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1. Suicidal behavior in ADHD: the role of comorbidity, psychosocial adversity, personality and genetic factors

Author

Georg C. Ziegler, Silke Groß, Andrea Boreatti, Monika Heine, Rhiannon V. McNeill, Thorsten M. Kranz, Marcel Romanos, Christian P. Jacob, Andreas Reif, Sarah Kittel-Schneider, and Klaus-Peter Lesch

Subjects
ADHD, Suicide attempt, Psychosocial adversity, Comorbidity, Serotonin, 5-HTTLPR, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Adult ADHD is associated with increased risk for suicide attempts, as indicated by investigations of population- and community-based cohorts. However, there is little data regarding suicide attempts in a clinical setting. To address this, we used a comprehensively phenotyped clinical adult ADHD (aADHD) cohort to assess to which extent comorbidity, psychosocial adversity, personality, and ADHD symptoms contribute to suicidal behavior in ADHD. Furthermore, we investigated a triallelic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR), which has previously been associated with suicidal behavior. Depression, substance use, eating, and posttraumatic stress disorders were independently associated with past suicide attempts, whereas anxiety, somatoform, and obsessive–compulsive spectrum disorders showed no association. Pulmonary diseases also showed an association with suicidal behavior. Psychosocial factors including occupational status, marital status/living situation, externalizing behavior and psychiatric family history were strongly associated with past suicide attempts. ADHD symptoms of inattention and hyperactivity/impulsivity were not associated with past suicide attempts after adjustment for psychiatric comorbidity and psychosocial adversity. However, the personality trait of neuroticism fully mediated the association between depression and suicidal behavior. 5-HTTLPR was not associated with suicidal behavior, but an interaction with ADHD symptoms and subtype was found. Our data suggest that psychiatric comorbidity and psychosocial adversity are key factors for suicidal behavior in aADHD, with neuroticism representing a critical mediator of the association between depression and suicidality. Further research, preferentially with longitudinal study designs is needed to better understand causal factors for suicidal behavior to enable effective preventive action.

Published
2024
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2. Association of polygenic risk scores and hair cortisol with mental health trajectories during COVID lockdown

Author

Kira F. Ahrens, Rebecca J. Neumann, Nina M. von Werthern, Thorsten M. Kranz, Bianca Kollmann, Björn Mattes, Lara M. C. Puhlmann, Danuta Weichert, Beat Lutz, Ulrike Basten, Christian J. Fiebach, Michèle Wessa, Raffael Kalisch, Klaus Lieb, Andreas G. Chiocchetti, Oliver Tüscher, Andreas Reif, and Michael M. Plichta

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract The COVID-19 pandemic is a global stressor with inter-individually differing influences on mental health trajectories. Polygenic Risk Scores (PRSs) for psychiatric phenotypes are associated with individual mental health predispositions. Elevated hair cortisol concentrations (HCC) and high PRSs are related to negative mental health outcomes. We analyzed whether PRSs and HCC are related to different mental health trajectories during the first COVID lockdown in Germany. Among 523 participants selected from the longitudinal resilience assessment study (LORA), we previously reported three subgroups (acute dysfunction, delayed dysfunction, resilient) based on weekly mental health (GHQ-28) assessment during COVID lockdown. DNA from blood was collected at the baseline of the original LORA study (n = 364) and used to calculate the PRSs of 12 different psychopathological phenotypes. An explorative bifactor model with Schmid-Leiman transformation was calculated to extract a general genetic factor for psychiatric disorders. Hair samples were collected quarterly prior to the pandemic for determining HCC (n = 192). Bivariate logistic regressions were performed to test the associations of HCC and the PRS factors with the reported trajectories. The bifactor model revealed 1 general factor and 4 sub-factors. Results indicate a significant association between increased values on the general risk factor and the allocation to the acute dysfunction class. The same was found for elevated HCC and the exploratorily tested sub-factor “childhood-onset neurodevelopmental disorders”. Genetic risk and long-term cortisol secretion as a potential indicator of stress, indicated by PRSs and HCC, respectively, predicted different mental health trajectories. Results indicate a potential for future studies on risk prediction.

Published
2022
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3. Is genetic risk of ADHD mediated via dopaminergic mechanism? A study of functional connectivity in ADHD and pharmacologically challenged healthy volunteers with a genetic risk profile

Author

Oliver Grimm, Lara Thomä, Thorsten M. Kranz, and Andreas Reif

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Recent GWAS allow us to calculate polygenic risk scores for ADHD. At the imaging level, resting-state fMRI analyses have given us valuable insights into changes in connectivity patterns in ADHD patients. However, no study has yet attempted to combine these two different levels of investigation. For this endeavor, we used a dopaminergic challenge fMRI study (L-DOPA) in healthy participants who were genotyped for their ADHD, MDD, schizophrenia, and body height polygenic risk score (PRS) and compared results with a study comparing ADHD patients and healthy controls. Our objective was to evaluate how L-DOPA-induced changes of reward-system-related FC are dependent on the individual polygenic risk score. FMRI imaging was used to evaluate resting-state functional connectivity (FC) of targeted subcortical structures in 27 ADHD patients and matched controls. In a second study, we evaluated the effect of ADHD and non-ADHD PRS in a L-DOPA-based pharmaco-fMRI-challenge in 34 healthy volunteers. The functional connectivity between the putamen and parietal lobe was decreased in ADHD patients. In healthy volunteers, the FC between putamen and parietal lobe was lower in ADHD high genetic risk participants. This direction of connectivity was reversed during L-DOPA challenge. Further findings are described for other dopaminergic subcortical structures. The FC between the putamen and the attention network showed the most consistent change in patients as well as in high-risk participants. Our results suggest that FC of the dorsal attention network is altered in adult ADHD as well as in healthy controls with higher genetic risk.

Published
2022
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4. Investigating the Association Between Polygenic Risk Scores for Alzheimer’s Disease With Cognitive Performance and Intrinsic Functional Connectivity in Healthy Adults

Author

Aliaa Ibnidris, Fabian Fußer, Thorsten M. Kranz, David Prvulovic, Andreas Reif, Johannes Pantel, Emiliano Albanese, Tarik Karakaya, and Silke Matura

Subjects
Alzheimer’s disease (AD), genetic disposition, polygenic risk score (PRS), cognition, intrinsic functional connectivity, resting-state fMRI, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

BackgroundAlzheimer’s disease (AD) pathology is present many years before the onset of clinical symptoms. AD dementia cannot be treated. Timely and early detection of people at risk of developing AD is key for primary and secondary prevention. Moreover, understanding the underlying pathology that is present in the earliest stages of AD, and the genetic predisposition to that might contribute to the development of targeted disease-modifying treatments.ObjectivesIn this study, we aimed to explore whether genetic disposition to AD in asymptomatic individuals is associated with altered intrinsic functional connectivity as well as cognitive performance on neuropsychological tests.MethodsWe examined 136 cognitively healthy adults (old group: mean age = 69.32, SD = 4.23; young group: mean age = 31.34, SD = 13.12). All participants had undergone resting-state functional magnetic resonance imagining (fMRI), DNA genotyping to ascertain polygenic risk scores (PRS), and neuropsychological testing for global cognition, working memory, verbal fluency, and executive functions.ResultsTwo-step hierarchical regression analysis revealed that higher PRS was significantly associated with lower scores in working memory tasks [Letter Number Span: ΔR2 = 0.077 (p < 0.05); Spatial Span: ΔR2 = 0.072 (p < 0.05)] in older adults (>60 years). PRS did not show significant modulations of the intrinsic functional connectivity of the posterior cingulate cortex (PCC) with other regions of interest in the brain that are affected in AD.ConclusionAllele polymorphisms may modify the effect of other AD risk factors. This potential modulation warrants further investigations, particularly in cognitively healthy adults.

Published
2022
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5. Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk

Author

Oliver Grimm, Heike Weber, Sarah Kittel-Schneider, Thorsten M. Kranz, Christian P. Jacob, Klaus-Peter Lesch, and Andreas Reif

Subjects
impulsivity, ADHD, polygenic risk score, venturesomeness, substance abuse disorder, attention, Psychiatry, RC435-571
Abstract

While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.

Published
2020
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6. Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults

Author

Silvia Biere, Thorsten M. Kranz, Silke Matura, Kristiyana Petrova, Fabian Streit, Andreas G. Chiocchetti, Oliver Grimm, Murielle Brum, Natalie Brunkhorst-Kanaan, Viola Oertel, Aliaksandr Malyshau, Andrea Pfennig, Michael Bauer, Thomas G. Schulze, Sarah Kittel-Schneider, and Andreas Reif

Subjects
polygenic risk score, bipolar disorder, genetic phenotypes, depression, ADHD, early recognition, Psychiatry, RC435-571
Abstract

Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD.Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes.Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls.Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.

Published
2020
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7. Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia

Author

Kevin W. Hoffman, Jakleen J. Lee, Cheryl M. Corcoran, David Kimhy, Thorsten M. Kranz, and Dolores Malaspina

Subjects
schizophrenia, microbiome, brain-derived neurotrophic factor, development, stress, cortisol, Psychiatry, RC435-571
Abstract

Early life adversity and prenatal stress are consistently associated with an increased risk for schizophrenia, although the exact pathogenic mechanisms linking the exposures with the disease remain elusive. Our previous view of the HPA stress axis as an elegant but simple negative feedback loop, orchestrating adaptation to stressors among the hypothalamus, pituitary, and adrenal glands, needs to be updated. Research in the last two decades shows that important bidirectional signaling between the HPA axis and intestinal mucosa modulates brain function and neurochemistry, including effects on glucocorticoid hormones and brain-derived neurotrophic factor (BDNF). The intestinal microbiome in earliest life, which is seeded by the vaginal microbiome during delivery, programs the development of the HPA axis in a critical developmental window, determining stress sensitivity and HPA function as well as immune system development. The crosstalk between the HPA and the Microbiome Gut Brain Axis (MGBA) is particularly high in the hippocampus, the most consistently disrupted neural region in persons with schizophrenia. Animal models suggest that the MGBA remains influential on behavior and physiology across developmental stages, including the perinatal window, early childhood, adolescence, and young adulthood. Understanding the role of the microbiome on critical risk related stressors may enhance or transform of understanding of the origins of schizophrenia and offer new approaches to increase resilience against stress effects for preventing and treating schizophrenia.

Published
2020
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8. The Emerging Role for Zinc in Depression and Psychosis

Author

Matthew A. Petrilli, Thorsten M. Kranz, Karine Kleinhaus, Peter Joe, Mara Getz, Porsha Johnson, Moses V. Chao, and Dolores Malaspina

Subjects
zinc dysfunction, psychosis, depression, glutamate, NMDA, Therapeutics. Pharmacology, RM1-950
Abstract

Zinc participation is essential for all physiological systems, including neural functioning, where it participates in a myriad of cellular processes. Converging clinical, molecular, and genetic discoveries illuminate key roles for zinc homeostasis in association with clinical depression and psychosis which are not yet well appreciated at the clinical interface. Intracellular deficiency may arise from low circulating zinc levels due to dietary insufficiency, or impaired absorption from aging or medical conditions, including alcoholism. A host of medications commonly administered to psychiatric patients, including anticonvulsants, oral medications for diabetes, hormones, antacids, anti-inflammatories and others also impact zinc absorption. Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range. Well powered clinical studies have shown beneficial effects of supplemental zinc in depression and it important to pursue research using zinc as a potential therapeutic option for psychosis as well. Meta-analyses support the adjunctive use of zinc in major depression and a single study now supports zinc for psychotic symptoms. This manuscript reviews the biochemistry and bench top evidence on putative molecular mechanisms of zinc as a psychiatric treatment.

Published
2017
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9. Early Life Stress Effects on the Glucocorticoid - BDNF interplay in the Hippocampus

Author

Nikolaos P Daskalakis, Edo Ronald eDe Kloet, Rachel eYehuda, Dolores eMalaspina, and Thorsten M. Kranz

Subjects
Hippocampus, BDNF, glucocorticoid, TrkB, HPA axis, early life stress, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Early life stress (ELS) is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress-susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid and/or neurotrophin signaling pathways. Glucocorticoid (GC) signaling mediates the regulation of the stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and glucocorticoid signaling pathways co-exist throughout the central nervous system (CNS), particularly in the hippocampus, which has high expression of glucocorticoid and mineralocorticoid receptors (GR and MR) as well as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB). This review addresses the effects of ELS paradigms on GC- and BDNF- dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders.

Published
2015
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11. Preliminary Findings Associate Hippocampal 1H-MR Spectroscopic Metabolite Concentrations with Psychotic and Manic Symptoms in Patients with Schizophrenia

Author

S.A. Perez, Julie Walsh-Messinger, Thorsten M. Kranz, E. Lotan, Oded Gonen, Dolores Malaspina, and Henry Rusinek

Subjects
medicine.medical_specialty, Psychosis, business.industry, Metabolite, Hippocampal formation, medicine.disease, Gastroenterology, Pathophysiology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Schizophrenia, Internal medicine, mental disorders, Cohort, medicine, Radiology, Nuclear Medicine and imaging, In patient, Neurology (clinical), medicine.symptom, business, Mania, 030217 neurology & neurosurgery
Abstract

BACKGROUND AND PURPOSE: Previous hippocampal proton MR spectroscopic imaging distinguished patients with schizophrenia from controls by elevated Cr levels and significantly more variable NAA and Cho concentrations. This goal of this study was to ascertain whether this metabolic variability is associated with clinical features of the syndrome, possibly reflecting heterogeneous hippocampal pathologies and perhaps variability in its “positive” (psychotic) and “negative” (social and emotional deficits) symptoms. MATERIALS AND METHODS: In a sample of 15 patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, we examined the association of NAA and Cho levels with research diagnostic interviews and clinical symptom ratings of the patients. Metabolite concentrations were previously obtained with 3D proton MR spectroscopic imaging at 3T, a technique that facilitates complete coverage of this small, irregularly shaped, bilateral, temporal lobe structure. RESULTS: The patient cohort comprised 8 men and 7 women (mean age, 39.1 [SD, 10.8] years, with a mean disease duration of 17.2 [SD, 10.8] years. Despite the relatively modest cohort size, we found the following: 1) Elevated Cho levels predict the positive (psychotic, r = 0.590, P = .021) and manic (r = 0.686, P = .005) symptom severity; and 2) lower NAA levels trend toward negative symptoms (r = 0.484, P = .08). No clinical symptoms were associated with Cr level or hippocampal volume (all, P ≥ .055). CONCLUSIONS: These preliminary findings suggest that NAA and Cho variations reflect different pathophysiologic processes, consistent with microgliosis/astrogliosis and/or lower vitality (reduced NAA) and demyelination (elevated Cho). In particular, the active state–related symptoms, including psychosis and mania, were associated with demyelination. Consequently, their deviations from the means of healthy controls may be a marker that may benefit precision medicine in selection and monitoring of schizophrenia treatment.

Published
2020

12. Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits

Author

Aet O’Leary, Noèlia Fernàndez-Castillo, Gabriela Gan, Yunbo Yang, Anna Y. Yotova, Thorsten M. Kranz, Lena Grünewald, Florian Freudenberg, Ester Antón-Galindo, Judit Cabana-Domínguez, Anais Harneit, Janina I. Schweiger, Kristina Schwarz, Ren Ma, Junfang Chen, Emanuel Schwarz, Marcella Rietschel, Heike Tost, Andreas Meyer-Lindenberg, Christiane A. Pané-Farré, Tilo Kircher, Alfons O. Hamm, Demian Burguera, Nina Roth Mota, Barbara Franke, Susann Schweiger, Jennifer Winter, Andreas Heinz, Susanne Erk, Nina Romanczuk-Seiferth, Henrik Walter, Andreas Ströhle, Lydia Fehm, Thomas Fydrich, Ulrike Lueken, Heike Weber, Thomas Lang, Alexander L. Gerlach, Markus M. Nöthen, Georg W. Alpers, Volker Arolt, Stephanie Witt, Jan Richter, Benjamin Straube, Bru Cormand, David A. Slattery, and Andreas Reif

Subjects
Neurons, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Mental illness, RNA, Neurones, Malalties mentals, Molecular Biology
Abstract

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

Published
2022
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13. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards 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Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

14. ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines

Author

Franziska Radtke, Viola Stella Palladino, Rhiannon V. McNeill, Andreas G. Chiocchetti, Denise Haslinger, Matthias Leyh, Danijel Gersic, Markus Frank, Lena Grünewald, Stephan Klebe, Oliver Brüstle, Katharina Günther, Frank Edenhofer, Thorsten M. Kranz, Andreas Reif, and Sarah Kittel‐Schneider

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, DNA Copy Number Variations, Attention Deficit Disorder with Hyperactivity, Ubiquitin-Protein Ligases, Medizin, Gene Expression, Humans, Pilot Projects, Genetics (clinical), Cell Line
Abstract

Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (PARK2) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with PARK2 CNVs in human-derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD PARK2 deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without PARK2 CNVs. The selected 10 genes of interest were associated with oxidative stress response (TP53, NQO1, and NFE2L2), ubiquitin pathway (UBE3A, UBB, UBC, and ATXN3) and with a function in mitochondrial quality control (PINK1, MFN2, and ATG5). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H-quinone-dehydrogenase 1 (NQO1) expression was significantly increased in PARK2 CNV carriers. In a multivariate analysis, ubiquitin C (UBC) was significantly upregulated in fibroblasts of PARK2 CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (NNAT) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine-proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in PARK2 CNV carriers compared to wildtype healthy controls and ADHD patients.

Published
2022
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15. Investigating the Association Between Polygenic Risk Scores for Alzheimer's Disease With Cognitive Performance and Intrinsic Functional Connectivity in Healthy Adults

Author

Aliaa Ibnidris, Fabian Fußer, Thorsten M. Kranz, David Prvulovic, Andreas Reif, Johannes Pantel, Emiliano Albanese, Tarik Karakaya, and Silke Matura

Subjects
Aging, Cognitive Neuroscience
Abstract

BackgroundAlzheimer’s disease (AD) pathology is present many years before the onset of clinical symptoms. AD dementia cannot be treated. Timely and early detection of people at risk of developing AD is key for primary and secondary prevention. Moreover, understanding the underlying pathology that is present in the earliest stages of AD, and the genetic predisposition to that might contribute to the development of targeted disease-modifying treatments.ObjectivesIn this study, we aimed to explore whether genetic disposition to AD in asymptomatic individuals is associated with altered intrinsic functional connectivity as well as cognitive performance on neuropsychological tests.MethodsWe examined 136 cognitively healthy adults (old group: mean age = 69.32, SD = 4.23; young group: mean age = 31.34, SD = 13.12). All participants had undergone resting-state functional magnetic resonance imagining (fMRI), DNA genotyping to ascertain polygenic risk scores (PRS), and neuropsychological testing for global cognition, working memory, verbal fluency, and executive functions.ResultsTwo-step hierarchical regression analysis revealed that higher PRS was significantly associated with lower scores in working memory tasks [Letter Number Span: ΔR2 = 0.077 (p < 0.05); Spatial Span: ΔR2 = 0.072 (p < 0.05)] in older adults (>60 years). PRS did not show significant modulations of the intrinsic functional connectivity of the posterior cingulate cortex (PCC) with other regions of interest in the brain that are affected in AD.ConclusionAllele polymorphisms may modify the effect of other AD risk factors. This potential modulation warrants further investigations, particularly in cognitively healthy adults.

Published
2021

16. Is genetic risk of ADHD mediated via dopaminergic mechanism? A study of functional connectivity in ADHD and pharmacologically challenged healthy volunteers with a genetic risk profile

Author

Oliver, Grimm, Lara, Thomä, Thorsten M, Kranz, and Andreas, Reif

Subjects
Adult, Levodopa, Brain Mapping, Attention Deficit Disorder with Hyperactivity, Risk Factors, Dopamine, Neural Pathways, Brain, Humans, Magnetic Resonance Imaging, Healthy Volunteers
Abstract

Recent GWAS allow us to calculate polygenic risk scores for ADHD. At the imaging level, resting-state fMRI analyses have given us valuable insights into changes in connectivity patterns in ADHD patients. However, no study has yet attempted to combine these two different levels of investigation. For this endeavor, we used a dopaminergic challenge fMRI study (L-DOPA) in healthy participants who were genotyped for their ADHD, MDD, schizophrenia, and body height polygenic risk score (PRS) and compared results with a study comparing ADHD patients and healthy controls. Our objective was to evaluate how L-DOPA-induced changes of reward-system-related FC are dependent on the individual polygenic risk score. FMRI imaging was used to evaluate resting-state functional connectivity (FC) of targeted subcortical structures in 27 ADHD patients and matched controls. In a second study, we evaluated the effect of ADHD and non-ADHD PRS in a L-DOPA-based pharmaco-fMRI-challenge in 34 healthy volunteers. The functional connectivity between the putamen and parietal lobe was decreased in ADHD patients. In healthy volunteers, the FC between putamen and parietal lobe was lower in ADHD high genetic risk participants. This direction of connectivity was reversed during L-DOPA challenge. Further findings are described for other dopaminergic subcortical structures. The FC between the putamen and the attention network showed the most consistent change in patients as well as in high-risk participants. Our results suggest that FC of the dorsal attention network is altered in adult ADHD as well as in healthy controls with higher genetic risk.

Published
2021

17. Genetische Grundlagen der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung

Author

Thorsten M. Kranz, Andreas Reif, and Oliver Grimm

Subjects
Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, Political science, medicine, Neurology (clinical), Family Practice, 030217 neurology & neurosurgery, 030227 psychiatry
Abstract

ZUSAMMENFASSUNGDie Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) zeigt eine hohe Erblichkeit in formalgenetischen Studien. Auch im Vergleich zu anderen psychiatrischen Erkrankungen ist die Heritabilität mit fast 80 % sehr hoch. Die Symptomatik der ADHS scheint jedoch graduell in der Normalbevölkerung vorzukommen. Neuere Arbeiten schätzen den Anteil der auf Einzelnukleotidvarianten beruhenden Heritabilität auf 22 %. Welcher Bereich der molekularen Genetik diese Differenz erklärt, ist unklar. In dem vorgelegten Übersichtsartikel geben wir einen Überblick über die Analyse häufiger und seltener Varianten. Während häufige Varianten in ersten Megaanalysen mit vielen tausend Patienten erste genomweite Ergebnisse bringen, die jedoch nur wenig Varianz erklären, zeigen sich die methodisch immer noch schwierigeren Analysen von seltenen Varianten erst in ihren Anfängen. Sie erklären in einigen wenigen individuellen Fällen jedoch eine beträchtliche Varianz. Hierzu werden Beispiele gegeben und diskutiert. Für die Praxis ist die kritische Kenntnis der Genetik der ADHS weder für Therapie noch Diagnostik zwingend. Möglicherweise werden in Zukunft auch seltene Varianten häufiger diagnostiziert werden. Um eine kompetente Beratung zu gewährleisten, ist die Kenntnis des aktuellen Forschungsstandes jedoch auch für den Praktiker von Belang.

Published
2019

18. Rapamycin blocks the neuroprotective effects of sex steroids in the adult birdsong system

Author

Kimberly E. Miller, Karin Lent, Moses V. Chao, Eliot A. Brenowitz, and Thorsten M. Kranz

Subjects
Telencephalon, 0301 basic medicine, Aging, medicine.medical_specialty, Neuroprotection, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Internal medicine, medicine, Animals, Testosterone, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Neurons, Sirolimus, Neuronal Plasticity, biology, Dihydrotestosterone, Estrogens, Neuroprotective Agents, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, nervous system, Forebrain, behavior and behavior mechanisms, biology.protein, Neuron, Vocalization, Animal, Sparrows, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, Hormone, Neurotrophin
Abstract

In adult songbirds, the telencephalic song nucleus HVC and its efferent target RA undergo pronounced seasonal changes in morphology. In breeding birds, there are increases in HVC volume and total neuron number, and RA neuronal soma area compared to nonbreeding birds. At the end of breeding, HVC neurons die through caspase-dependent apoptosis and thus, RA neuron size decreases. Changes in HVC and RA are driven by seasonal changes in circulating testosterone (T) levels. Infusing T, or its metabolites 5α-dihydrotestosterone (DHT) and 17 β-estradiol (E2), intracerebrally into HVC (but not RA) protects HVC neurons from death, and RA neuron size, in nonbreeding birds. The phosphoinositide 3-kinase (PI3K)-Akt (a serine/threonine kinase)-mechanistic target of rapamycin (mTOR) signaling pathway is a point of convergence for neuroprotective effects of sex steroids and other trophic factors. We asked if mTOR activation is necessary for the protective effect of hormones in HVC and RA of adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii). We transferred sparrows from breeding to nonbreeding hormonal and photoperiod conditions to induce regression of HVC neurons by cell death and decrease of RA neuron size. We infused either DHT + E2, DHT + E2 plus the mTOR inhibitor rapamycin, or vehicle alone in HVC. Infusion of DHT + E2 protected both HVC and RA neurons. Coinfusion of rapamycin with DHT + E2, however, blocked the protective effect of hormones on HVC volume and neuron number, and RA neuron size. These results suggest that activation of mTOR is an essential downstream step in the neuroprotective cascade initiated by sex steroid hormones in the forebrain.

Published
2019

19. Characterization of Age and Polarity at Onset in Bipolar Disorder

Author

Aiden Corvin, Maria Grigoroiu-Serbanescu, Mark Hyman Rapaport, Frederike T. Fellendorf, Urs Heilbronner, Mariam M. Al Eissa, John J Nurnberger, Claire O'Donovan, Claire Slaney, Mark A. Frye, Niamh L. O'Brien, Roland Hasler, Michael John Owen, Michael Conlon O'Donovan, Farah Klöhn-Saghatolislam, Markus M. Nöthen, Scott R. Clark, Mikael Landén, Lina Jonsson, Peter Falkai, Qingqin S. Li, Alessio Squassina, Simon Schmitt, Gustavo Turecki, Heike Anderson-Schmidt, Jonathan Repple, Sofie R. Aminoff, Eduard Vieta, Katherine Gordon-Smith, Stéphane Jamain, William Byerley, Hélène Richard-Lepouriel, Fermín Mayoral, Francis J. McMahon, Marin Veldic, Ingrid Melle, Andrew McQuillin, Nicholas Bass, Gloria Roberts, Douglas M. Ruderfer, John B. Vincent, Nelson B. Freimer, Kirov George, Wei Xu, Susan L. McElroy, Ceylan Balaban, Marco P. Boks, Franziska Degenhardt, Paul E. Croarkin, Wade H. Berrettini, Piotr M. Czerski, Fernando S. Goes, Peter P. Zandi, Sabrina K. Schaupp, Barbara W. Schweizer, Andrew M. McIntosh, Marcella Rietschel, Helena Pelin, Evelyn J. Bromet, Marion Leboyer, Ole A. Andreassen, Georgia Panagiotaropoulou, Alessia Fiorentino, Sally I. Sharp, Torbjørn Elvsåshagen, Kristina Adorjan, Monika Budde, Lisa Jones, Thomas G. Schulze, Vihra Milanova, Janos Kalman, Tim B. Bigdeli, Esther Jiménez, Abigail Ortiz, Dolores Malaspina, Kevin S. O’Connell, Sergi Papiol, Mario Maj, Tim Hahn, Frederike Stein, Jordan W. Smoller, Tomas Novak, Katrin Gade, J. Raymond DePaulo, Sarah Kittel-Schneider, Julia-Katharina Pfarr, Martin Alda, James A. Knowles, Sven Cichon, David Craig, Eli A. Stahl, William A. Scheftner, Bruno Etain, Annabel Vreeker, Guy A. Rouleau, Stephan Ripke, Clement C. Zai, Frank Bellivier, Giovanni Severino, Palmiero Monteleone, Ian Jones, Bertram Müller-Myhsok, Mark Adams, John Strauss, Philip B. Mitchell, Andreas Reif, Fabian Streit, Roel A. Ophoff, James L. Kennedy, Nils Opel, Raffaella Ardau, Paul Grof, Peter R. Schofield, Susanne Bengesser, Maria Hake, Loes M. Olde Loohuis, Joanna Pawlak, Daniela Reich-Erkelenz, Ingrid Agartz, Maria Del Zompo, Antonio Benabarre, Bernhard T. Baune, Arianna Di Florio, Ashley L. Comes, Michael Gill, Cristiana Cruceanu, Susanne Meinert, William Coryell, Alessio Maria Monteleone, Fanny Senner, Trine Vik Lagerberg, Jose Guzman-Parra, Erik Pålsson, Elliot S. Gershon, Melvin G. McInnis, Pavla Stopkova, Nikolaos Koutsouleris, René S. Kahn, Janice M. Fullerton, Howard J. Edenberg, Tilo Kircher, Nina Dalkner, Udo Dannlowski, Rolf Adolfsson, Alfonso Tortorella, Jean-Michel Aubry, James B. Potash, Catina Chillotti, Eva Z. Reininghaus, Janet L. Sobell, Thorsten M. Kranz, Tina Meller, Ayman H. Fanous, Kai Ringwald, K Oliver Schubert, Andreas J. Forstner, Till F. M. Andlauer, Helena Medeiros, Mirko Manchia, Joanna M. Biernacka, Katharina Brosch, Julie Garnham, Olav B. Smeland, Eva C. Schulte, Carlos N. Pato, Nicholas John Craddock, Srdjan Djurovic, Pablo Cervantes, Michele T. Pato, John R. Kelsoe, Claudia Pisanu, Joanna Twarowska-Hauser, and William Lawson

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, Genome-wide association study, Disease, Heritability, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Schizophrenia, Internal medicine, medicine, Bipolar disorder, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.

Published
2021

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

Author

James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno

Subjects
Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; 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.

Published
2021

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

Author

Niamh Mullins, Andreas J. Forstner, Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Børte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bækvad-Hansen, Nicholas Bass, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Franziska Degenhardt, Srdjan Djurovic, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, Valentina Escott-Price, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Joel Gelernter, Marianne Giørtz Pedersen, Ian R. Gizer, Scott D. Gordon, Katherine Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Per Hoffmann, Peter A. Holmans, Laura Huckins, Stéphane Jamain, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, James L. Kennedy, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Maria Koromina, Thorsten M. Kranz, Henry R. Kranzler, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Phil H. Lee, Shawn E. Levy, Catrin Lewis, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Sigurdur H. Magnusson, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Steven A. McCarroll, Nathaniel W. McGregor, Peter McGuffin, James D. McKay, Helena Medeiros, Sarah E. Medland, Vincent Millischer, Grant W. Montgomery, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, James B. Potash, Digby Quested, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, John P. Rice, Fabio Rivas, Margarita Rivera, Julian Roth, Panos Roussos, Douglas M. Ruderfer, Cristina Sánchez-Mora, Eva C. Schulte, Fanny Senner, Sally Sharp, Paul D. Shilling, Engilbert Sigurdsson, Lea Sirignano, Claire Slaney, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, Christine Søholm Hansen, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, John S. Strauss, Beata Świątkowska, Chikashi Terao, Thorgeir E. Thorgeirsson, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, James T. R. Walters, Stephanie H. Witt, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, Lea Zillich, HUNT All-In Psychiatry, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Gulja Babadjanova, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Douglas H. R. Blackwood, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley Catts, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans Henskens, Jan Hillert, Kyung Sue Hong, David M. Hougaard, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, Ian Jones, Lisa A. Jones, René S. Kahn, John R. Kelsoe, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Nicholas G. Martin, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Patricia Michie, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Ketil J. Oedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Chris Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Roy H. Perlis, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Cynthia Shannon Weickert, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Thomas W. Weickert, Thomas Werge, Naomi R. Wray, John-Anker Zwart, Joanna M. Biernacka, John I. Nurnberger, Sven Cichon, Howard J. Edenberg, Eli A. Stahl, Andrew McQuillin, Arianna Di Florio, Roel A. Ophoff, and Ole A. Andreassen

Subjects
Genetics, 0303 health sciences, Druggability, Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, medicine, Bipolar disorder, Synaptic signaling, Prefrontal cortex, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD 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 eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2020

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

Author

Niamh, Mullins, Andreas J, Forstner, Kevin S, O'Connell, Brandon, Coombes, Jonathan R I, Coleman, Zhen, Qiao, Thomas D, Als, Tim B, Bigdeli, Sigrid, Børte, Julien, Bryois, Alexander W, Charney, Ole Kristian, Drange, Michael J, Gandal, Saskia P, Hagenaars, Masashi, Ikeda, Nolan, Kamitaki, Minsoo, Kim, Kristi, Krebs, Georgia, Panagiotaropoulou, Brian M, Schilder, Laura G, Sloofman, Stacy, Steinberg, Vassily, Trubetskoy, Bendik S, Winsvold, Hong-Hee, Won, Liliya, Abramova, Kristina, Adorjan, Esben, Agerbo, Mariam, Al Eissa, Diego, Albani, Ney, Alliey-Rodriguez, Adebayo, Anjorin, Verneri, Antilla, Anastasia, Antoniou, Swapnil, Awasthi, Ji Hyun, Baek, Marie, Bækvad-Hansen, Nicholas, Bass, Michael, Bauer, Eva C, Beins, Sarah E, Bergen, Armin, Birner, Carsten, Bøcker Pedersen, Erlend, Bøen, Marco P, Boks, Rosa, Bosch, Murielle, Brum, Ben M, Brumpton, Nathalie, Brunkhorst-Kanaan, Monika, Budde, Jonas, Bybjerg-Grauholm, William, Byerley, Murray, Cairns, Miquel, Casas, Pablo, Cervantes, Toni-Kim, Clarke, Cristiana, Cruceanu, Alfredo, Cuellar-Barboza, Julie, Cunningham, David, Curtis, Piotr M, Czerski, Anders M, Dale, Nina, Dalkner, Friederike S, David, Franziska, Degenhardt, Srdjan, Djurovic, Amanda L, Dobbyn, Athanassios, Douzenis, Torbjørn, Elvsåshagen, Valentina, Escott-Price, I Nicol, Ferrier, Alessia, Fiorentino, Tatiana M, Foroud, Liz, Forty, Josef, Frank, Oleksandr, Frei, Nelson B, Freimer, Louise, Frisén, Katrin, Gade, Julie, Garnham, Joel, Gelernter, Marianne, Giørtz Pedersen, Ian R, Gizer, Scott D, Gordon, Katherine, Gordon-Smith, Tiffany A, Greenwood, Jakob, Grove, José, Guzman-Parra, Kyooseob, Ha, Magnus, Haraldsson, Martin, Hautzinger, Urs, Heilbronner, Dennis, Hellgren, Stefan, Herms, Per, Hoffmann, Peter A, Holmans, Laura, Huckins, Stéphane, Jamain, Jessica S, Johnson, Janos L, Kalman, Yoichiro, Kamatani, James L, Kennedy, Sarah, Kittel-Schneider, James A, Knowles, Manolis, Kogevinas, Maria, Koromina, Thorsten M, Kranz, Henry R, Kranzler, Michiaki, Kubo, Ralph, Kupka, Steven A, Kushner, Catharina, Lavebratt, Jacob, Lawrence, Markus, Leber, Heon-Jeong, Lee, Phil H, Lee, Shawn E, Levy, Catrin, Lewis, Calwing, Liao, Susanne, Lucae, Martin, Lundberg, Donald J, MacIntyre, Sigurdur H, Magnusson, Wolfgang, Maier, Adam, Maihofer, Dolores, Malaspina, Eirini, Maratou, Lina, Martinsson, Manuel, Mattheisen, Steven A, McCarroll, Nathaniel W, McGregor, Peter, McGuffin, James D, McKay, Helena, Medeiros, Sarah E, Medland, Vincent, Millischer, Grant W, Montgomery, Jennifer L, Moran, Derek W, Morris, Thomas W, Mühleisen, Niamh, O'Brien, Claire, O'Donovan, Loes M, Olde Loohuis, Lilijana, Oruc, Sergi, Papiol, Antonio F, Pardiñas, Amy, Perry, Andrea, Pfennig, Evgenia, Porichi, James B, Potash, Digby, Quested, Towfique, Raj, Mark H, Rapaport, J Raymond, DePaulo, Eline J, Regeer, John P, Rice, Fabio, Rivas, Margarita, Rivera, Julian, Roth, Panos, Roussos, Douglas M, Ruderfer, Cristina, Sánchez-Mora, Eva C, Schulte, Fanny, Senner, Sally, Sharp, Paul D, Shilling, Engilbert, Sigurdsson, Lea, Sirignano, Claire, Slaney, Olav B, Smeland, Daniel J, Smith, Janet L, Sobell, Christine, Søholm Hansen, Maria, Soler Artigas, Anne T, Spijker, Dan J, Stein, John S, Strauss, Beata, Świątkowska, Chikashi, Terao, Thorgeir E, Thorgeirsson, Claudio, Toma, Paul, Tooney, Evangelia-Eirini, Tsermpini, Marquis P, Vawter, Helmut, Vedder, James T R, Walters, Stephanie H, Witt, Simon, Xi, Wei, Xu, Jessica Mei Kay, Yang, Allan H, Young, Hannah, Young, Peter P, Zandi, Hang, Zhou, Lea, Zillich, Rolf, Adolfsson, Ingrid, Agartz, Martin, Alda, Lars, Alfredsson, Gulja, Babadjanova, Lena, Backlund, Bernhard T, Baune, Frank, Bellivier, Susanne, Bengesser, Wade H, Berrettini, Douglas H R, Blackwood, Michael, Boehnke, Anders D, Børglum, Gerome, Breen, Vaughan J, Carr, Stanley, Catts, Aiden, Corvin, Nicholas, Craddock, Udo, Dannlowski, Dimitris, Dikeos, Tõnu, Esko, Bruno, Etain, Panagiotis, Ferentinos, Mark, Frye, Janice M, Fullerton, Micha, Gawlik, Elliot S, Gershon, Fernando S, Goes, Melissa J, Green, Maria, Grigoroiu-Serbanescu, Joanna, Hauser, Frans, Henskens, Jan, Hillert, Kyung Sue, Hong, David M, Hougaard, Christina M, Hultman, Kristian, Hveem, Nakao, Iwata, Assen V, Jablensky, Ian, Jones, Lisa A, Jones, René S, Kahn, John R, Kelsoe, George, Kirov, Mikael, Landén, Marion, Leboyer, Cathryn M, Lewis, Qingqin S, Li, Jolanta, Lissowska, Christine, Lochner, Carmel, Loughland, Nicholas G, Martin, Carol A, Mathews, Fermin, Mayoral, Susan L, McElroy, Andrew M, McIntosh, Francis J, McMahon, Ingrid, Melle, Patricia, Michie, Lili, Milani, Philip B, Mitchell, Gunnar, Morken, Ole, Mors, Preben Bo, Mortensen, Bryan, Mowry, Bertram, Müller-Myhsok, Richard M, Myers, Benjamin M, Neale, Caroline M, Nievergelt, Merete, Nordentoft, Markus M, Nöthen, Michael C, O'Donovan, Ketil J, Oedegaard, Tomas, Olsson, Michael J, Owen, Sara A, Paciga, Chris, Pantelis, Carlos, Pato, Michele T, Pato, George P, Patrinos, Roy H, Perlis, Danielle, Posthuma, Josep Antoni, Ramos-Quiroga, Andreas, Reif, Eva Z, Reininghaus, Marta, Ribasés, Marcella, Rietschel, Stephan, Ripke, Guy A, Rouleau, Takeo, Saito, Ulrich, Schall, Martin, Schalling, Peter R, Schofield, Thomas G, Schulze, Laura J, Scott, Rodney J, Scott, Alessandro, Serretti, Cynthia, Shannon Weickert, Jordan W, Smoller, Hreinn, Stefansson, Kari, Stefansson, Eystein, Stordal, Fabian, Streit, Patrick F, Sullivan, Gustavo, Turecki, Arne E, Vaaler, Eduard, Vieta, John B, Vincent, Irwin D, Waldman, Thomas W, Weickert, Thomas, Werge, Naomi R, Wray, John-Anker, Zwart, Joanna M, Biernacka, John I, Nurnberger, Sven, Cichon, Howard J, Edenberg, Eli A, Stahl, Andrew, McQuillin, Arianna, Di Florio, Roel A, Ophoff, and Ole A, Andreassen

Subjects
Major Histocompatibility Complex, Multifactorial Inheritance, Bipolar Disorder, Phenotype, Genome, Human, Risk Factors, Case-Control Studies, Quantitative Trait Loci, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

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.

Published
2020

23. Hippocampal metabolite concentrations in schizophrenia vary in association with rare gene variants in the TRIO gene

Author

Haley Rhodes, Adriana Heguy, Moses V. Chao, Julie Walsh-Messinger, Kevin W. Hoffman, Oded Gonen, Thorsten M. Kranz, and Dolores Malaspina

Subjects
Genetics, Metabolite, Hippocampal formation, Biology, medicine.disease, Hippocampus, Polymorphism, Single Nucleotide, Psychiatry and Mental health, chemistry.chemical_compound, chemistry, Schizophrenia, medicine, Autism, Humans, Association (psychology), Gene, Biological Psychiatry
Published
2020

24. Hippocampal Metabolite Concentrations in A Schizophrenia Case Series Vary in Association With Rare Gene Variants For Schizophrenia Versus Autism

Author

Thorsten M. Kranz, Kevin W. Hoffmann, Dolores Malaspina, Oded Gonen, Haley Rhodes, Moses V. Chao, and Adriana Heguy

Subjects
Genetics, business.industry, Metabolite, Hippocampal formation, medicine.disease, chemistry.chemical_compound, chemistry, Schizophrenia, mental disorders, medicine, Autism, Association (psychology), business, Gene
Abstract

BackgroundRare variants in the TRIO gene are associated with schizophrenia and autism spectrum disorders (ASD), which are commonly comorbid. ASD may define a specific schizophrenia subtype. This study examined person-specific hippocampal metabolite concentrations for 4 schizophrenia cases harboring rare variants in TRIO or its interaction partner ARMS/KIDINS220 and 5 cases with other rare variants.MethodsNine of 19 cases from a prior imaging study underwent targeted exome sequencing. Multi-voxel 1H-MRS imaging of the entire 3-dimensional hippocampus found only increased Creatine [Cr] (cellular energy use) concentration, distinguished cases at the group level. However, concentrations of N-acetyl-aspartate [NAA] (neuronal integrity) and choline [Cho] (membrane turnover/myelination) concentrations had a greater variance in cases than controls.ResultsFour cases with rare, missense-coding mutations or non-frameshift deletions in TRIO or ARMS/KIDINS220 had significantly lower [Cho] than the other 5 (1.78 ± 0.18 mM versus 2.67 ± 0.8 mM: t = 3.55, p = 0.005) but similar [NAA]. Two cases harboring rare variants in the SLC39A1 zinc transporter had the lowest [NAA]. (8.41 ± 0 80 mM versus 10.35 ± 2.03 mM, t = 4.52, p = 0.001). The highest [Cho] accompanied rare variants in SORCS2 and SORT, associated with schizophrenia and Alzheimer’s Disease.LimitationsThis preliminary study of a small sample of exceptionally well characterized cases requires replication in larger samples for clinical utility.ConclusionsThe hippocampus is vulnerable to more than one pathology causing schizophrenia. TRIO rare variants predicted significantly lower Cho, indicating reduced myelin. [Cho] and [NAA] may have importance for choosing and monitoring schizophrenia treatment.

Published
2020

25. Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia

Author

Jakleen J. Lee, Cheryl M. Corcoran, Thorsten M. Kranz, Kevin W. Hoffman, David Kimhy, and Dolores Malaspina

Subjects
lcsh:RC435-571, Gut–brain axis, microbiome, Review, Biology, cortisol, 03 medical and health sciences, stress, 0302 clinical medicine, Intestinal mucosa, lcsh:Psychiatry, medicine, Neurochemistry, Microbiome, development, Brain-derived neurotrophic factor, Psychiatry, Stressor, brain-derived neurotrophic factor, medicine.disease, 030227 psychiatry, schizophrenia, Psychiatry and Mental health, Prenatal stress, Schizophrenia, Neuroscience, 030217 neurology & neurosurgery
Abstract

Early life adversity and prenatal stress are consistently associated with an increased risk for schizophrenia, although the exact pathogenic mechanisms linking the exposures with the disease remain elusive. Our previous view of the HPA stress axis as an elegant but simple negative feedback loop, orchestrating adaptation to stressors among the hypothalamus, pituitary, and adrenal glands, needs to be updated. Research in the last two decades shows that important bidirectional signaling between the HPA axis and intestinal mucosa modulates brain function and neurochemistry, including effects on glucocorticoid hormones and brain-derived neurotrophic factor (BDNF). The intestinal microbiome in earliest life, which is seeded by the vaginal microbiome during delivery, programs the development of the HPA axis in a critical developmental window, determining stress sensitivity and HPA function as well as immune system development. The crosstalk between the HPA and the Microbiome Gut Brain Axis (MGBA) is particularly high in the hippocampus, the most consistently disrupted neural region in persons with schizophrenia. Animal models suggest that the MGBA remains influential on behavior and physiology across developmental stages, including the perinatal window, early childhood, adolescence, and young adulthood. Understanding the role of the microbiome on critical risk related stressors may enhance or transform of understanding of the origins of schizophrenia and offer new approaches to increase resilience against stress effects for preventing and treating schizophrenia.

Published
2020

26. Genetics of ADHD: What Should the Clinician Know?

Author

Thorsten M. Kranz, Oliver Grimm, and Andreas Reif

Subjects
Multifactorial Inheritance, Genetic syndromes, MEDLINE, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Polygenic risk score, Attention deficit, Genetics, medicine, Humans, ADHD, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, Genetic risk, 030304 developmental biology, 0303 health sciences, Copy number, business.industry, Genetic Disorders (F Goes, Section Editor), Heritability, medicine.disease, Hyperactivity, Review article, Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Clinical psychology
Abstract

Purpose of Review Attention deficit hyperactivity disorder (ADHD) shows high heritability in formal genetic studies. In our review article, we provide an overview on common and rare genetic risk variants for ADHD and their link to clinical practice. Recent findings The formal heritability of ADHD is about 80% and therefore higher than most other psychiatric diseases. However, recent studies estimate the proportion of heritability based on singlenucleotide variants (SNPs) at 22%. It is a matter of debate which genetic mechanisms explain this huge difference. While frequent variants in first mega-analyses of genome-wideassociation study data containing several thousand patients give the first genome-wide results, explaining only little variance, the methodologically more difficult analyses of rare variants are still in their infancy. Some rare genetic syndromes show higher prevalence for ADHD indicating a potential role for a small number of patients. In contrast, polygenic risk scores (PRS) could potentially be applied to every patient. We give an overview how PRS explain different behavioral phenotypes in ADHD and how they could be used for diagnosis and therapy prediction. Summary Knowledge about a patient’s genetic makeup is not yet mandatory for ADHD therapy or diagnosis. PRS however have been introduced successfully in other areas of clinical medicine, and their application in psychiatry will begin within the next years. In order to ensure competent advice for patients, knowledge of the current state of research is useful forpsychiatrists.

Published
2020

27. Serum zinc levels in acute psychiatric patients: A case series

Author

Thorsten M. Kranz, Dolores Malaspina, Samantha Redman, Matthew A. Petrilli, Mara Getz, Peter Joe, and Samoon Ahmad

Subjects
Adult, Male, medicine.medical_specialty, Psychosis, chemistry.chemical_element, Zinc, Violence, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Patient group, Psychiatry, Biological Psychiatry, Depression (differential diagnoses), Inpatients, Serum zinc, business.industry, Mental Disorders, Middle Aged, medicine.disease, 030227 psychiatry, Aggression, Psychiatry and Mental health, Mood, chemistry, Acute Disease, Zinc deficiency, Female, business, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract

Zinc dysregulation is linked to neuropsychiatric disorders and a beneficial response to zinc supplementation has been demonstrated for depression. In this case series, we examined serum zinc levels with respect to clinical factors among 20 acutely ill psychiatric cases admitted to a large urban public hospital. The results showed frank clinical zinc insufficiency in a quarter of the subjects. Group-wise analyses showed a significant association between reduced serum zinc and diagnosis of depression, and reduced serum zinc in those with aggressive, assaultive, or violent behaviors. By contrast, relatively elevated zinc levels were observed in a subset of psychotic cases on antipsychotics and mood stabilizers who had no mood symptoms. In summary, clinical zinc insufficiency was common in these acutely admitted psychiatric cases. Zinc supplementation may ameliorate symptoms in certain cases and should be considered in treatment planning. A separate patient group had elevated zinc levels, which could conceivably be pathogenic. Larger studies are needed to confirm and extend this pilot data.

Published
2018

28. Rare missense coding variants in oxytocin receptor ( OXTR ) in schizophrenia cases are associated with early trauma exposure, cognition and emotional processing

Author

Robert C. Froemke, Antonio Egidio Nardi, Thorsten M. Kranz, Dolores Malaspina, André Barciela Veras, Mara Getz, Moses V. Chao, Julie Walsh-Messinger, and Gilberto Alves

Subjects
Adult, Male, medicine.medical_specialty, Mutation, Missense, Poison control, Psychological Trauma, Bioinformatics, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Adverse Childhood Experiences, medicine, Humans, Cognitive Dysfunction, Emotional expression, Affective Symptoms, Psychiatry, Biological Psychiatry, Sex Offenses, Environmental exposure, Middle Aged, medicine.disease, Oxytocin receptor, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Sexual abuse, Receptors, Oxytocin, Schizophrenia, Case-Control Studies, Anxiety, Female, Sex offense, medicine.symptom, Psychology, 030217 neurology & neurosurgery
Abstract

Background Oxytocin is a peptide hormone that influences the integration of social cognition with behavior and affect regulation. Oxytocin also prominently directs the transition of neuronal GABA neurotransmission from excitatory to inhibitory after birth. The oxytocin receptor (OXTR) is linked to schizophrenia, a heterogeneous syndrome. Relationships of OXTR polymorphisms with specific clinical features could aid in evaluating any role of oxytocin in the pathogenesis of schizophrenia. Method Schizophrenia cases with rare missense coding OXTR single nucleotide variants (SNVs) were identified from a well-characterized sample of cases and controls who were assessed for symptoms, cognition and early life trauma. Results Five of 48 cases showed rare OXTR variants. Compared to the other cases they had less severe negative symptoms (deficits in emotional expression and motivation) and less severe general psychopathology scores (depression and anxiety). They demonstrated lower nonverbal (performance) than verbal intelligence due to deficient perceptual organization and slow processing speed. They also reported greater early trauma exposure (physical and sexual abuse and emotional trauma). Conclusion Cases carrying rare OXTR SNVs had less negative and affective symptoms than other cases, but similar psychotic symptoms, along with specific cognitive deficits. The clinical characterization of these cases occurred in association with environmental exposure to early trauma, especially sexual abuse, which may have influenced the expression of schizophrenia in subjects harboring specific SNVs in the OXTR.

Published
2018

29. Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder

Author

Thorsten M. Kranz, Marnie Kopp, Christine M. Freitag, Michael Sachse, Eftichia Duketis, Regina Waltes, Katharina Görgen, Franziska Degenhardt, Andreas G. Chiocchetti, Tomasz A. Jarczok, and Jobst Meyer

Subjects
0301 basic medicine, Genetics, Autism Diagnostic Interview, General Neuroscience, Single-nucleotide polymorphism, medicine.disease, Oxytocin receptor, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Autism spectrum disorder, Meta-analysis, Endophenotype, medicine, Autism, Neurology (clinical), Allele, Psychology, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract

Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Published
2016

30. Short duration of marriage at conception as an independent risk factor for schizophrenia

Author

Susan Harlap, Yechiel Friedlander, Karen Rothman, Sulaima Daboul, Mara Getz, Caitlin Gilman, Thorsten M. Kranz, Karine Kleinhaus, and Dolores Malaspina

Subjects
Adult, Male, Parents, Time Factors, Adolescent, Offspring, Sexual Behavior, Population, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Medicine, Humans, Risk factor, Marriage, education, Short duration, Biological Psychiatry, Aged, Aged, 80 and over, education.field_of_study, Pregnancy, business.industry, Proportional hazards model, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Schizophrenia, Relative risk, Fertilization, Female, business, 030217 neurology & neurosurgery, Demography
Abstract

Short duration of marriage (DoM) is a risk factor for preeclampsia that is also related to the risk for schizophrenia. This analysis examined the risk for schizophrenia associated with DoM and its independence from parental psychiatric disorders, parental ages and fathers' age at marriage. Method Relative Risks (RR) for schizophrenia were estimated using continuous and stratified Cox proportional hazards models in the 90,079 offspring from the prospective population-based Jerusalem birth cohort study (1964–1976). Schizophrenia diagnos in offspring and parental diagnoses of schizophrenia or other psychiatric conditions were identified by cross-linkage to Israel's psychiatric case registry. DoM and paternal age at marriage were abstracted from birth certificates. Results In the full model, RR for schizophrenia decreased for each 5 years DoM: 0.83 (0.75–0.95), ptrend = 0.0015. Stratified analyses showed the greatest RR risk for DoM Conclusions Offspring born to couples married for less than 3 years, across all paternal ages, harbored a small increased risk for schizophrenia, which was independent of parental psychiatric disorders and paternal age. Fathers who married late had particularly short DoM, which, along with paternal age, completely explained the risks related to later paternal age at marriage. Further studies are needed to replicate these results and examine if pathogenic pathways include prenatal immune activation.

Published
2018

31. Sex-Specific Differences in Oxytocin Receptor Expression and Function for Parental Behavior

Author

Jennifer K. Schiavo, Jess Minder, Bianca J. Marlin, Mariela Mitre, Xinying Zhang, Thomas A. Neubert, Troy A. Hackett, Thorsten M. Kranz, Moses V. Chao, Hediye Erdjument-Bromage, and Robert C. Froemke

Subjects
0301 basic medicine, lcsh:Medical technology, lcsh:QH426-470, Original Articles, Biology, Auditory cortex, Oxytocin receptor, Maternal Physiology, lcsh:Genetics, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, lcsh:R855-855.5, Prosocial behavior, Oxytocin, Neuroplasticity, medicine, Receptor, Paternal care, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

Parental care is among the most profound behavior expressed by humans and other animals. Despite intense interest in understanding the biological basis of parental behaviors, it remains unknown how much of parenting is encoded by the genome and which abilities instead are learned or can be refined by experience. One critical factor at the intersection between innate behaviors and experience-dependent learning is oxytocin, a neurohormone important for maternal physiology and neuroplasticity. Oxytocin acts throughout the body and brain to promote prosocial and maternal behaviors and modulates synaptic transmission to affect neural circuit dynamics. Recently we developed specific antibodies to mouse oxytocin receptors, found that oxytocin receptors are left lateralized in female auditory cortex, and examined how oxytocin enables maternal behavior by sensitizing the cortex to infant distress sounds. In this study we compare oxytocin receptor expression and function in male and female mice. Receptor expression is higher in adult female left auditory cortex than in right auditory cortex or males. Developmental profiles and mRNA expression were comparable between males and females. Behaviorally, male and female mice began expressing parental behavior similarly after cohousing with experienced females; however, oxytocin enhanced parental behavior onset in females but not males. This suggests that left lateralization of oxytocin receptor expression in females provides a mechanism for accelerating maternal behavior onset, although male mice can also effectively co-parent after experience with infants. The sex-specific pattern of oxytocin receptor expression might genetically predispose female cortex to respond to infant cues, which both males and females can also rapidly learn.

Published
2017

32. Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease

Author

Yinghua Chen, Moses V. Chao, Shaoli Che, Melissa J. Alldred, Thorsten M. Kranz, Irina Elarova, Stephen D. Ginsberg, Elliott J. Mufson, Scott E. Counts, Michael Malek-Ahmadi, Freddy Jeanneteau, Nathan S. Kline Institute for Psychiatric Research (NKI), New York State Office of Mental Health, New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Skirball Institute of Biomolecular Medicine, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Department of Translational Science and Molecular Medicine, Michigan State University [East Lansing], Michigan State University System-Michigan State University System, and Barrow Neurological Institute

Subjects
Male, Cognitive Neuroscience, [SDV]Life Sciences [q-bio], Hippocampus, Receptors, Nerve Growth Factor, Tropomyosin receptor kinase B, Tropomyosin receptor kinase A, Hippocampal formation, Trk receptors, Tropomyosin receptor kinase C, Article, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Humans, Medicine, Cognitive Dysfunction, 0501 psychology and cognitive sciences, Nerve Growth Factors, CA1 Region, Hippocampal, Aged, Aged, 80 and over, Brain-derived neurotrophic factor, biology, business.industry, Pyramidal Cells, 05 social sciences, brain-derived neurotrophic factor, neuritic plaques, nervous system, neurofibrillary tangles, Trk receptor, Disease Progression, biology.protein, Female, business, Neuroscience, microarray, 030217 neurology & neurosurgery, Neurotrophin
Abstract

International audience; Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD.

Published
2017

33. Transglutaminase-5 related schizophrenia

Author

Dolores Malaspina, Mara Getz, Peter Joe, Shannon Delaney, Samantha Redman, Moses V. Chao, Lea Ann Chen, and Thorsten M. Kranz

Subjects
0301 basic medicine, Male, Psychiatric Status Rating Scales, medicine.medical_specialty, Transglutaminases, business.industry, Schizophrenia (object-oriented programming), 03 medical and health sciences, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, Quality of life, Mutation (genetic algorithm), Psychiatric status rating scales, Mutation, Quality of Life, Schizophrenia, Medicine, Humans, Female, business, Psychiatry, 030217 neurology & neurosurgery, Biological Psychiatry, Transglutaminase 5
Published
2017

34. The Emerging Role for Zinc in Depression and Psychosis

Author

Dolores Malaspina, Mara Getz, Matthew A. Petrilli, Peter Joe, Karine Kleinhaus, Thorsten M. Kranz, Moses V. Chao, and Porsha Johnson

Subjects
0301 basic medicine, Psychosis, chemistry.chemical_element, glutamate, Zinc, Review, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Zinc transporter, medicine, Pharmacology (medical), psychosis, Beneficial effects, Normal range, Depression (differential diagnoses), business.industry, lcsh:RM1-950, medicine.disease, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, chemistry, NMDA, depression, business, zinc dysfunction, 030217 neurology & neurosurgery, Hormone
Abstract

Zinc participation is essential for all physiological systems, including neural functioning, where it participates in a myriad of cellular processes. Converging clinical, molecular, and genetic discoveries illuminate key roles for zinc homeostasis in association with clinical depression and psychosis which are not yet well appreciated at the clinical interface. Intracellular deficiency may arise from low circulating zinc levels due to dietary insufficiency, or impaired absorption from aging or medical conditions, including alcoholism. A host of medications commonly administered to psychiatric patients, including anticonvulsants, oral medications for diabetes, hormones, antacids, anti-inflammatories and others also impact zinc absorption. Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range. Well powered clinical studies have shown beneficial effects of supplemental zinc in depression and it important to pursue research using zinc as a potential therapeutic option for psychosis as well. Meta-analyses support the adjunctive use of zinc in major depression and a single study now supports zinc for psychotic symptoms. This manuscript reviews the biochemistry and bench top evidence on putative molecular mechanisms of zinc as a psychiatric treatment.

Published
2017
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35. Early trauma and clinical features of schizophrenia cases influenced by the BDNF Val66Met allele

Author

Thorsten M. Kranz, Mara Getz, Antonio Egidio Nardi, Clayton Peixoto, André Barciela Veras, Peter F. Buckley, Julie Walsh Messinger, Dolores Malaspina, Raymond R. Goetz, and Moses V. Chao

Subjects
Adult, Male, Adolescent, Genotype, DNA Mutational Analysis, MEDLINE, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Methionine, Polymorphism (computer science), Schizophrenic Psychology, Medicine, Humans, Child Abuse, Allele, Young adult, Biological Psychiatry, Genetic Association Studies, business.industry, Brain-Derived Neurotrophic Factor, Valine, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Schizophrenia, Female, business, 030217 neurology & neurosurgery
Published
2017

36. M95. Rare Genetic Variants and Novel Missense Coding Mutations in the Neurotrophin Signaling Pathway Genes With Focus on the Scaffold Protein ARMS/KIDINS220 and Rho-GEF TRIO Are Implicated in Psychosis Risk

Author

Thorsten M. Kranz

Subjects
Scaffold protein, Genetics, Mutation, Psychosis risk, Neurotrophin signaling pathway, Genetic variants, Biology, medicine.disease_cause, Psychiatry and Mental health, Abstracts, medicine, Missense mutation, Human genome, Gene
Abstract

Background: Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others.

Published
2017

37. Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice

Author

Thorsten M. Kranz, Jean-Marie Launay, Sheila Harroch, Françoise Lazarini, Véronique Dubreuil, Sylvie Granon, Arnaud Cressant, Jan Sap, Jing Kong, Jacques Callebert, Dolores Malaspina, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Département de Neuroscience - Department of Neuroscience, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), New York University School of Medicine, NYU System (NYU), Génétique Humaine et Fonctions Cognitives, Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139, Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay ( Neuro-PSI ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Département de Neuroscience, Institut Pasteur [Paris], Department of psychiatry, New York University Langone School of Medicine, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-IFR139, and Université Paris Diderot - Paris 7 ( UPD7 )

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Serotonin, Dopamine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, Anxiety, Mental disorders, Amygdala, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, 03 medical and health sciences, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Mice, 0302 clinical medicine, Contactins, Internal medicine, Phosphatase, medicine, Animals, Social behavior, Prefrontal cortex, Swimming, Pharmacology, Mice, Knockout, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Receptor-Like Protein Tyrosine Phosphatases, Class 5, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, medicine.disease, Corpus Striatum, Aggression, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Monoamine neurotransmitter, Schizophrenia, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Psychology, 030217 neurology & neurosurgery, Clinical psychology, medicine.drug
Abstract

The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG −/− , PTPRZ −/− , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ −/− mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO. PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy.

Published
2017

38. 172. Receptor Protein Tyrosine Phosphatases in Schizophrenia

Author

Moses V. Chao, Sheila Harrock, Thorsten M. Kranz, Dolores Malaspina, and Oded Gonen

Subjects
medicine.medical_specialty, Endocrinology, Chemistry, Schizophrenia (object-oriented programming), Internal medicine, Phosphatase, medicine, Tyrosine, Receptor, Biological Psychiatry
Published
2018

39. The chromosome 15q14 locus for bipolar disorder and schizophrenia: Is C15orf53 a major candidate gene?

Author

Savira Ekawardhani, Hans Bauer, Claude P. Muller, Ulrike Schuelter, Fabian Streit, Andrea B. Schote, Andreas Reif, Thorsten M. Kranz, Jobst Meyer, Darja Henseler, Michelle K. Lin, Simone R. Witzmann, Jonathan D. Turner, Farmacologie en Toxicologie, and RS: CARIM School for Cardiovascular Diseases

Subjects
Adult, Male, Candidate gene, Genetic Linkage, Bipolar disorder, Locus (genetics), Biology, Open Reading Frames, Gene expression, medicine, Humans, Genetic Predisposition to Disease, Gene, Biological Psychiatry, Genetic association, Genetics, Chromosomes, Human, Pair 15, Haplotype, Segregation, Catatonia, Middle Aged, medicine.disease, C15orf53, Psychiatry and Mental health, Periodic catatonia, Genetic Loci, Case-Control Studies, Schizophrenia, Etiology, Female, Genome-Wide Association Study
Abstract

Bipolar disorder (BD) and schizophrenia are complexly inherited and highly heritable disorders with currently unknown etiologies. Recently, two independent genome-wide association studies for BD identified a small region on chromosome 15q14-15.1, pointing to a locus close to the gene C15orf53 . Previously, this genomic region was also found to co-segregate with periodic catatonia (SCZD10, OMIM % 605419 ), an unsystematic schizophrenia according to Leonhard's classification, in several multiplex families, thus pointing to overlapping etiologies of both conditions. A susceptibility locus on chromosome 15q14-15.1 was narrowed down to a 4.38 Mb region in these affected families followed by mutation and segregation analyses of C15orf53 . Association analysis of individuals affected by BD and/or SCZD10 ( n = 274) and controls ( n = 230) and expression analyses in distinct post-mortem human limbic brain tissues were conducted. C15orf53 revealed no mutations in our SCZD10 family members, but segregation of two common haplotypes was found. No association of identified haplotypes was found in our case–control samples. Gene expression could be demonstrated for immune-system-derived cells but not for the post-mortem human limbic brain tissue. Our results indicate that C15orf53 is probably neither causative for the etiology of BD nor for SCZD10 in our samples.

Published
2012

41. Opposite effect of membrane raft perturbation on transport activity of KCC2 and NKCC1

Author

Eckhard Friauf, Kai Kaila, Anna-Maria Hartmann, Peter Blaesse, Thorsten M. Kranz, Jens Schindler, Meike Wenz, and Hans Gerd Nothwang

Subjects
Glycosylation, Sodium-Potassium-Chloride Symporters, Detergents, Transferrin receptor, Kidney, Synaptic Transmission, Biochemistry, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, Membrane Microdomains, 0302 clinical medicine, Chlorides, Cations, Animals, Homeostasis, Humans, Solute Carrier Family 12, Member 2, 030304 developmental biology, Neurons, 0303 health sciences, Symporters, Chemistry, Lipid microdomain, Membrane raft, Neural Inhibition, Membrane transport, Rats, Cholesterol, Membrane, Animals, Newborn, Solubility, Biophysics, lipids (amino acids, peptides, and proteins), Sphingomyelin, Cotransporter, 030217 neurology & neurosurgery, Intracellular, Brain Stem
Abstract

In the majority of neurons, the intracellular Cl(-) concentration is set by the activity of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) and the K(+)-Cl(-) cotransporter (KCC2). Here, we investigated the cotransporters' functional dependence on membrane rafts. In the mature rat brain, NKCC1 was mainly insoluble in Brij 58 and co-distributed with the membrane raft marker flotillin-1 in sucrose density flotation experiments. In contrast, KCC2 was found in the insoluble fraction as well as in the soluble fraction, where it co-distributed with the non-raft marker transferrin receptor. Both KCC2 populations displayed a mature glycosylation pattern. Disrupting membrane rafts with methyl-beta-cyclodextrin (MbetaCD) increased the solubility of KCC2, yet had no effect on NKCC1. In human embryonic kidney-293 cells, KCC2 was strongly activated by a combined treatment with MbetaCD and sphingomyelinase, while NKCC1 was inhibited. These data indicate that membrane rafts render KCC2 inactive and NKCC1 active. In agreement with this, inactive KCC2 of the perinatal rat brainstem largely partitioned into membrane rafts. In addition, the exposure of the transporters to MbetaCD and sphingomyelinase showed that the two transporters differentially interact with the membrane rafts. Taken together, membrane raft association appears to represent a mechanism for co-ordinated regulation of chloride transporter function.

Published
2009

42. Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity

Author

Adriana Heguy, Oded Gonen, Raymond R. Goetz, Thorsten M. Kranz, Dolores Malaspina, Karen Rothman, Sheila Harroch, Moses V. Chao, Sumya Hasan, Mariana Lazar, Daniel Antonius, Robert Mazgaj, and Adam Berns

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Mutation, Missense, Prefrontal Cortex, Nerve Tissue Proteins, Article, 03 medical and health sciences, 0302 clinical medicine, Cognition, Internal medicine, medicine, Humans, Prefrontal cortex, Pathological, Biological Psychiatry, Anterior cingulate cortex, Intelligence Tests, Psychiatric Status Rating Scales, Aspartic Acid, Polymorphism, Genetic, Intelligence quotient, Genetic heterogeneity, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Membrane Proteins, medicine.disease, Verbal reasoning, Magnetic Resonance Imaging, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, nervous system, Psychotic Disorders, Schizophrenia, Biomarker (medicine), Female, Schizophrenic Psychology, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3 T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (χ2 = 18.40, p < .0001). In cases, it predicted verbal intelligence (r = .469, p = .043) and trait negative symptoms (diminished emotional range (r = −.624, p = .010); curbed interests, r = −.558, p = .025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies.

Published
2015

43. Early Life Stress Effects on Glucocorticoid—BDNF Interplay in the Hippocampus

Author

Dolores Malaspina, Thorsten M. Kranz, Nikolaos P. Daskalakis, Rachel Yehuda, and Edo Ronald de Kloet

Subjects
hippocampus, Mini Review, Central nervous system, early life stress, Tropomyosin receptor kinase B, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Glucocorticoid receptor, Neurotrophic factors, medicine, glucocorticoid receptor, Receptor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, HPA axis, TrkB, medicine.anatomical_structure, BDNF, nervous system, HPA-axis, biology.protein, glucocorticoid, Signal transduction, Psychology, Neuroscience, 030217 neurology & neurosurgery, Glucocorticoid, medicine.drug, Neurotrophin
Abstract

Early life stress (ELS) is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress-susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid and/or neurotrophin signaling pathways. Glucocorticoid (GC) signaling mediates the regulation of the stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and glucocorticoid signaling pathways co-exist throughout the central nervous system (CNS), particularly in the hippocampus, which has high expression of glucocorticoid and mineralocorticoid receptors (GR and MR) as well as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB). This review addresses the effects of ELS paradigms on GC- and BDNF- dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders.

Published
2015
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44. Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder

Author

Thorsten M, Kranz, Marnie, Kopp, Regina, Waltes, Michael, Sachse, Eftichia, Duketis, Tomasz A, Jarczok, Franziska, Degenhardt, Katharina, Görgen, Jobst, Meyer, Christine M, Freitag, and Andreas G, Chiocchetti

Subjects
Genotype, Autism Spectrum Disorder, Receptors, Oxytocin, Humans, Child, Polymorphism, Single Nucleotide, Alleles
Abstract

Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889GA in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Published
2015

45. Paternal age and mental health of offspring

Author

Dolores Malaspina, Thorsten M. Kranz, and Caitlin Gilman

Subjects
Adult, Male, medicine.medical_specialty, medicine.risk_factor, Internationality, Adolescent, Population, Comorbidity, Article, Paternal Age, Age Distribution, Pregnancy, Risk Factors, medicine, Humans, Bipolar disorder, Paternal age effect, education, Psychiatry, Child, education.field_of_study, Evidence-Based Medicine, business.industry, Incidence, Mental Disorders, Infant, Newborn, Obstetrics and Gynecology, Infant, Middle Aged, Mental illness, medicine.disease, Mental health, Reproductive Medicine, Schizophrenia, Child, Preschool, Autism, Female, business, Maternal Age
Abstract

The influence of paternal age on the risk for sporadic forms of Mendelian disorders is well known, but a burgeoning recent literature demonstrates, in addition, a paternal age effect for complex neuropsychiatric conditions, including schizophrenia, autism, bipolar disorder, and even for learning potential, expressed as intelligence. Mental illness is costly to patients, their family, and the public health system, accounting for the largest portion of disability costs in our economy. The delayed onset of neuropsychiatric conditions and lack of physical manifestations at birth are common frequencies in the population that have obscured the recognition that a portion of the risks for mental conditions is associated with paternal age. Identification of these risk pathways may be leveraged for knowledge about mental function and for future screening tests. However, only a small minority of at-risk offspring are likely to have such a psychiatric or learning disorder attributable to paternal age, including the children of older fathers.

Published
2015

46. De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample

Author

Orly Manor, Jill Harkavy-Friedman, Adriana Heguy, Marco Seandel, Pesach Lichtenberg, Julie Walsh-Messinger, Yechiel Friedlander, Moses V. Chao, Sheila Harroch, Dolores Malaspina, Igor Dolgalev, and Thorsten M. Kranz

Subjects
Adult, Male, Parents, Population, New York, Datasets as Topic, Disease, Biology, Gene mutation, medicine.disease_cause, Article, medicine, Humans, Genetic Predisposition to Disease, Allele, Israel, education, Gene, Biological Psychiatry, Exome sequencing, Genetics, education.field_of_study, Mutation, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Sequence Analysis, DNA, medicine.disease, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, Female
Abstract

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent–offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF < 0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.

Published
2015

47. Unusual 5'-regulatory structure and regulation of the murine Mlc1 gene: Lack of promoter-specific functional elements

Author

Matthias Eckhardt, Thorsten M. Kranz, Yanina Revsin, Darja Henseler, Maaike H. van der Mark, Jobst Meyer, Jonathan D. Turner, Claude P. Muller, and Michelle K. Lin

Subjects
Regulation of gene expression, Genetics, Reporter gene, Exon, Cell culture, In silico, Gene expression, Biology, Biochemistry, Gene, Function (biology)
Abstract

The MLC1 gene is involved in an autosomal recessive neurological disorder, megalencephalic leucoencephalopathy with subcortical cysts (MLC), which is characterized by macrocephaly during the first year of life and swollen white matter (leucoencephaly). Variants of MLC1 have also been associated with psychiatric disorders such as schizophrenia, major depression and bipolar disorder. Currently, little is known about the encoded protein (MLC1). Judging from its similarity to other known proteins, it may serve as a trans-membrane transporter. However, the function of the encoded protein and its gene regulation has not been investigated successfully so far. We investigated the 5’ region of the murine Mlc1 with respect to regulatory elements for gene expression. A promoter search and an in silico analysis were conducted. Luciferase reporter gene constructs with potential promoter regions were created to study promoter activity in vitro. We found two alternative first exons for the murine Mlc1 but were not able to detect any promoter activity for the investigated reporter gene constructs in different cell lines, thus pointing to the presence of essential cis-acting elements far outside of the region. In silico analysis indicated an uncommon promoter structure for Mlc1, with CCAAT-boxes representing the only noticeable elements.

Published
2011

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