Biology subjects

Mueller-Myhsok, B.

Publications and source records attributed to Mueller-Myhsok, B..

10 recordsLinked to original sources

bioRxiv2024

Sex-specific fear acquisition following early life stress is linked to amygdala glutamate metabolism

Early life stress (ELS) adversely affects physiological and behavioral outcomes, increasing the vulnerability to stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD prevalence is significantly higher in women and is partially mediated by genetic risk variants. Understanding how sex influences the interaction of PTSD risk genes, such as FKBP5, with trauma-related behaviors is crucial for uncovering PTSDs neurobiological pathways. The development of in-depth behavioral analysis tools using unsupervised behavioral classification is thereby a crucial tool to increase the understanding of the behavioral outcomes related to stress-induced fear memory formation. The current study investigates the sex-specific effects of ELS exposure by using the limited bedding and nesting (LBN) paradigm. The LBN exposure disrupted different facets of the hypothalamic-pituitary-adrenal (HPA) axis in a sex-specific manner directly after stress and at adult age. Moreover, freezing was altered by LBN exposure in both the acquisition and the retrieval of fear in a sex-dependent manner. Unsupervised behavioral analysis revealed a higher active fear response after LBN exposure during fear acquisition in females, but not in males. The regulation of the HPA axis is closely intertwined with cellular metabolism and core regulatory cascades. To investigate the impact of LBN exposure on tissue-specific metabolism, a metabolomic pathway analysis in the basolateral amygdala revealed a specific sex- and stress-dependent effect on purine, pyrimidine, and glutamate metabolism. The present study highlights the intricate interplay between metabolic pathways and the neurobiological substrates implicated in fear memory formation and stress regulation. Overall, these findings highlight the importance of considering sex-specific metabolic alterations in understanding the neurobiological mechanisms underlying stress-related disorders and offer potential avenues for targeted interventions.

animal behavior and cognition↗

bioRxiv2022

Automatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress

Severe stress exposure is a global problem with long-lasting negative behavioral and physiological consequences, increasing the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and social behavioral changes. The current developments of markerless pose estimation tools allow for more complex and socially relevant behavioral tests, but the application of these tools to social behavior remains to be explored. Here, we introduce the open-source tool "DeepOF" to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut annotated pose estimation data. The supervised pipeline relies on pre-trained classifiers to detect defined traits for both single and dyadic animal behavior. Subsequently, the unsupervised pipeline explores the behavioral repertoire of the animals without label priming, which has the potential of pointing towards previously unrecognized motion motifs that are systematically different across conditions. We here provide evidence that the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter. The stress-induced social behavior shows a state of arousal that fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. DeepOF aims to facilitate reproducibility and unification of behavioral classification of social behavior by providing an open-source tool, which can significantly advance the study of rodent individual and social behavior, thereby enabling novel biological insights as well as drug development for psychiatric disorders.

neuroscience↗

bioRxiv2020

Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

RationaleGenetic factors undoubtedly contribute to the development of congenital heart disease (CHD), but still remain mostly ill-defined. ObjectiveIdentification of genetic risk factors associated with CHD and functional analysis of SNP-carrying genes. Methods and ResultsGenetic association study of 1,440 Caucasian CHD patients from the German Heart Center Munich collected from March 2009 to June 2016, 2,594 patients of previous studies provided by the Newcastle University and 8,486 controls underwent meta-analysis to detect single nucleotide polymorphisms (SNPs) associated with CHD. Results4,034 Caucasian CHD patients strictly classified according to the Society of Thoracic Surgeons nomenclature and 8,486 controls were included. One SNP on chromosome 5 reached genome-wide significance across all CHD phenotypes (rs185531658,OR:2.16, p=5.28x10-9) and was also indicative for septal defects (OR:2.16, p=6.15x10-8). One region on chromosome 20 pointing to the MACROD2 locus, identified four SNPs (rs150246290,OR:3.78, p=1.27x10-10; rs149890280,OR:3.74, p=1.8x10-10; rs149467721,OR:3.53; p=1.39x10-9, rs77094733,OR:3.53, p=1.73x10-9) in patients with transposition of the great arteries (TGA). A second region was detected on chromosome 8 located at ZBTB10 (rs148563140,OR:3.42, p=3.28x10-8; rs143638934,OR:3.42, p=3.51x10-8) in the same subgroup. Three highly significant risk variants on chromosome 17 (rs76774446,OR:1.60, p=9.95x10-8; rs11874,OR:1.60, p=6.64x10-8; rs17677363,OR:1.60, p=9.81x10-8) within the GOSR2 locus were identified in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence expression of WNT3, and variant rs870142 related to septal defects is proposed to influence expression of MSX1. Cardiac differentiation of human and murine induced pluripotent stem cells and single cell RNAseq analyses of developing murine and human hearts show essential functional roles for MACROD2, GOSR2, WNT3 and MSX1 at all developmental stages. ConclusionsFor the first time genetic risk factors in CHD patients with TGA and ATAV were identified. Several candidate genes play an essential functional role in heart development at the embryonic, newborn and adult stage.

genomics↗

bioRxiv2020

"The Heidelberg Five" Personality Dimensions: Genome-wide Associations, Polygenic Risk for Neuroticism, and Psychopathology 20 Years after Assessment

The HeiDE study ( Heidelberger Langzeitstudie zu Risikofaktoren und Diagnose chronischer Erkrankungen) is a longitudinal population-based study that started in the 1990s and, at baseline, assessed an array of health-related personality questionnaires in 5 133 individuals. Five latent personality dimensions (The Heidelberg Five) were identified and interpreted as Emotional Lability (ELAB), Lack of Behavioral Control (LBCN), Type A Behavior (TYAB), Locus of Control over Disease (LOCC), and Psychoticism (PSYC). A subset of participants (n=3 268; after quality control) were genotyped on whole-genome arrays at follow-up. To further characterize The Heidelberg Five, we analyzed genomic underpinnings, their relations to the genetic basis of the Big Five trait Neuroticism, and longitudinal associations with lifetime psychiatric symptoms. SNP-based heritability was significant for ELAB (34%) and LBCN (29%). Five separate genome-wide association studies (GWAS) using factor scores on personality dimensions as phenotypes were conducted, only the phenotype PSYC yielded a genome-wide significant finding (p<5x10-8, top SNP rs138223660). Gene-based analyses identified significant findings for ELAB (Integrin Subunit Beta 5), TYAB (Coiled-coil Domain Containing 83), and PSYC (Nuclear Receptor Subfamily 1 Group H Member 4). Polygenic risk scores for Neuroticism, phenotypically related to ELAB, were associated with ELAB, but not with the remaining Heidelberg Five. Longitudinally, all personality dimensions were related to depressive symptoms at follow-up, with ELAB, LBCN, and PSYC also associated with lifetime anxiety symptoms. These results highlight the clinical importance of health-related personality traits, and identify LBCN as a heritable "executive function" personality trait.

genomics↗

bioRxiv2019

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression.

IntroductionIts imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression.\n\nMethodsPolygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank.\n\nResultsAll cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression.\n\nConclusionsThe phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.

genetics↗

bioRxiv2019

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

BackgroundTherapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic clocks and that SD functions through resetting dysregulated genes; additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression. MethodsPatients (N=78) and controls (N=15) underwent SD, with blood taken at the same time of day before, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted. ResultsCircadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD; in non-responders, little response was observed. ConclusionsOur findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level.

epidemiology↗

bioRxiv2019

Cis-epistasis at the LPA locus and risk of coronary artery disease

Identification of epistasis affecting complex human traits has been challenging. Focusing on known coronary artery disease (CAD) risk loci, we explore pairwise statistical interactions between 8,068 SNPs from ten CAD genome-wide association studies (n=30,180). We discovered rs1800769 and rs9458001 in the vicinity of the LPA locus to interact in modulating CAD risk (P=1.75x10-13). Specific genotypes (e.g., rs1800769 CT) displayed either significantly decreased or increased risk for CAD in the context of genotypes of the respective other SNP (e.g., rs9458001 GG vs. AA). In the UK Biobank (n=450,112) significant interaction of this SNP pair was replicated for CAD (P=3.09x10-22), and was also found for aortic valve stenosis (P=6.95x10-7) and peripheral arterial disease (P=2.32x10-4). Identical interaction patterns affected circulating lipoprotein(a) (n=5,953; P=8.7x10-32) and hepatic apolipoprotein(a) (apo(a)) expression (n=522, P=2.6x10-11). We further interrogated potential biological implications of the variants and propose a mechanism explaining epistasis that ultimately may translate to substantial cardiovascular risks.

genetics↗

bioRxiv2018

Epigenetic derepression of FKBP5 by aging and stress contributes to NF-kB-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are poorly understood. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress exposure along the lifespan could confer disease risk by epigenetically deregulating molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with mechanistic in vitro investigations, we found that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n=3,131), aging and stress-related phenotypes were synergistically associated with epigenetic derepression of FKBP5. These age/stress-related epigenetic effects were recapitulated in an in vitro model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-{kappa}B-related gene networks. Accordingly, experiments in immune cells showed that FKBP5 overexpression promotes inflammation by strengthening the interactions of NF-{kappa}B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-{kappa}B. Further, the age/stress-related epigenetic signature enhanced FKBP5 responsivity to NF-{kappa}B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that FKBP5-NF-{kappa}B signaling mediates inflammation associated with aging and stress, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.\n\nSignificanceDiseases of the aging are the leading cause of morbidity and mortality. Elucidating the molecular mechanisms through which modifiable factors, such as psychosocial stress, confer risk for aging-related disease can have profound implications. Here, by combining studies in humans with experiments in cells, we find that aging and stress synergize to epigenetically derepress FKBP5, a protein implicated in stress physiology. Higher FKBP5 promotes inflammation by activating the master immune regulator NF-{kappa}B, whereas opposing FKBP5 - either genetically or pharmacologically- prevents the effects on NF-{kappa}B. Further, the age/stress-related epigenetic signature of FKBP5 is associated with history of myocardial infarction, a disease state linked to inflammation. These findings provide molecular insights into stress-related disease and may point to novel biomarker and treatment possibilities.

genomics↗

bioRxiv2018

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families as well as 438 subjects from an independent, sporadic BD case-control cohort were analysed. Polygenic risk scores (PRS) for BD, schizophrenia, and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had significantly higher PRS for all three psychiatric disorders than the independent controls, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and sporadic BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses, therefore, demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. The PRS explained only part of the observed phenotypic variance and rare variants might have also contributed to disease development.

genetics↗

bioRxiv2017

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. We isolated monocytes from 134 genotyped individuals, stimulated the cells with three defined microbe-associated molecular patterns (LPS, MDP, and ppp-dsRNA), and profiled the transcriptome at three time points. After mapping expression quantitative trait loci (eQTL), we identified 417 response eQTLs (reQTLs) with differing effect between the conditions. We characterized the dynamics of genetic regulation on early and late immune response, and observed an enrichment of reQTLs in distal cis-regulatory elements. Response eQTLs are also enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover novel reQTL effects in multiple GWAS loci, and show a stronger enrichment of response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli modifying genetic predisposition to disease.

genetics↗