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Article ; Online: Schizophrenia polygenic risk scores, clinical variables and genetic pathways as predictors of phenotypic traits of bipolar I disorder.

Grigoroiu-Serbanescu, Maria / van der Veen, Tracey / Bigdeli, Tim / Herms, Stefan / Diaconu, Carmen C / Neagu, Ana Iulia / Bass, Nicholas / Thygesen, Johan / Forstner, Andreas J / Nöthen, Markus M / McQuillin, Andrew

Journal of affective disorders

2024 Volume 356, Page(s) 507–518

Abstract: Aim: We investigated the predictive value of polygenic risk scores (PRS) derived from the schizophrenia GWAS (Trubetskoy et al., 2022) (SCZ3) for phenotypic traits of bipolar disorder type-I (BP-I) in 1878 BP-I cases and 2751 controls from Romania and ... ...

Abstract	Aim: We investigated the predictive value of polygenic risk scores (PRS) derived from the schizophrenia GWAS (Trubetskoy et al., 2022) (SCZ3) for phenotypic traits of bipolar disorder type-I (BP-I) in 1878 BP-I cases and 2751 controls from Romania and UK. Methods: We used PRSice-v2.3.3 and PRS-CS for computing SCZ3-PRS for testing the predictive power of SCZ3-PRS alone and in combination with clinical variables for several BP-I subphenotypes and for pathway analysis. Non-linear predictive models were also used. Results: SCZ3-PRS significantly predicted psychosis, incongruent and congruent psychosis, general age-of-onset (AO) of BP-I, AO-depression, AO-Mania, rapid cycling in univariate regressions. A negative correlation between the number of depressive episodes and psychosis, mainly incongruent and an inverse relationship between increased SCZ3-SNP loading and BP-I-rapid cycling were observed. In random forest models comparing the predictive power of SCZ3-PRS alone and in combination with nine clinical variables, the best predictions were provided by combinations of SCZ3-PRS-CS and clinical variables closely followed by models containing only clinical variables. SCZ3-PRS performed worst. Twenty-two significant pathways underlying psychosis were identified. Limitations: The combined RO-UK sample had a certain degree of heterogeneity of the BP-I severity: only the RO sample and partially the UK sample included hospitalized BP-I cases. The hospitalization is an indicator of illness severity. Not all UK subjects had complete subphenotype information. Conclusion: Our study shows that the SCZ3-PRS have a modest clinical value for predicting phenotypic traits of BP-I. For clinical use their best performance is in combination with clinical variables.
Language	English
Publishing date	2024-04-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	135449-8
ISSN	1573-2517 ; 0165-0327
ISSN (online)	1573-2517
ISSN	0165-0327
DOI	10.1016/j.jad.2024.04.066
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Article ; Online: Generation of induced pluripotent stem cells from two ADHD patients and two healthy controls.

Yde Ohki, Cristine Marie / Walter, Natalie Monet / Rickli, Michelle / Van Puyenbroeck, Pakita / Döring, Christian / Hoffmann, Per / Herms, Stefan / Maria Werling, Anna / Walitza, Susanne / Grünblatt, Edna

Stem cell research

2023 Volume 69, Page(s) 103084

Abstract: Attention-deficit hyperactivity disorder is a neurodevelopmental disorder which prevalence has been increasing in the past decades, affecting more than 5% of children, adolescents worldwide. Regarding etiology, polygenic, environmental factors contribute ...

Abstract	Attention-deficit hyperactivity disorder is a neurodevelopmental disorder which prevalence has been increasing in the past decades, affecting more than 5% of children, adolescents worldwide. Regarding etiology, polygenic, environmental factors contribute to the occurrence of ADHD even though molecular mechanisms are not known. Understanding the pathophysiology in patient-specific cells is crucial for the discovery of potential predictive markers, the establishment of new therapeutic targets. In this study, we generated further lines from ADHD patients, healthy controls using Sendai virus transduction, which may help on the study of ADHD at the molecular, cellular levels.
MeSH term(s)	Child ; Adolescent ; Humans ; Attention Deficit Disorder with Hyperactivity ; Induced Pluripotent Stem Cells ; Neurodevelopmental Disorders
Language	English
Publishing date	2023-03-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2023.103084
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Article ; Online: Relationships between neurotransmitter receptor densities and expression levels of their corresponding genes in the human hippocampus.

Zhao, Ling / Mühleisen, Thomas W / Pelzer, Dominique I / Burger, Bettina / Beins, Eva C / Forstner, Andreas J / Herms, Stefan / Hoffmann, Per / Amunts, Katrin / Palomero-Gallagher, Nicola / Cichon, Sven

NeuroImage

2023 Volume 273, Page(s) 120095

Abstract: Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro ... ...

Abstract	Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro receptor autoradiography and RNA sequencing to quantify, in the same tissue samples (7 subjects), the densities of 14 receptors and expression levels of their corresponding 43 genes in the Cornu Ammonis (CA) and dentate gyrus (DG) of human hippocampus. Significant differences in receptor densities between both structures were found only for metabotropic receptors, whereas significant differences in RNA expression levels mostly pertained ionotropic receptors. Receptor fingerprints of CA and DG differ in shapes but have similar sizes; the opposite holds true for their "RNA fingerprints", which represent the expression levels of multiple genes in a single area. In addition, the correlation coefficients between receptor densities and corresponding gene expression levels vary widely and the mean correlation strength was weak-to-moderate. Our results suggest that receptor densities are not only controlled by corresponding RNA expression levels, but also by multiple regionally specific post-translational factors.
MeSH term(s)	Humans ; Hippocampus/physiology ; Receptors, Neurotransmitter/genetics ; Receptors, Neurotransmitter/metabolism ; RNA/metabolism ; Autoradiography
Chemical Substances	Receptors, Neurotransmitter ; RNA (63231-63-0)
Language	English
Publishing date	2023-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1147767-2
ISSN	1095-9572 ; 1053-8119
ISSN (online)	1095-9572
ISSN	1053-8119
DOI	10.1016/j.neuroimage.2023.120095
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Zs.A 3664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Abelson Helper Integration Site 1 haplotypes and peripheral blood expression associates with lithium response and immunomodulation in bipolar patients.

Sakrajda, Kosma / Bilska, Karolina / Czerski, Piotr M / Narożna, Beata / Dmitrzak-Węglarz, Monika / Heilmann-Heimbach, Stefanie / Brockschmidt, Felix F / Herms, Stefan / Nöthen, Markus M / Cichon, Sven / Więckowska, Barbara / Rybakowski, Janusz K / Pawlak, Joanna / Szczepankiewicz, Aleksandra

Psychopharmacology

2023 Volume 241, Issue 4, Page(s) 727–738

Abstract: Rationale: In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity ... ...

Abstract	Rationale: In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment. Objectives: We hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the AHI1 haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether AHI1 expression and lithium treatment correlate with innate inflammatory response genes. Results: We genotyped seven AHI1 single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased AHI1 expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (TLR4, CASP4, CASP5, NLRP3, IL1A, IL1B, IL6, IL10, IL18) in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers. Conclusions: Our study suggests the involvement of AHI1 in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory IL10, suggesting lithium's immunomodulatory potential.
MeSH term(s)	Humans ; Lithium/pharmacology ; Lithium/therapeutic use ; Bipolar Disorder/drug therapy ; Bipolar Disorder/genetics ; Haplotypes ; Interleukin-10 ; Antimanic Agents/therapeutic use ; Lithium Compounds/pharmacology ; Lithium Compounds/therapeutic use
Chemical Substances	Lithium (9FN79X2M3F) ; Interleukin-10 (130068-27-8) ; Antimanic Agents ; Lithium Compounds
Language	English
Publishing date	2023-12-01
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-023-06505-5
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Article ; Online: Generation of integration-free induced pluripotent stem cell lines from four pediatric ADHD patients.

Grossmann, Leoni / Yde Ohki, Cristine Marie / Döring, Christian / Hoffmann, Per / Herms, Stefan / Werling, Anna Maria / Walitza, Susanne / Grünblatt, Edna

Stem cell research

2021 Volume 53, Page(s) 102268

Abstract: Human induced pluripotent stem cell (iPSC) lines have been derived from four male patients with childhood attention-deficit hyperactivity disorder (ADHD). Children and adolescents between the ages 6 and 18 suffering from ADHD were recruited for this work. ...

Abstract	Human induced pluripotent stem cell (iPSC) lines have been derived from four male patients with childhood attention-deficit hyperactivity disorder (ADHD). Children and adolescents between the ages 6 and 18 suffering from ADHD were recruited for this work. Isolated keratinocytes or peripheral blood mononuclear cells from the participants were reprogrammed into iPSCs using non-integrating Sendai virus to deliver the reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc.
MeSH term(s)	Adolescent ; Attention Deficit Disorder with Hyperactivity ; Cell Differentiation ; Cellular Reprogramming ; Child ; Humans ; Induced Pluripotent Stem Cells ; Keratinocytes ; Leukocytes, Mononuclear ; Male ; Sendai virus
Language	English
Publishing date	2021-02-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1876-7753
ISSN (online)	1876-7753
DOI	10.1016/j.scr.2021.102268
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Article ; Online: Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers.

Ziegler, Georg C / Radtke, Franziska / Vitale, Maria Rosaria / Preuße, André / Klopocki, Eva / Herms, Stefan / Lesch, Klaus-Peter

Stem cell research

2021 Volume 56, Page(s) 102526

Abstract: Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication ...

Abstract	Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries.
MeSH term(s)	Cell Differentiation ; Cell Line ; Cellular Reprogramming ; DNA Copy Number Variations ; Germ Layers ; Glucose Transporter Type 3 ; Humans ; Induced Pluripotent Stem Cells ; Leukocytes, Mononuclear
Chemical Substances	Glucose Transporter Type 3 ; SLC2A3 protein, human
Language	English
Publishing date	2021-09-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2021.102526
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Article ; Online: Generation of integration-free induced pluripotent stem cells from healthy individuals.

Yde Ohki, Cristine Marie / Grossmann, Leoni / Döring, Christian / Hoffmann, Per / Herms, Stefan / Werling, Anna Maria / Walitza, Susanne / Grünblatt, Edna

Stem cell research

2021 Volume 53, Page(s) 102269

Abstract: Ten human induced pluripotent stem cell (iPSC) lines have been derived from five healthy controls matched to a study including Attention-Deficit Hyperactivity Disorder patients (ADHD). Both female and male children and adolescents aged 6-18 years were ... ...

Abstract	Ten human induced pluripotent stem cell (iPSC) lines have been derived from five healthy controls matched to a study including Attention-Deficit Hyperactivity Disorder patients (ADHD). Both female and male children and adolescents aged 6-18 years were recruited. Isolated keratinocyte cells from the participants were reprogrammed into iPSCs using non-integrating Sendai virus to deliver the reprogramming factors Oct3/4, Sox2, Klf4 and cMyc.
MeSH term(s)	Adolescent ; Attention Deficit Disorder with Hyperactivity ; Cell Differentiation ; Cellular Reprogramming ; Child ; Female ; Humans ; Induced Pluripotent Stem Cells ; Keratinocytes ; Male ; Sendai virus
Language	English
Publishing date	2021-02-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1876-7753
ISSN (online)	1876-7753
DOI	10.1016/j.scr.2021.102269
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Article ; Online: High-dimensional immune profiling identifies a biomarker to monitor dimethyl fumarate response in multiple sclerosis.

Diebold, Martin / Galli, Edoardo / Kopf, Andreas / Sanderson, Nicholas S R / Callegari, Ilaria / Benkert, Pascal / Gonzalo Núñez, Nicolás / Ingelfinger, Florian / Herms, Stefan / Cichon, Sven / Kappos, Ludwig / Kuhle, Jens / Becher, Burkhard / Claassen, Manfred / Derfuss, Tobias

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 31, Page(s) e2205042119

Abstract: Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS). Despite its wide clinical use, the mechanisms underlying clinical response are not understood. This study aimed to reveal immune markers of therapeutic response to DMF ... ...

Abstract	Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS). Despite its wide clinical use, the mechanisms underlying clinical response are not understood. This study aimed to reveal immune markers of therapeutic response to DMF treatment in MS. For this purpose, we prospectively collected peripheral blood mononuclear cells (PBMCs) from a highly characterized cohort of 44 individuals with MS before and at 12 and 48 wk of DMF treatment. Single cells were profiled using high-dimensional mass cytometry. To capture the heterogeneity of different immune subsets, we adopted a bioinformatic multipanel approach that allowed cell population-cluster assignment of more than 50 different parameters, including lineage and activation markers as well as chemokine receptors and cytokines. Data were further analyzed in a semiunbiased fashion implementing a supervised representation learning approach to capture subtle longitudinal immune changes characteristic for therapy response. With this approach, we identified a population of memory T helper cells expressing high levels of neuroinflammatory cytokines (granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon γ [IFNγ]) as well as CXCR3, whose abundance correlated with treatment response. Using spectral flow cytometry, we confirmed these findings in a second cohort of patients. Serum neurofilament light-chain levels confirmed the correlation of this immune cell signature with axonal damage. The identified cell population is expanded in peripheral blood under natalizumab treatment, substantiating a specific role in treatment response. We propose that depletion of GM-CSF-, IFNγ-, and CXCR3-expressing T helper cells is the main mechanism of action of DMF and allows monitoring of treatment response.
MeSH term(s)	Biomarkers, Pharmacological/metabolism ; Cytokines/metabolism ; Dimethyl Fumarate/pharmacology ; Dimethyl Fumarate/therapeutic use ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Humans ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/therapeutic use ; Interferon-gamma/metabolism ; Lymphocyte Depletion ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/immunology ; Single-Cell Analysis ; T-Lymphocytes, Helper-Inducer/drug effects ; T-Lymphocytes, Helper-Inducer/immunology
Chemical Substances	Biomarkers, Pharmacological ; Cytokines ; Immunosuppressive Agents ; Interferon-gamma (82115-62-6) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Dimethyl Fumarate (FO2303MNI2)
Language	English
Publishing date	2022-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2205042119
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Zs.A 1148: Show issues

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Article ; Online: Gene expression is stable in a complete CIB1 knockout keratinocyte model.

Imahorn, Elias / Aushev, Magomet / Herms, Stefan / Hoffmann, Per / Cichon, Sven / Reichelt, Julia / Itin, Peter H / Burger, Bettina

Scientific reports

2020 Volume 10, Issue 1, Page(s) 14952

Abstract: Epidermodysplasia verruciformis (EV) is a genodermatosis characterized by the inability of keratinocytes to control cutaneous β-HPV infection and a high risk for non-melanoma skin cancer (NMSC). Bi-allelic loss of function variants in TMC6, TMC8, and ... ...

Abstract	Epidermodysplasia verruciformis (EV) is a genodermatosis characterized by the inability of keratinocytes to control cutaneous β-HPV infection and a high risk for non-melanoma skin cancer (NMSC). Bi-allelic loss of function variants in TMC6, TMC8, and CIB1 predispose to EV. The correlation between these proteins and β-HPV infection is unclear. Its elucidation will advance the understanding of HPV control in human keratinocytes and development of NMSC. We generated a cell culture model by CRISPR/Cas9-mediated deletion of CIB1 to study the function of CIB1 in keratinocytes. Nine CIB1 knockout and nine mock control clones were generated originating from a human keratinocyte line. We observed small changes in gene expression as a result of CIB1 knockout, which is consistent with the clearly defined phenotype of EV patients. This suggests that the function of human CIB1 in keratinocytes is limited and involves the restriction of β-HPV. The presented model is useful to investigate CIB1 interaction with β-HPV in future studies.
MeSH term(s)	Calcium-Binding Proteins/deficiency ; Calcium-Binding Proteins/metabolism ; Cell Line ; Epidermodysplasia Verruciformis/genetics ; Epidermodysplasia Verruciformis/metabolism ; Epidermodysplasia Verruciformis/pathology ; Gene Expression Regulation ; Gene Knockout Techniques ; Humans ; Keratinocytes/metabolism ; Keratinocytes/pathology ; Models, Biological
Chemical Substances	CIB1 protein, human ; Calcium-Binding Proteins
Language	English
Publishing date	2020-09-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-71889-9
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Article ; Online: Genome-wide Association Study of Postoperative Cognitive Dysfunction in Older Surgical Patients.

Rickenbacher, Marc / Reinbold, Céline S / Herms, Stefan / Hoffmann, Per / Cichon, Sven / Wueest, Alexandra S / Monsch, Andreas U / Steiner, Luzius A / Goettel, Nicolai

Journal of neurosurgical anesthesiology

2020 Volume 34, Issue 2, Page(s) 248–250

MeSH term(s)	Aged ; Delirium/psychology ; Genome-Wide Association Study ; Humans ; Neuropsychological Tests ; Postoperative Cognitive Complications/genetics ; Postoperative Cognitive Complications/physiopathology
Language	English
Publishing date	2020-12-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1018119-2
ISSN	1537-1921 ; 0898-4921
ISSN (online)	1537-1921
ISSN	0898-4921
DOI	10.1097/ANA.0000000000000749
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