHODS AND MATERIALS Primary Insomnia Patients Our sleep laboratory is a referral center for patients with probable neuropsychiatric sleep disorders but not for patients with Study Objective: To test the hypothesis that a 44-base-pair insertion/deletion polymorphism in the 5' regulatory region of the serotonin transporter gene (5-HTTLPR) is associated with primary insomnia. Design: Association study. Setting: Sleep laboratory at the Central Institute of Mental Health, Mannheim, Germany. Patients: 157 patients with primary insomnia and 827 healthy controls. Interventions: N/A. Measurement and Results: We found the short (s-) allele of the 5-HTTLPR to be significantly more frequent in patients suffering from insomnia than in control individuals (47.1% vs. 39.9%: OR = 1.34). Conclusions: This finding contributes to the understanding of the pathophysiology of primary insomnia and suggests a biological basis between the prevalent comorbidity of primary insomnia and other psychiatric disorders.
doi:10.1093/sleep/33.3.343 pmid:20337192 pmcid:PMC2831428 fatcat:aymmydnskjb65j4au6cxdjwkia

Urbanicity, behavior problems and HPA axis regulation in preschoolers

Pauline S. Effenberger, Tabea S. Send, Maria Gilles, Isabell A.-C. Wolf, Josef Frank, Stephan Bongard, Robert Kumsta, Stephanie H. Witt, Marcella Rietschel, Michael Deuschle, Fabian Streit
2022 Psychoneuroendocrinology  
Growing up in cities is associated with increased risk for developing mental health problems. Stress exposure and altered stress regulation have been proposed as mechanisms linking urbanicity and psychopathology, with most research conducted in adult populations. Here, we focus on early childhood, and investigate urbanicity, behavior problems and the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, a central circuit of the stress system, in a sample of N = 399 preschoolers aged 45
more » ... nths. Urbanicity was coded dichotomously distinguishing between residences with more or less than 100,000 inhabitants. Behavior problems were measured using the Child Behavior Checklist (CBCL) 1½ - 5. Cortisol stress reactivity was assessed using an age-appropriated game-like stress task, and cortisol in the first morning urine was measured to assess nocturnal HPA axis activity. Urbanicity was not associated with behavior problems, urinary cortisol or the cortisol stress response. Neither urinary cortisol nor salivary cortisol response after stress exposure were identified as mediators of the relationship between urbanicity and behavior problems. The findings suggest no strong association of urbanicity with behavior problems and HPA axis regulation in preschool age. To our knowledge, this is the youngest sample to date studying the relationship between urbanicity and behavior problems as well as HPA axis regulation. Future research should examine at which age associations can first be identified and which mechanisms contribute to these relationships.
doi:10.1016/j.psyneuen.2022.105660 pmid:35033927 fatcat:xxfwyli2rvawne7ejjunyr3mwi

Associations between SNPs and immune-related circulating proteins in schizophrenia

Man K. Chan, Jason D. Cooper, Stefanie Heilmann-Heimbach, Josef Frank, Stephanie H. Witt, Markus M. Nöthen, Johann Steiner, Marcella Rietschel, Sabine Bahn
2017 Scientific Reports  
Apo-H APOH rs9892748 17 −0.10 2.87E-02 1.79E-01 57 Apolipoprotein(a) Lpa LPA exm-rs7770628 6 −0.76 1.46E-04 1.82E-03 95 rs73596816 6 −2.13 4.88E-06 7.22E-05 100 rs10455872 6  ...  exm-rs769449 19 0.30 1.10E-03 1.18E-02 81 rs769449 19 0.30 1.10E-03 1.18E-02 81 rs72654473 19 −0.34 1.10E-03 1.18E-02 89 rs7412 19 −0.49 5.66E-06 8.18E-05 99 Apolipoprotein H  ... 
doi:10.1038/s41598-017-12986-0 pmid:28974776 pmcid:PMC5626704 fatcat:av73kqzbujbydonrjujxybubqe

Methylome-wide change associated with response to electroconvulsive therapy in depressed patients

Lea Sirignano, Josef Frank, Laura Kranaster, Stephanie H. Witt, Fabian Streit, Lea Zillich, Alexander Sartorius, Marcella Rietschel, Jerome C. Foo
2021 Translational Psychiatry  
AbstractElectroconvulsive therapy (ECT) is a quick-acting and powerful antidepressant treatment considered to be effective in treating severe and pharmacotherapy-resistant forms of depression. Recent studies have suggested that epigenetic mechanisms can mediate treatment response and investigations about the relationship between the effects of ECT and DNA methylation have so far largely taken candidate approaches. In the present study, we examined the effects of ECT on the methylome associated
more » ... ith response in depressed patients (n = 34), testing for differentially methylated CpG sites before the first and after the last ECT treatment. We identified one differentially methylated CpG site associated with the effect of ECT response (defined as >50% decrease in Hamilton Depression Rating Scale score, HDRS), TNKS (q < 0.05; p = 7.15 × 10−8). When defining response continuously (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 (p = 3.94 × 10−7). Regional analyses identified two differentially methylated regions on chromosomes 8 (Šídák's p = 0.0031) and 20 (Šídák's p = 4.2 × 10−5) associated with ΔHDRS. Functional pathway analysis did not identify any significant pathways. A confirmatory look at candidates previously proposed to be involved in ECT mechanisms found CpG sites associated with response only at the nominally significant level (p < 0.05). Despite the limited sample size, the present study was able to identify epigenetic change associated with ECT response suggesting that this approach, especially when involving larger samples, has the potential to inform the study of mechanisms involved in ECT and severe and treatment-resistant depression.
doi:10.1038/s41398-021-01474-9 pmid:34091594 fatcat:nusvsemupbds7oh4edai3upfqm

Neurocognitive Endophenotypes of Schizophrenia and Bipolar Disorder and Possible Associations with FKBP Variant rs3800373

Amra Memic, Fabian Streit, Lejla Hasandedic, Stephanie H Witt, Jana Strohmaier, Marcella Rietschel, Lilijana Oruc
2018 Medicinski arhiv  
Schizophrenia(SCZ) and Bipolar disorder (BD) are frequently occurring and impairing disorders that affect around 1% of the population. Important endophenotypes in the genetic research of SCZ and BD are cognitive functions. Core symptoms for SCZ and BD are impairments in working memory, declarative memory and attention, all of which fulfill the criteria for an endophenotype. The FK506 Binding Protein 5 (FKBP5) gene codes for a co-chaperone of the glucocorticoid receptor and has been reported to
more » ... e associated with cognition. The aims of our research were to determine the degree of cognitive impairment in patients suffering from SCZ and BD and to explore the association of the FKBP5 variant rs3800373 genotype with the cognitive endophenotypes. Patients and healthy controls were recruited over a period of two years from the Psychiatric Clinic, Clinical Center University of Sarajevo. Genotyping and neuropsychological assessments were performed for 263 subjects (129 SCZ, 53 BD, and 81 healthy controls [HC]). Neuropsychological assessments were performed for all patients with the Trail Making Test-A&B (TMT-A&B) and Digit-span forward&backwards tasks. The single nucleotide polymorphism (SNP) rs3800373 in the FKBP5 gene was genotyped using Infinium PsychArray Bead Chips. SCZ and BD patients performed lower than HC in the TMT-A&B and in the Digit-span backwards task, while no differences were observed between SCZ and BD patients. While SCZ patients performed lower than HC in the Digit-span forwards task, there were no differences between BD and HC or between BD and SCZ. Rs 3800373 was not associated with performance in the TMT-A&B or Digit-span forwards&backwards tasks. SCZ and BD share largely overlapping neurocognitive characteristics. Rs3800373 was not associated with performance in the neuropsychological tests. However, given the limited sample size, the results do not exclude an association with the rs3800373 variant in a larger sample. Furthermore, as the analysis was limited to one SNP, the results cannot be generalized to other genetic variants in FKBP5.
doi:10.5455/medarh.2018.72.352-356 pmid:30524168 pmcid:PMC6282916 fatcat:6x6gvoujenat5hrgxzr6u3pfgi

Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways [article]

Jerome Clifford Foo, Nina Trautmann, Carsten Sticht, Jens Treutlein, Josef Frank, Fabian Streit, Stephanie H Witt, Carolina De La Torre, Steffen Conrad von Heydendorff, Lea Sirignano, Junfang Chen, Bertram Mueller-Myhsok (+5 others)
2019 bioRxiv   pre-print
T h e m e c h a n i s m s t h r o u g h w h i c h S D e x e r t s i t s a n t i d e p r e s s a n t e f f e c t s n e v e r t h e l e  ...  c o m m u n i c a t i o n w i t h T h e r m o F i s h e r ) .  ... 
doi:10.1101/628172 fatcat:cjljyuy3a5bhjnhg5ty5cl6p4y

Functional Connectivity Analyses in Imaging Genetics: Considerations on Methods and Data Interpretation

Johannes Bedenbender, Frieder M. Paulus, Sören Krach, Martin Pyka, Jens Sommer, Axel Krug, Stephanie H. Witt, Marcella Rietschel, Davide Laneri, Tilo Kircher, Andreas Jansen, Yong He
2011 PLoS ONE  
Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders ("imaging genetics"). A data analysis approach that is widely applied is "functional connectivity". In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called "seed point") and other brain voxels is determined. In this technical note, we show how the choice of freely
more » ... data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters.
doi:10.1371/journal.pone.0026354 pmid:22220190 pmcid:PMC3248388 fatcat:44d3cffefjbyfkgtlznmsvcqqy

Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways

Jerome C. Foo, Nina Trautmann, Carsten Sticht, Jens Treutlein, Josef Frank, Fabian Streit, Stephanie H. Witt, Carolina De La Torre, Steffen Conrad von Heydendorff, Lea Sirignano, Junfang Chen, Bertram Müller-Myhsok (+5 others)
2019 Translational Psychiatry  
Participants remained awake from~0600 h on Day 2 to 1800 h on Day 3 (36 h). On Day 3, participants underwent recovery sleep from 1800-0100 h.  ...  It should be noted that the recovery sleep episode was a total of 7 h in length (i.e. 1800-0100 h) after a 36 h homeostatic buildup of sleep pressure; this may not be long enough for homeostasis to recover  ... 
doi:10.1038/s41398-019-0671-7 pmid:31852885 pmcid:PMC6920477 fatcat:cgiogkbdzrbm7m25vqoucdxrey

The Effect of Neurogranin on Neural Correlates of Episodic Memory Encoding and Retrieval

Axel Krug, Sören Krach, Andreas Jansen, Vanessa Nieratschker, Stephanie H. Witt, N. Jon Shah, Markus M. Nöthen, Marcella Rietschel, Tilo Kircher
2011 Schizophrenia Bulletin  
Neurogranin (NRGN) is the main postsynaptic protein regulating the availability of calmodulin-Ca(21) in neurons. NRGN is expressed exclusively in the brain, particularly in dendritic spines and has been implicated in spatial learning and hippocampal plasticity. Genetic variation in rs12807809 in the NRGN gene has recently been confirmed to be associated with schizophrenia in a meta-analysis of genome-wide association studies: the T-allele was found to be genome-wide significantly associated
more » ... schizophrenia. Cognitive tests and personality questionnaires were administered in a large sample of healthy subjects. Brain activation was measured with functional magnetic resonance imaging (fMRI) during an episodic memory encoding and retrieval task in a subsample. All subjects were genotyped for NRGN rs12807809. There was no effect of genotype on personality or cognitive measures in the large sample. Homozygote carriers of the T-allele showed better performance in the retrieval task during fMRI. After controlling for memory performance, differential brain activation was evident in the anterior cingulate cortex for the encoding and posterior cingulate regions during retrieval. We could demonstrate that rs12807809 of NRGN is associated with differential neural functioning in the anterior and posterior cingulate. These areas are involved in episodic memory processes and have been implicated in the pathophysiology of schizophrenia in structural and functional imaging as well as postmortem studies.
doi:10.1093/schbul/sbr076 pmid:21799211 pmcid:PMC3523918 fatcat:2qb5codkd5dcbknhkxzg5dfwlq

Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling

John D. Kanady, Stephanie J. Munger, Marlys H. Witte, Alexander M. Simon
2015 Developmental Biology  
., 2005; Witte et al., 2009) .  ...  Lymphedema in utero may cause these bone malformations by impairing the migration of tissues during embryonic development (Witt et al., 1987) .  ... 
doi:10.1016/j.ydbio.2015.06.004 pmid:26079578 pmcid:PMC4529811 fatcat:delxkfsz3bdgfdtkj47mnruuii

Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions [article]

Lea Zillich, Josef Frank, Fabian Streit, Marion M Friske, Jerome C Foo, Lea Sirignano, Stefanie Heilmann-Heimbach, Franziska Degenhardt, Per Hoffmann, Anita C Hansson, Markus M Noethen, Marcella Rietschel (+2 others)
2021 medRxiv   pre-print
Alcohol Use Disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n=53) and controls (n=58) using a brain region-specific approach. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum
more » ... ), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted Correlation Network Analysis (WGCNA), gene-set and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < .05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < .05) were found in the CN (n=6), VS (n=18) and ACC (n=1). These findings were mapped to several genes including IREB2, SLC30A8, and DDAH2. In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD
doi:10.1101/2021.08.01.21261118 fatcat:mdtwf3jwz5asffjwzk5w3hizuu
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