Publications by authors named "Stephanie H Witt"

158 Publications

Ventral Striatal-Hippocampus Coupling During Reward Processing as a Stratification Biomarker for Psychotic Disorders.

Biol Psychiatry 2021 Jul 24. Epub 2021 Jul 24.

Systems Neuroscience in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany. Electronic address:

Background: Altered ventral striatal (vST) activation to reward expectancy is a well-established intermediate phenotype for psychiatric disorders, specifically schizophrenia (SZ). Preclinical research suggests that striatal alterations are related to a reduced inhibition by the hippocampal formation, but its role in human transdiagnostic reward-network dysfunctions is not well understood.

Methods: We performed functional magnetic resonance imaging during reward processing in 728 individuals including healthy control subjects (n = 396), patients (SZ: n = 46; bipolar disorder: n = 45; major depressive disorder: n = 60), and unaffected first-degree relatives (SZ: n = 46; bipolar disorder: n = 50; major depressive disorder: n = 85). We assessed disorder-specific differences in functional vST-hippocampus coupling and transdiagnostic associations with dimensional measures of positive, negative, and cognitive symptoms. We also probed the genetic underpinning using polygenic risk scores for SZ in a subset of healthy participants (n = 295).

Results: Functional vST-hippocampus coupling was 1) reduced in patients with SZ and bipolar disorder (p < .05, small-volume corrected [SVC]); 2) associated transdiagnostically to dimensional measures of positive (p = .01, SVC) and cognitive (p = .02, SVC), but not negative, (p > .05, SVC) symptoms; and 3) reduced in first-degree relatives of patients with SZ (p = .017, SVC) and linked to the genetic risk for SZ in healthy participants (p = .035).

Conclusions: We provide evidence that reduced vST-hippocampus coupling during reward processing is an endophenotype for SZ linked to positive and cognitive symptoms, supporting current preclinical models of the emergence of psychosis. Moreover, our data indicate that vST-hippocampus coupling is familial and linked to polygenic scores for SZ, supporting the use of this measure as an intermediate phenotype for psychotic disorders.
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http://dx.doi.org/10.1016/j.biopsych.2021.07.016DOI Listing
July 2021

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Sci Rep 2021 09 8;11(1):17823. Epub 2021 Sep 8.

Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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http://dx.doi.org/10.1038/s41598-021-97140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426488PMC
September 2021

Microbiome profiles are associated with cognitive functioning in 45-month-old children.

Brain Behav Immun 2021 Nov 6;98:151-160. Epub 2021 Aug 6.

Stanley Division of Developmental Neurovirology, Department of Pediatrics. Johns Hopkins School of Medicine, Baltimore, MD, United States.

Prenatal, perinatal, and postnatal factors have been shown to shape neurobiological functioning and alter the risk for mental disorders later in life. The gut microbiome is established early in life, and interacts with the brain via the brain-immune-gut axis. However, little is known about how the microbiome relates to early-life cognitive functioning in children. The present study, where the fecal microbiome of 380 children was characterized using 16S rDNA and metagenomic sequencing aimed to investigate the association between the microbiota and cognitive functioning of children at the age of 45 months measured with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Overall the microbiome profile showed a significant association with cognitive functioning. A strong correlation was found between cognitive functioning and the relative abundance of an unidentified genus of the family Enterobacteriaceae. Follow-up mediation analyses revealed significant mediation effects of the level of this genus on the association of maternal smoking during pregnancy and current cigarette smoking with cognitive function. Metagenomic sequencing of a subset of these samples indicated that the identified genus was most closely related to Enterobacter asburiae. Analysis of metabolic potential showed a nominally significant association of cognitive functioning with the microbial norspermidine biosynthesis pathway. Our results indicate that alteration of the gut microflora is associated with cognitive functioning in childhood. Furthermore, they suggest that the altered microflora might interact with other environmental factors such as maternal cigarette smoking. Interventions directed at altering the microbiome should be explored in terms of improving cognitive functioning in young children.
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http://dx.doi.org/10.1016/j.bbi.2021.08.001DOI Listing
November 2021

Interaction of developmental factors and ordinary stressful life events on brain structure in adults.

Neuroimage Clin 2021 21;30:102683. Epub 2021 Apr 21.

Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Hans-Meerwein-Str. 6, 35032 Marburg, Germany; Marburg University Hospital - UKGM, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.

An interplay of early environmental and genetic risk factors with recent stressful life events (SLEs) in adulthood increases the risk for adverse mental health outcomes. The interaction of early risk and current SLEs on brain structure has hardly been investigated. Whole brain voxel-based morphometry analysis was performed in N = 786 (64.6% female, mean age = 33.39) healthy subjects to identify correlations of brain clusters with commonplace recent SLEs. Genetic and early environmental risk factors, operationalized as those for severe psychopathology (i.e., polygenic scores for neuroticism, childhood maltreatment, urban upbringing and paternal age) were assessed as modulators of the impact of SLEs on the brain. SLEs were negatively correlated with grey matter volume in the left medial orbitofrontal cortex (mOFC, FWE p = 0.003). This association was present for both, positive and negative, life events. Cognitive-emotional variables, i.e., neuroticism, perceived stress, trait anxiety, intelligence, and current depressive symptoms did not account for the SLE-mOFC association. Further, genetic and environmental risk factors were not correlated with grey matter volume in the left mOFC cluster and did not affect the association between SLEs and left mOFC grey matter volume. The orbitofrontal cortex has been implicated in stress-related psychopathology, particularly major depression in previous studies. We find that SLEs are associated with this area. Important early life risk factors do not interact with current SLEs on brain morphology in healthy subjects.
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http://dx.doi.org/10.1016/j.nicl.2021.102683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102615PMC
July 2021

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

Transl Psychiatry 2021 06 5;11(1):347. Epub 2021 Jun 5.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Electroconvulsive 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 with 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). When defining response continuously (ΔHDRS), the top suggestive differentially methylated CpG site was in FKBP5 (p = 3.94 × 10). Regional analyses identified two differentially methylated regions on chromosomes 8 (Šídák's p = 0.0031) and 20 (Šídák's p = 4.2 × 10) 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.
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http://dx.doi.org/10.1038/s41398-021-01474-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179923PMC
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Effects of polygenic risk for major mental disorders and cross-disorder on cortical complexity.

Psychol Med 2021 Apr 8:1-12. Epub 2021 Apr 8.

Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg, Rudolf-Bultmann-Str. 8, 35039Marburg, Germany.

Background: MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood.

Methods: We extracted cortical complexity values from structural MRI data of 580 healthy participants using the CAT12 toolbox. Polygenic risk scores (PRS) for schizophrenia, bipolar disorder, major depression, and cross-disorder (incorporating cumulative genetic risk for depression, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder) were computed and used in separate general linear models with cortical complexity as the regressand. In brain regions that showed a significant association between polygenic risk for mental disorders and cortical complexity, volume of interest (VOI)/region of interest (ROI) analyses were conducted to investigate additional changes in their volume and cortical thickness.

Results: The PRS for depression was associated with cortical complexity in the right orbitofrontal cortex (right hemisphere: p = 0.006). A subsequent VOI/ROI analysis showed no association between polygenic risk for depression and either grey matter volume or cortical thickness. We found no associations between cortical complexity and polygenic risk for either schizophrenia, bipolar disorder or psychiatric cross-disorder when correcting for multiple testing.

Conclusions: Changes in cortical complexity associated with polygenic risk for depression might facilitate well-established volume changes in orbitofrontal cortices in depression. Despite the absence of psychopathology, changed cortical complexity that parallels polygenic risk for depression might also change reward systems, which are also structurally affected in patients with depressive syndrome.
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http://dx.doi.org/10.1017/S0033291721001082DOI Listing
April 2021

Childhood trauma and insulin-like growth factors in amniotic fluid: An exploratory analysis of 79 women.

Psychoneuroendocrinology 2021 05 27;127:105180. Epub 2021 Feb 27.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Perinatal stress has adverse effects on fetal outcome, yet the effect of early maternal trauma on fetal outcome has scarcely been studied. We investigated effects of maternal childhood trauma and current environment on important regulators of prenatal growth, fetal insulin-like growth factor (IGF)-1 and IGF-2 in amniotic fluid and assessed the impact of IGFs on newborn anthropometrics.

Methods: 79 pregnant women in their second trimester who underwent amniocentesis (15.9 ± 0.9 weeks of gestational age) and their newborns at birth were analyzed. Maternal childhood trauma was assessed using the childhood trauma questionnaire (CTQ) and current environment was operationalized by assessing maternal psychosocial, physical health and endocrine measurements in amniotic fluid.

Results: In this exploratory analysis of 79 pregnant women, maternal childhood trauma, defined as reporting at least low scores on any of the CTQ subscales, negatively correlated with fetal IGF-1 (M = 3.48 vs. 2.98; p = 0.012) and IGF-2 (Mdn = 4.99 vs. 4.70; p = 0.002). Trauma severity, defined as the overall trauma score, negatively correlated with fetal IGF-2 (r = -0.24; p = 0.037). From trauma subscales, maternal sexual abuse correlated with fetal IGF-1 (r = -0.32; p = 0.006) and IGF-2 (r = -0.39; p = 0.001). Maternal BMI negatively correlated with fetal IGF-1 (r = -0.26; p = 0.023) and IGF-2 (r = -0.29; p = 0.011). Newborn anthropometrics were operationalized by length, weight, sex, gestational age, length/gestational age and weight/gestational age at birth. Fetal weight at birth associated with a trend with fetal IGF-1 when controlling for BMI. Maternal hypothalamus-pituitary-adrenal axis activity and maternal exercise did not contribute significantly to predicting fetal IGFs. Maternal childhood trauma (β = -0.27; p = 0.011) and BMI (β = -0.24; p = 0.026) remained significantly associated with fetal IGF-1. Maternal childhood trauma (β = -0.32; p = 0.003), maternal BMI (β = -0.30; p = 0.005) and maternal sexual abuse (β = -0.22; p = 0.049) remained significantly associated with fetal IGF-2 and with a trend with fetal IGF-1 (β = -0.21; p = 0.076) when excluding women with gestational diabetes.

Conclusion: Maternal childhood trauma and BMI associate negatively with fetal IGF-1 and IGF-2 in amniotic fluid. Controlling for maternal BMI, fetal weight at birth remains associated with a trend with fetal IGF-1. The presented data suggests that childhood trauma can affect endocrine measurements of the developing next generation, providing a mechanism by which adverse maternal life events are transmitted to the next generation.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105180DOI Listing
May 2021

Rhythm of Fetoplacental 11β-Hydroxysteroid Dehydrogenase Type 2 - Fetal Protection From Morning Maternal Glucocorticoids.

J Clin Endocrinol Metab 2021 05;106(6):1630-1636

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, Mannheim, Germany.

Context: Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11β-HSD2 have not been studied.

Objective: We hypothesized that fetoplacental 11β-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11β-HSD2 activity.

Methods: In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11β-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11β-HSD2 rhythm and association with "acute affective or anxiety disorder" (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and "acute anxiety disorder" (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated.

Results: Activity of 11β-HSD2 correlated with time of amniocentesis, peaking in the morning (r = -0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11β-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = -0.225; P = 0.047).

Conclusion: Our study indicates a time-specific alteration of fetoplacental 11β-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge.
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http://dx.doi.org/10.1210/clinem/dgab113DOI Listing
May 2021

"The Heidelberg Five" personality dimensions: Genome-wide associations, polygenic risk for neuroticism, and psychopathology 20 years after assessment.

Am J Med Genet B Neuropsychiatr Genet 2021 03 15;186(2):77-89. Epub 2021 Feb 15.

Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.

HeiDE is a longitudinal population-based study that started in the 1990s and, at baseline, assessed an array of health-related personality questionnaires in 5133 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). At follow-up, 3268 HeiDE participants (post-QC) were genotyped on single nucleotide polymorphism (SNP) arrays. 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 psychiatric symptoms at follow-up. SNP-based heritability was significant for ELAB (34%) and LBCN (29%). A genome-wide association study for each personality dimension was conducted; only the phenotype PSYC yielded a genome-wide significant finding (p < 5 × 10 , top SNP rs138223660). Gene-based analyses identified significant findings for ELAB, TYAB, and PSYC. Polygenic risk scores for Neuroticism were only associated with ELAB. Each of The Heidelberg Five was related to depressive symptoms at follow-up. ELAB, LBCN, and PSYC were 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.
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http://dx.doi.org/10.1002/ajmg.b.32837DOI Listing
March 2021

Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families.

Transl Psychiatry 2021 01 11;11(1):31. Epub 2021 Jan 11.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.
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http://dx.doi.org/10.1038/s41398-020-01146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801527PMC
January 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 06 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

Molecular characterization of ulcerative colitis-associated colorectal carcinomas.

Mod Pathol 2021 06 14;34(6):1153-1166. Epub 2020 Dec 14.

Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). In contrast to sporadic colorectal tumorigenesis, TP53 mutations occur early in the progression from inflamed colonic epithelium to dysplasia to CRC, and are sometimes readily detectable in inflamed, (yet) non-dysplastic mucosa. Here, we analyzed formalin-fixed paraffin-embedded tissue samples from 19 patients with long-standing UC (median 18 years, range 3 to 34) who had developed CRC as a consequence of chronic inflammation of the large bowel. We performed microsatellite instability testing, copy number analysis by array-based comparative genomic hybridization, mutation analysis by targeted next generation sequencing (48-gene panel) and TP53 immunostaining. The results were compared to The Cancer Genome Atlas (TCGA) data on sporadic CRC. All UC-CRC lesions in our cohort were microsatellite stable. Overall, genomic imbalances of UC-CRCs showed patterns of chromosomal aneuploidies characteristic for sporadic CRC with the exception of gains of chromosome arm 5p (12 of 23 UC-CRC, 52%), which are rare in sporadic CRCs from TCGA (21 of 144, 15%; FDR adjusted P = 0.006). UC-CRCs showed a predilection for TP53 alterations, which was the most frequently mutated gene in our cohort (20 of 23, 87%). Interestingly, spatially separated tumor lesions from individual patients tended to harbor distinct TP53 mutations. Similar to CRCs arising in a background of Crohn's colitis, the genetic landscape of UC-CRCs was characterized by TP53 mutations and chromosomal aneuploidies including gains of chromosome arm 5p. Both alterations harbor the potential for early detection in precursor lesions, thus complementing morphologic diagnosis.
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http://dx.doi.org/10.1038/s41379-020-00722-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154647PMC
June 2021

Childhood maltreatment and cognitive functioning: the role of depression, parental education, and polygenic predisposition.

Neuropsychopharmacology 2021 04 14;46(5):891-899. Epub 2020 Aug 14.

Department of Psychiatry, University of Münster, Münster, Germany.

Childhood maltreatment is associated with cognitive deficits that in turn have been predictive for therapeutic outcome in psychiatric patients. However, previous studies have either investigated maltreatment associations with single cognitive domains or failed to adequately control for confounders such as depression, socioeconomic environment, and genetic predisposition. We aimed to isolate the relationship between childhood maltreatment and dysfunction in diverse cognitive domains, while estimating the contribution of potential confounders to this relationship, and to investigate gene-environment interactions. We included 547 depressive disorder and 670 healthy control participants (mean age: 34.7 years, SD = 13.2). Cognitive functioning was assessed for the domains of working memory, executive functioning, processing speed, attention, memory, and verbal intelligence using neuropsychological tests. Childhood maltreatment and parental education were assessed using self-reports, and psychiatric diagnosis was based on DSM-IV criteria. Polygenic scores for depression and for educational attainment were calculated. Multivariate analysis of cognitive domains yielded significant associations with childhood maltreatment (η² = 0.083, P < 0.001), depression (η² = 0.097, P < 0.001), parental education (η² = 0.085, P < 0.001), and polygenic scores for depression (η² = 0.021, P = 0.005) and educational attainment (η² = 0.031, P < 0.001). Each of these associations remained significant when including all of the predictors in one model. Univariate tests revealed that maltreatment was associated with poorer performance in all cognitive domains. Thus, environmental, psychopathological, and genetic risk factors each independently affect cognition. The insights of the current study may aid in estimating the potential impact of different loci of interventions for cognitive dysfunction. Future research should investigate if customized interventions, informed by individual risk profiles and related cognitive preconditions, might enhance response to therapeutic treatments.
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http://dx.doi.org/10.1038/s41386-020-00794-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115656PMC
April 2021

Association of Locomotor Activity During Sleep Deprivation Treatment With Response.

Front Psychiatry 2020 21;11:688. Epub 2020 Jul 21.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Disrupted circadian rhythms and sleep patterns are frequently observed features of psychiatric disorders, and especially mood disorders. Sleep deprivation treatment (SD) exerts rapid but transient antidepressant effects in depressed patients and has gained recognition as a model to study quick-acting antidepressant effects. It is of interest how locomotor activity patterns during SD might be associated with and potentially predict treatment response. The present study is an analysis of locomotor activity data, previously collected over a 24 h period, to examine the night of SD (Trautmann et al. 2018) as mood disorder patients suffering from a depressive episode (n = 78; after exclusions n = 59) underwent SD. In this exploratory analysis, the associations between response to SD, locomotor activity, and subjective mood during the 24 h period of SD were explored. Higher levels of activity overall were observed in non-responders (n = 18); in particular, non-responders moved more during the evening of SD until midnight and remained high thereafter. In contrast, activity in responders (n = 41) decreased during the evening and increased in the morning. Subjective mood was not found to be associated with locomotor activity. The window of data available in this analysis being limited, additional data from before and after the intervention are required to fully characterize the results observed. The present results hint at the possible utility of locomotor activity as a predictor and early indicator of treatment response, and suggest that the relationship between SD and locomotor activity patterns should be further investigated.
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http://dx.doi.org/10.3389/fpsyt.2020.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385277PMC
July 2020

Polygenic risk for schizophrenia and schizotypal traits in non-clinical subjects.

Psychol Med 2020 Aug 6:1-11. Epub 2020 Aug 6.

Department of Psychiatry and Psychotherapy, Philipps-University and University Hospital Marburg, UKGM, Rudolf-Bultmann-Str. 8, 35039Marburg, Germany.

Background: Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood.

Methods: We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors.

Results: We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy.

Conclusions: This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).
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http://dx.doi.org/10.1017/S0033291720002822DOI Listing
August 2020

Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study.

Mol Autism 2020 06 23;11(1):54. Epub 2020 Jun 23.

Department of Psychiatry and Psychotherapy, Philipps-University Marburg, 35039, Marburg, Germany.

Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction.
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http://dx.doi.org/10.1186/s13229-020-00345-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310295PMC
June 2020

Replication of a hippocampus specific effect of the tescalcin regulating variant rs7294919 on gray matter structure.

Eur Neuropsychopharmacol 2020 07 23;36:10-17. Epub 2020 May 23.

Department of Psychiatry, University of Münster, Albert-Schweitzer-Campus 1, Building A9, 48149 Münster, Germany. Electronic address:

While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association.
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http://dx.doi.org/10.1016/j.euroneuro.2020.03.021DOI Listing
July 2020

Leptin predicts cortical and subcortical gray matter volume recovery in alcohol dependent patients: A longitudinal structural magnetic resonance imaging study.

Horm Behav 2020 08 11;124:104749. Epub 2020 May 11.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Germany; Feuerlein Center on Translational Addiction Medicine (FCTS), University of Heidelberg, Germany.

The neuroprotective effects of leptin and its role in addictive disorders has been highlighted by several recent studies. However, its potential effects on morphological alterations in alcohol dependence are yet to be investigated. Associations between leptin and the longitudinal courses of gray matter volume (GMV) and cortical thickness (CT) were investigated in N = 62 alcohol-dependent patients that underwent structural magnetic resonance imaging after a mean abstinence of 12 (baseline) and 27 days (follow-up) respectively. Blood samples were collected at baseline to determine leptin levels. A cohort of N = 74 healthy individuals served as a reference sample. At baseline, alcohol-dependent patients compared to healthy controls displayed smaller GMV in the insula, parts of the superior, middle and inferior frontal gyri and hippocampal regions and thinner CT in the insula, parts of the superior and middle frontal cortices, the lateral orbitofrontal cortex and parts of the occipital and lingual cortices that partially recovered during abstinence (p < 0.05). In alcohol-dependent patients, leptin was a significant predictor of GMV and CT recovery in the areas that showed the strongest whole-brain effects, specifically GMV in the right insula (R = 0.070, p = 0.040) and left inferior frontal triangular gyrus (R = 0.076, p = 0.040), as well as CT in the left insula (R = 0.158, p = 0.004) and right superior frontal cortex (R = 0.180, p = 0.004). Present results support the role of leptin in predicting GMV and CT recovery during the first month of abstinence in alcohol-dependent patients.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104749DOI Listing
August 2020

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Mol Psychiatry 2021 06 16;26(6):2457-2470. Epub 2020 Mar 16.

Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
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http://dx.doi.org/10.1038/s41380-020-0689-5DOI Listing
June 2021

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: a longitudinal clinical study.

Addiction 2020 11 12;115(11):2034-2044. Epub 2020 Mar 12.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.

Background And Aims: Withdrawal is a serious and sometimes life-threatening event in alcohol-dependent individuals. It has been suggested that epigenetic processes may play a role in this context. This study aimed to identify genes and pathways involved in such processes which hint to relevant mechanisms underlying withdrawal.

Design: Cross-sectional case-control study and longitudinal within-cases study during alcohol withdrawal and after 2 weeks of recovery SETTING: Addiction medicine departments in two university hospitals in southern Germany.

Participants/cases: Ninety-nine alcohol-dependent male patients receiving in-patient treatment and suffering from severe withdrawal symptoms during detoxification and 95 age-matched male controls.

Measurements: Epigenome-wide methylation patterns were analyzed in patients during acute alcohol withdrawal and after 2 weeks of recovery, as well as in age-matched controls using Illumina EPIC bead chips. Methylation levels of patients and controls were tested for association with withdrawal status. Tests were adjusted for technical and batch effects, age, smoking and cell type distribution. Single-site analysis, as well as an analysis of differentially methylated regions and gene ontology analysis, were performed.

Findings: We found pronounced epigenome-wide significant [false discovery rate (FDR) < 0.05] differences between patients during withdrawal and after 2 weeks [2876 cytosine-phosphate-guanine (CpG) sites], as well as between patients and controls (9845 and 6094 CpG sites comparing patients at time-point 1 and patients at time-point 2 versus controls, respectively). Analysis of differentially methylated regions and involved pathways revealed an over-representation of gene ontology terms related to the immune system response. Differences between patients and controls diminished after recovery (> 800 CpG sites less), suggesting a partial reversibility of alcohol- and withdrawal-related methylation.

Conclusions: Acute alcohol withdrawal in severely dependent male patients appears to be associated with extensive changes in epigenome-wide methylation patterns. In particular, genes involved in immune system response seem to be affected by this condition.
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http://dx.doi.org/10.1111/add.15020DOI Listing
November 2020

Oxytocin attenuates neural response to emotional faces in social drinkers: an fMRI study.

Eur Arch Psychiatry Clin Neurosci 2021 Aug 19;271(5):873-882. Epub 2020 Feb 19.

Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

Introduction: Oxytocin is a key mediator of emotional and social behavior that seems to be of relevance for the development and maintenance of addictive behaviors. We thus investigated the effect of oxytocin on neural response and behavior during a face-matching task in a sample of social drinkers.

Methods: Thirteen social drinkers underwent a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging face-matching task with and without prior intranasal application of 24 international units oxytocin. Effects of oxytocin and task condition (faces, shapes) on brain activation and individual task performance were assessed.

Results: Face-matching compared to shape-matching trials resulted in higher brain activation in the bilateral amygdala, hippocampus and parts of the occipital gyri. Oxytocin application vs. placebo reduced activation in bilateral amygdala, parts of the frontal gyri, and the parietal lobe. Region of interest analyses indicated that the oxytocin-induced attenuation of amygdala response was specific to face-stimuli and associated with lower subjective alcohol craving, and a lower percentage of heavy-drinking days (defined as ≥ 5 standard drinks/day).

Conclusion: For the first time, we could show that a larger oxytocin-induced attenuation of amygdala response to fearful faces is associated with lower subjective craving for alcohol and percentage of heavy drinking days in social drinkers. Modulation of amygdala activation, induced by emotional stimuli, might represent a neurobiological substrate of oxytocin's protective effects on drug seeking behavior.
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http://dx.doi.org/10.1007/s00406-020-01115-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236029PMC
August 2021

Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families.

Transl Psychiatry 2020 02 4;10(1):57. Epub 2020 Feb 4.

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

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (p < 0.006) and schizophrenia (p = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.
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http://dx.doi.org/10.1038/s41398-020-0732-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026119PMC
February 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Rhythm and blues: Influence of CLOCK T3111C on peripheral electrophysiological indicators of negative affective processing.

Physiol Behav 2020 05 13;219:112831. Epub 2020 Feb 13.

Personality and Individual Differences, Institute of Psychology I, Technische Universität Dresden, Dresden, Germany.

Dysfunction in the circadian system has been linked to emotion regulation and mood disorders with genetic variation in clock genes as likely contributors. Here, we focused on endophenotypes of affective processing and investigated in two independent samples of healthy individuals (n=99, n=108) whether genotypes of a functional single nucleotide polymorphism (SNP) in the gene encoding CLOCK (CLOCK T3111C, rs1801260) differed in physiological responses to emotional stimuli. Both samples underwent an emotional startle paradigm with startle responses being measured via EMG. In the second sample, skin conductance responses as well as corrugator and zygomaticus activity were also assessed. In both samples, CLOCK T3111C was associated with overall startle responses to loud noise bursts with T/T homozygotes showing consistently more marked responses. However, in the all-female second sample, the effects of CLOCK on skin conductance responses to the same loud noise bursts depended on hormone status: similar to the startle results, in free-cycling women T/T homozygotes showed more pronounced skin conductance response (SCR) compared to C allele carriers. The opposite was true for women using combined oral contraceptives (COC). A further CLOCK × hormone status interaction effect was found for corrugator activity. In free-cycling women, T/T homozygotes presented with less corrugator activity to affective pictures compared to C allele carriers, while the opposite pattern emerged for COC users. The findings emphasize the potential role of CLOCK for affect and mood.
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http://dx.doi.org/10.1016/j.physbeh.2020.112831DOI Listing
May 2020

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

Neuropsychopharmacology 2020 07 14;45(8):1346-1352. Epub 2020 Feb 14.

Department of Clinical Psychology, Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.

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 from 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.
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http://dx.doi.org/10.1038/s41386-020-0637-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297989PMC
July 2020

An Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study.

JAMA Psychiatry 2020 05;77(5):523-533

Department of Psychiatry, Ruhr University Bochum, LWL University Hospital, Bochum, Germany.

Importance: Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations.

Objective: To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement.

Design, Setting, And Participants: This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019.

Main Outcomes And Measures: A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables.

Results: Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean [SD] partial η2 = 0.014 [0.003]) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort.

Conclusions And Relevance: Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.4910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042925PMC
May 2020

The role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder.

Int J Bipolar Disord 2020 Feb 12;8(1). Epub 2020 Feb 12.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.

Background: Stressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known.

Methods: We explored the role of DNA methylation in response to recent stressful life events in a cohort of bipolar patients from the longitudinal PsyCourse study (n = 96). Peripheral blood DNA methylomes were profiled at two time points for over 850,000 methylation sites. The association between impact ratings of stressful life events and DNA methylation was assessed, first by interrogating methylation sites in the vicinity of candidate genes previously implicated in the stress response and, second, by conducting an exploratory epigenome-wide association analysis. Third, the association between epigenetic aging and change in stress and symptom measures over time was investigated.

Results: Investigation of methylation signatures over time revealed just over half of the CpG sites tested had an absolute difference in methylation of at least 1% over a 1-year period. Although not a single CpG site withstood correction for multiple testing, methylation at one site (cg15212455) was suggestively associated with stressful life events (p < 1.0 × 10). Epigenetic aging over a 1-year period was not associated with changes in stress or symptom measures.

Conclusions: To the best of our knowledge, our study is the first to investigate epigenome-wide methylation across time in bipolar patients and in relation to recent, non-traumatic stressful life events. Limited and inconclusive evidence warrants future longitudinal investigations in larger samples of well-characterized bipolar patients to give a complete picture regarding the role of DNA methylation in the course of bipolar disorder.
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http://dx.doi.org/10.1186/s40345-019-0176-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013010PMC
February 2020

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

Transl Psychiatry 2019 12 18;9(1):343. Epub 2019 Dec 18.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Therapeutic 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. Patients (N = 78) and controls (N = 15) underwent SD, with blood taken at the same time of day before SD, 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. Circadian 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. Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level.
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http://dx.doi.org/10.1038/s41398-019-0671-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920477PMC
December 2019
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