TY  - JOUR
AB  - OBJECTIVE: A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the developing brain. METHODS: The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development. RESULTS: The GR was expressed in all cell types, with increasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation- and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors. CONCLUSIONS: These findings suggest that excessive glucocorticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.
AU  - Cruceanu, C.*
AU  - Dony, L.
AU  - Krontira, A.C.*
AU  - Fischer, D.S.
AU  - Roeh, S.*
AU  - Di Giaimo, R.*
AU  - Kyrousi, C.*
AU  - Kaspar, L.*
AU  - Knauer-Arloth, J.
AU  - Czamara, D.*
AU  - Martinelli, S.*
AU  - Wehner, S.*
AU  - Breen, M.S.*
AU  - Koedel, M.*
AU  - Sauer, S.*
AU  - Sportelli, V.*
AU  - Rex-Haffner, M.*
AU  - Cappello, S.
AU  - Theis, F.J.
AU  - Binder, E.B.*
C1  - 63441
C2  - 51435
CY  - 800 Maine Ave Sw, Suite 900, Washington, Dc 20024 Usa
SP  - 375-387
TI  - Cell-type-specific impact of glucocorticoid receptor activation on the developing brain: A cerebral organoid study.
JO  - Am. J. Psychiatry
VL  - 179
IS  - 5
PB  - Amer Psychiatric Publishing, Inc
PY  - 2021
SN  - 0002-953X
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h(2)SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS: Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h(2)SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.
AU  - Duncan, L.*
AU  - Yilmaz, Z.*
AU  - Gaspar, H.*
AU  - Walters, R.*
AU  - Goldstein, J.I.*
AU  - Anttila, V.*
AU  - Bulik-Sullivan, B.*
AU  - Ripke, S.*
AU  - Thornton, L.M.*
AU  - Hinney, A.*
AU  - Daly, M.*
AU  - Sullivan, P.F.*
AU  - Zeggini, E.*
AU  - Breen, G.*
AU  - Bulik, C.M.*
AU  - Eating Disorders Working Group of the Psychiatric Genomics Consortium (Wichmann, H.-E.
AU  - Tschöp, M.H.)
C1  - 52033
C2  - 43719
SP  - 850-858
TI  - Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa.
JO  - Am. J. Psychiatry
VL  - 174
IS  - 9
PY  - 2017
SN  - 0002-953X
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The authors previously reported an association between the D-amino acid oxidase activator (DAOA)/G30 locus and both schizophrenia and bipolar affective disorder. Given the presumed role of DAOA/G30 in the neurochemistry of psychosis and its localization in a schizophrenia and bipolar affective disorder linkage region (13q34), it was hypothesized that the bipolar affective disorder finding would be mainly due to an association with psychotic features. METHOD: The marker/haplotype associations obtained in a subset of 173 bipolar affective disorder patients with psychotic features were similar to those in the overall patient group, suggesting that stratification on the basis of psychotic features in general might be too crude a procedure. The authors therefore tested whether confining caseness to specific psychotic features would improve detection of genotype-phenotype correlations. RESULTS: In a logistic regression, "persecutory delusions" were found to be the only significant explanatory variable for the DAOA/G30 risk genotype among 21 OPCRIT symptoms of psychosis. The authors therefore tested for association between DAOA/G30 and bipolar affective disorder in the 90 cases with a history of persecutory delusions. Whereas this subset showed strong association (odds ratio=1.83 for the best marker), the remaining larger sample of 165 patients with no such history did not differ from comparison subjects, suggesting that the association between DAOA/G30 and bipolar affective disorder is due to persecutory delusions. This was confirmed in an independent study of 294 bipolar affective disorder patients and 311 comparison subjects from Poland, in which an association between bipolar affective disorder and DAOA/G30 was only seen when case definition was restricted to cases with persecutory delusions. CONCLUSIONS: These data suggest that bipolar affective disorder with persecutory delusions constitutes a distinct subgroup of bipolar affective disorder that overlaps with schizophrenia.
AU  - Schulze, T.G.*
AU  - Ohlraun, S.*
AU  - Czerski, P.M.*
AU  - Schumacher, J.*
AU  - Heidmann, V.*
AU  - Kovalenko, S.*
AU  - Abou Jamra, R.*
AU  - Becker, T.*
AU  - Leszczynska-Rodziewicz, A.*
AU  - Hauser, J.*
AU  - Illig, T.
AU  - Klopp, N.
AU  - Wellek, S.*
AU  - Cichon, S.*
AU  - Henn, F.A.*
AU  - McMahon, F.J.*
AU  - Maier, W.*
AU  - Propping, P.*
AU  - Noethen, M.M.*
AU  - Rietschel, M.*
C1  - 3358
C2  - 23272
SP  - 2101-2108
TI  - Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: A first step toward a molecular genetic classicfication of psychiatric phenotypes.
JO  - Am. J. Psychiatry
VL  - 162
IS  - 11
PY  - 2005
SN  - 0002-953X
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Progress in resuscitation medicine allows an increasing proportion of patients to survive an out-of-hospital cardiac arrest. However, little is known about long-term adaptation to the vital breakdown. The present study assessed the long-term prevalence and severity of emotional disability of cardiac arrest survivors and ascertained whether survivors suffer from recurrent and intrusive recollections of the cardiac arrest. METHOD: Follow-up analysis was performed on all cardiac arrest survivors discharged from the hospital over a 5-year interval (1990–1994) in a defined inner city and suburban area. From 118 initially hospitalized cardiac arrest survivors, 45 patients were discharged alive from the hospital. After a mean follow-up period of 39 months (range=22–64), 25 patients exhibited sufficient cerebral performance for psychodiagnostic assessment; 21 patients were assessed. RESULTS: Despite an impaired ability to concentrate, cardiac arrest survivors had levels of psychological adjustment at follow-up that were similar to those of 35 cardiac patients whose clinical course was not complicated by cardiac arrest. However, the diagnosis of psychotraumatic symptoms in cardiac arrest survivors led to a sharp separation between favorable and nonfavorable outcome in affective regulation and level of functioning. Of the cardiac arrest patients, those with high scores of intrusion and avoidance (N=8) reported an enduring sense of demoralization with significantly more somatic complaints, depression, anxiety, lack of confidence in the future, and narrowing of social activities than those with low scores (N=11). Long-acting sedation at illness onset significantly predicted a favorable outcome. CONCLUSIONS: This study provides the first empirical evidence that the application of the posttraumatic stress disorder paradigm in the long-term evaluation of cardiac arrest survivors significantly contributes to defining a patient population at high risk for serious emotional disability.
AU  - Ladwig, K.-H.
AU  - Schoefinius, A.*
AU  - Dammann, G.*
AU  - Danner, R.*
AU  - Gürtler, R.*
AU  - Herrmann, R.*
C1  - 21499
C2  - 19620
SP  - 912-919
TI  - Long-Acting Psychotraumatic Properties of a Cardiac Arrest Experience.
JO  - Am. J. Psychiatry
VL  - 156
IS  - 6
PY  - 1999
SN  - 0002-953X
ER  -