Author: "Andreas Reif" / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

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282 results on '"Andreas Reif"'

1. Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder

Author: Mara Parellada, Kerstin Konrad, Mark A. Bellgrove, Stefan Ehrlich, Thomas Frodl, Ruth O'Gorman Tuura, Evdokia Anagnostou, J. Antoni Ramos-Quiroga, David Coghill, Clyde Francks, Georgii Karkashadze, Damien A. Fair, Francisco X. Castellanos, Oscar Vilarroya, Eugenio H. Grevet, Yash Patel, Eileen Daly, Clodagh M. Murphy, Klaus-Peter Lesch, Kirsten O'Hearn, Claiton H.D. Bau, Jeffery N. Epstein, Daan van Rooij, Liesbeth Reneman, Eileen Oberwelland-Weiss, Timothy J. Silk, Yanli Zhang-James, Christine M. Freitag, Jane McGrath, Tomáš Paus, Jan Haavik, Louise Gallagher, Ting Li, Merel Postema, Celso Arango, Barbara Franke, Sara Calderoni, Jaap Oosterlaan, Andreas Reif, Paulo Mattos, Iva Ilioska, Leanne Tamm, Paul M. Thompson, Joost Janssen, Pieter J. Hoekstra, Neda Jahanshad, Jacqueline Fitzgerald, Odile A. van den Heuvel, Pedro G.P. Rosa, Tobias Banaschewski, Joseph A. King, Katya Rubia, Christine Deruelle, Marieke Klein, Stephen V. Faraone, Philip Shaw, Premika S.W. Boedhoe, Kerstin Jessica Plessen, Luisa Lázaro, Alessandra Retico, Jan K. Buitelaar, Paul Pauli, Guillaume Auzias, Joel T. Nigg, Christine Ecker, Annette Conzelmann, Jonna Kuntsi, Sarah Durston, Beatriz Luna, Silvia Brem, Marlene Behrmann, Jason P. Lerch, Susanne Walitza, Martine Hoogman, Filippo Muratori, Ilan Dinstein, Rosa Calvo, Mario Rodrigues Louzã, Geraldo F. Busatto, Daniel Brandeis, Institut de Neurosciences de la Timone (INT), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Neurology, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], CHILDREN, Review Article, 0302 clinical medicine, Transtorno do espectro autista, pathology [Brain], 130 000 Cognitive Neurology & Memory, GENETIC INFLUENCES, Neurociències, Multicenter Studies as Topic, Review Articles, Mapeamento encefálico, ComputingMilieux_MISCELLANEOUS, LIFE-SPAN, neuroimaging, Radiological and Ultrasound Technology, Consórcios de saúde, 05 social sciences, ENIGMA, Brain, 220 Statistical Imaging Neuroscience, Transtorno do déficit de atenção com hiperatividade, Autism spectrum disorders, Cerebral cortex, Trastorns de l'espectre autista, 3. Good health, IMAGING FINDINGS, Escorça cerebral, cortex, Autism spectrum disorder, Cortex, Trastorns per dèficit d'atenció amb hiperactivitat en els adults, Anatomy, Psychology, diagnostic imaging [Autism Spectrum Disorder], Clinical psychology, medicine.medical_specialty, DEFICIT HYPERACTIVITY DISORDER, BRAIN ABNORMALITIES, ADHD, ASD, subcortical volumes, Brain Structure and Function, Neuroimaging, pathology [Autism Spectrum Disorder], behavioral disciplines and activities, 050105 experimental psychology, 03 medical and health sciences, mental disorders, medicine, Attention deficit hyperactivity disorder, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, ddc:610, diagnostic imaging [Brain], METAANALYSIS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurosciences, pathology [Attention Deficit Disorder with Hyperactivity], medicine.disease, Mental health, Subcortical volumes, Attention Deficit Disorder with Hyperactivity, Attention deficit disorder with hyperactivity in adults, Autism, diagnostic imaging [Attention Deficit Disorder with Hyperactivity], Neurology (clinical), Working group, 170 000 Motivational & Cognitive Control, CORTICAL THICKNESS, 030217 neurology & neurosurgery
Abstract: Human brain mapping 43(1), 37-55 (2022). doi:10.1002/hbm.25029 special issue: "Special Issue: The ENIGMA Consortium: the first 10 years / Issue Edited by: P.M. Thompson, N. Jahanshad, L. Schmaal, J.A. Turner, A. Winkler, S.I. Thomopoulos, G.F. Egan, P. Kochunov", Published by Wiley-Liss, New York, NY
Published: 2022
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2. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Author: Stephen V. Faraone, Barbara Franke, Isabella Vainieri, Christine M. Freitag, Alejandro Arias Vasquez, Jan K. Buitelaar, Ylva Ginsberg, Bru Cormand, Sarah Kittel-Schneider, Rhiannon V. McNeill, Jonna Kuntsi, Marta Ribasés, Marcel Romanos, Andreas Reif, Catharina A. Hartman, Henrik Larsson, J. Antoni Ramos-Quiroga, Jan Haavik, Gara Arteaga-Henríquez, Silke Matura, Isabell Brikell, Tobias Banaschewski, and P. Asherson
Subjects: Cognitive Neuroscience, Longevity, Diabetes mellitus type II, Disease, Behavioral Neuroscience, Environmental risk, medicine, Humans, Multimorbidity, Attention deficit hyperactivity disorder, Obesity, Somatic disorders, Disease burden, Migraine, Epilepsy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Brain, medicine.disease, Non-mental disease, Asthma, Neuropsychology and Physiological Psychology, Increased risk, Attention-deficit/hyperactivity disorder, Attention Deficit Disorder with Hyperactivity, Elimination disorders, Narrative review, business, Clinical psychology
Abstract: Contains fulltext : 248384.pdf (Publisher’s version ) (Open Access) Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.
Published: 2022
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3. Alcohol use disorders and ADHD

Author: Stephen V. Faraone, Andreas Reif, Josep Antoni Ramos Quiroga, Yanli Zhang-James, and Mathias Luderer
Subjects: Adult, Conduct Disorder, medicine.medical_specialty, Substance-Related Disorders, Cognitive Neuroscience, Binge drinking, Impulsivity, behavioral disciplines and activities, Behavioral Neuroscience, Reward system, Pharmacotherapy, mental disorders, medicine, Humans, Psychiatry, Medical treatment, business.industry, medicine.disease, Alcoholism, Neuropsychology and Physiological Psychology, Attention Deficit Disorder with Hyperactivity, Conduct disorder, Oppositional defiant, Impulsive Behavior, medicine.symptom, Substance use, business
Abstract: Despite a growing literature on the complex bidirectional relationship of ADHD and substance use, reviews specifically focusing on alcohol are scarce. ADHD and AUD show a significant genetic overlap, including genes involved in gluatamatergic and catecholaminergic neurotransmission. ADHD drives risky behavior and negative experiences throughout the lifespan that subsequently enhance a genetically increased risk for Alcohol Use Disorders (AUD). Impulsive decisions and a maladaptive reward system make individuals with ADHD vulnerable for alcohol use and up to 43 % develop an AUD; in adults with AUD, ADHD occurs in about 20 %, but is vastly under-recognized and under-treated. Thus, routine screening and treatment procedures need to be implemented in AUD treatment. Long-acting stimulants or non-stimulants can be used to treat ADHD in individuals with AUD. However, it is crucial to combine medical treatment for ADHD with pharmacotherapy and psychotherapy for AUD, and other comorbid disorders. Identification of individuals at risk for AUD, especially those with ADHD and conduct disorder or oppositional defiant disorder, is a key factor to prevent negative outcomes.
Published: 2021
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4. DSM-5 and ICD-11 criteria for bipolar disorder

Author: Chantal Henry, Andreas Reif, René Ernst Nielsen, Ana González-Pinto, Rasmus Wentzer Licht, Eva Z. Reininghaus, Aysegul Yildiz, Trine Vik Lagerberg, Ralph Kupka, Mikael Landén, Guy M. Goodwin, Andreas Bechdolf, Michael Bauer, Jan Scott, Mónica Martínez-Cengotitabengoa, Andrea Fagiolini, Ole A. Andreassen, Veerle Bergink, Philipp Ritter, Lars Vedel Kessing, Marcella Rietschel, Gunnar Morken, Emanuel Severus, John R. Geddes, Eduard Vieta, Bruno Etain, Thomas G. Schulze, Tomas Hajek, and Mirko Manchia
Subjects: medicine.medical_specialty, Delayed Diagnosis, Validity of diagnosis, Bipolar disorder, Prevalence, DSM-5, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, SDG 3 - Good Health and Well-being, International Classification of Diseases, ICD-11, Intervention (counseling), mental disorders, Medicine, Humans, Pharmacology (medical), Family history, Psychiatry, Biological Psychiatry, Pharmacology, Diagnostic delay, Delayed early intervention, business.industry, medicine.disease, 030227 psychiatry, Diagnostic and Statistical Manual of Mental Disorders, Psychiatry and Mental health, Neurology, Diagnostic validity, Narrative review, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: This narrative review summarizes and discusses the implications of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and the upcoming International Classification of Diseases (ICD)-11 classification systems on the prevalence of bipolar disorder and on the validity of the DSM-5 diagnosis of bipolar disorder according to the Robin and Guze criteria of diagnostic validity. Here we review and discuss current data on the prevalence of bipolar disorder diagnosed according to DSM-5 versus DSM-IV, and data on characteristics of bipolar disorder in the two diagnostic systems in relation to extended Robin and Guze criteria: 1) clinical presentation, 2) associations with para-clinical data such as brain imaging and blood-based biomarkers, 3) delimitation from other disorders, 4) associations with family history / genetics, 5) prognosis and long-term follow-up, and 6) treatment effects. The review highlights that few studies have investigated consequences for the prevalence of the diagnosis of bipolar disorder and for the validity of the diagnosis. Findings from these studies suggest a substantial decrease in the point prevalence of a diagnosis of bipolar with DSM-5 compared with DSM-IV, ranging from 30-50%, but a smaller decrease in the prevalence during lifetime, corresponding to a 6% reduction. It is concluded that it is likely that the use of DSM-5 and ICD-11 will result in diagnostic delay and delayed early intervention in bipolar disorder. Finally, we recommend areas for future research. (c) 2021 Elsevier B.V. and ECNP. All rights reserved.
Published: 2021
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5. Parental ADHD in pregnancy and the postpartum period – A systematic review

Author: Rhiannon V. McNeill, Andreas Reif, Sarah Kittel-Schneider, Boris B. Quednow, Anna Linda Leutritz, University of Zurich, and Kittel-Schneider, Sarah
Subjects: 2805 Cognitive Neuroscience, Adult, Parents, medicine.medical_specialty, Cognitive Neuroscience, medicine.medical_treatment, Breastfeeding, 610 Medicine & health, behavioral disciplines and activities, 3206 Neuropsychology and Physiological Psychology, Behavioral Neuroscience, Pregnancy, 2802 Behavioral Neuroscience, mental disorders, medicine, Humans, Parent-Child Relations, Child, Psychiatry, Methylphenidate, business.industry, Postpartum Period, Atomoxetine, medicine.disease, Child development, Stimulant, Neuropsychology and Physiological Psychology, Lisdexamfetamine, Attention Deficit Disorder with Hyperactivity, 10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics, Central Nervous System Stimulants, Female, business, Postpartum period, medicine.drug
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders worldwide, and in the majority of patients persists into adulthood. However, it remains unclear how maternal ADHD could affect pregnancy and birth as well as early mother-(father)-child interaction. There are several studies investigating the effect of depressed or anxious parents on parent-child-interactions in early infancy, but data about the influence of parental ADHD is lacking although it is a common mental disorder in parents. Additionally, the prescription of stimulant and other ADHD medication for adult ADHD patients is rising due to improved diagnostic procedures and a greater awareness of this disorder in adulthood among psychiatrists and psychologists. However, this leads to increased numbers of treated ADHD women that wish to have children or experience unplanned pregnancies while taking stimulant medication. In our systematic review we aimed at analysing the current evidence for the association of maternal ADHD with pregnancy and birth outcomes, pregnancy risks and health behaviour in pregnancy, as well as the association of parental ADHD with early parent-child interaction and early child development in the first 3 years. Furthermore, we reviewed recent evidence on the risks of stimulant and non-stimulant treatment for ADHD in pregnancy and lactation.
Published: 2021
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6. Transdiagnostic neuroimaging of reward system phenotypes in ADHD and comorbid disorders

Author: Marieke Klein, Martine Hoogman, Michael M. Plichta, Oliver Grimm, Jan K. Buitelaar, Daan van Rooij, Barbara Franke, and Andreas Reif
Subjects: Adult, Cognitive Neuroscience, Neuroimaging, Clinical biomarker, 03 medical and health sciences, Behavioral Neuroscience, Reward system, 0302 clinical medicine, Reward, Longitudinal prediction, 130 000 Cognitive Neurology & Memory, mental disorders, medicine, Humans, 0501 psychology and cognitive sciences, 050102 behavioral science & comparative psychology, Depression (differential diagnoses), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.diagnostic_test, 05 social sciences, medicine.disease, Magnetic Resonance Imaging, Comorbidity, Substance abuse, Phenotype, Neuropsychology and Physiological Psychology, Attention Deficit Disorder with Hyperactivity, Psychology, Functional magnetic resonance imaging, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Contains fulltext : 237708pub.pdf (Publisher’s version ) (Open Access) Contains fulltext : 237708.pdf (Author’s version postprint ) (Open Access) ADHD is a disorder characterized by changes in the reward system and which is highly comorbid with other mental disorders, suggesting common neurobiological pathways. Transdiagnostic neuroimaging findings could help to understand whether a dysregulated reward pathway might be the actual link between ADHD and its comorbidities. We here synthesize ADHD neuroimaging findings on the reward system with findings in obesity, depression, and substance use disorder including their comorbid appearance regarding neuroanatomical features (structural MRI) and activation patterns (resting-state and functional MRI). We focus on findings from monetary-incentive-delay (MID) and delay-discounting (DD) tasks and then review data on striatal connectivity and volumetry. Next, for better understanding of comorbidity in adult ADHD, we discuss these neuroimaging features in ADHD, obesity, depression and substance use disorder and ask whether ADHD heterogeneity and comorbidity are reflected by a common dysregulation in the reward system. Finally, we highlight conceptual issues related to heterogeneous paradigms, different phenotyping, longitudinal prediction and highlight some promising future directions for using striatal reward functioning as a clinical biomarker.
Published: 2021

7. Adulte Aufmerksamkeitsdefizit‑/Hyperaktivitätsstörung und Komorbidität: neue Befunde zu epidemiologischen und genetischen Faktoren

Author: Andreas Reif and Sarah Kittel-Schneider
Subjects: Gynecology, medicine.medical_specialty, business.industry, General Medicine, medicine.disease, Comorbidity, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Neurology, medicine, Attention deficit hyperactivity disorder, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Alle grosen, bevolkerungsbasierten administrativen Studien sprechen aktuell fur eine signifikante Komorbiditat von adulter Aufmerksamkeitsdefizit‑/Hyperaktivitatsstorung (ADHS) mit Sucht‑, Angst- und vor allem Stimmungserkrankungen. Mit zunehmendem Alter steigt in diesen Untersuchungen das Risiko fur eine dieser komorbiden Storungen an. Die neuesten genomweiten Assoziations- und Korrelationsstudien geben zudem Hinweise fur gemeinsame genetische Risikofaktoren der ADHS mit insbesondere unipolarer Depression, bipolarer Storung, Autismusspektrumstorungen, Tourette-Syndrom und zu einem geringeren Mase mit Schizophrenie. Die einzige negative genetische Korrelation zeigte sich mit Anorexia nervosa. Auch Kokain- und Cannabiskonsum sind signifikant positiv genetisch mit ADHS korreliert. Zudem konnten bei einigen spezifischen somatischen Erkrankungen ein erhohtes Auftreten bei Patienten mit adulter ADHS gefunden werden. Besonders signifikant waren diese positiven Assoziationen bei Ubergewicht, Migrane, Schlafstorungen, Asthma und Zoliakie. Keine Assoziation wurde fur ADHS und Erkrankungen des Herz-Kreislauf-Systems gefunden. Auch hier gibt es erste Hinweise auf gemeinsame Risikogene, die Datenlage ist aber noch nicht ausreichend, um abschliesende Feststellungen zu machen. Zum Teil handelt es sich bei den assoziierten somatischen Erkrankungen wohl auch um Differenzialdiagnosen, wenn sich die ADHS-Symptomatik nach adaquater Behandlung wie z. B. bei einer obstruktiven Schlafapnoe verbessert. Umso wichtiger ist es aber, diese psychischen und somatischen Differenzialdiagnosen und Komorbiditaten bei der Diagnostik und Behandlung adulter ADHS-Patienten im Blick zu haben, um deren generelle Gesundheit und Lebensqualitat zu verbessern.
Published: 2020
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8. Neuronal response to high negative affective stimuli in major depressive disorder: An fMRI study

Author: Christian Knöchel, Michael Stäblein, A. Ciaramidaro, Marleen Hagen, David Prvulovic, A.-C. Huthmacher, J. Dvořák, Viola Oertel, Marco Trettin, Dominik Kraft, Andreas Reif, Sofia Wenzler, Naddy Ghirmai, Marietheres Hilke, Ceylan Balaban, and Silke Matura
Subjects: medicine.medical_specialty, Emotions, Prefrontal Cortex, Audiology, behavioral disciplines and activities, Arousal, Premotor cortex, IAPS, Dorsolateral Prefrontal Cortex, medicine, Humans, Affective processing, Valence (psychology), International Affective Picture System, Brain Mapping, Depressive Disorder, Major, medicine.diagnostic_test, Depression, fMRI, Brain, Magnetic resonance imaging, Neurophysiology, medicine.disease, Magnetic Resonance Imaging, Dorsolateral prefrontal cortex, Psychiatry and Mental health, Clinical Psychology, medicine.anatomical_structure, Major depressive disorder, Psychology
Abstract: Disturbed emotion processing underlies depression. We examined the neuronal underpinnings of emotional processing in patients (PAT) with major depressive disorder (MDD) compared to healthy volunteers (HV) using functional magnetic resonance (fMRI) scan.Thirty-six MDD patients and 30 HV underwent T2-weighted fMRI assessments during the presentation of an implicit affective processing task in three conditions. They differed regarding their affective quality (=valence, high negative, low negative and neutral stimuli) and regarding the arousal based on stimuli from the International Affective Picture System.Group contrasts showed lower left-sided activation in dorsolateral prefrontal cortex (DLPFC), anterior PFC, precentral and premotor cortex in PAT compared with HV (Cluster-level threshold, 5000 iterations, p0.01). We found a significant interaction effect of valence and group, a significant effect of emotional valence and a significant effect of group. All effects were shown in brain regions within the emotional network (Cluster-level threshold, 5000 iterations, p0.01). Higher arousal (rho=-0.33, p0.01) and higher valence (rho=-0.33, p0.01) during high negative stimuli presentation as well as more severe depression (Beck Depression Inventory II [BDI II]; r = 0.39, p = 0.01) were significantly negatively associated with left DLFPC activity in patients.Potential influence of psychopharmacological drugs on functional activation is one of the most discussed source of bias in studies with medicated psychiatric patients.The results highlight the importance of left DLPFC during the processing of negative emotional stimuli in MDD. The integration of a neurophysiological model of emotional processing in MDD may help to clarify and improve therapeutic options.
Published: 2022

9. Outcomes associated with different vaccines in individuals with bipolar disorder and impact on the current COVID-19 pandemic- a systematic review

Author: Isabel Hodl, Ana González-Pinto, Rasmus Wentzer Licht, Nina Bonkat, Bruno Etain, Frederike T. Fellendorf, Jan Scott, Lars Vedel Kessing, Veerle Bergink, Marcella Rietschel, Trine Vik Lagerberg, Chantal Henry, Tomas Hajek, Mirko Manchia, Aysegul Yildiz, Ralph Kupka, Mikael Landén, Phillip Ritter, Nina Dalkner, Guy M. Goodwin, Eva Z. Reininghaus, Alessio Squassina, René Ernst Nieslen, Gunnar Morken, Andreas Reif, Eduard Vieta, Christoph U. Correll, Andreas Bechdolf, Michael Bauer, Mónica Martínez-Cengotitabengoa, Ole A. Andreassen, Andrea Fagiolini, Thomas G. Schulze, Etain, Bruno, Medical University Graz, University of Cagliari, Dalhousie University [Halifax], University of Barcelona, Frankfurt University Hospital, National Institute of Mental Health [Klecany, Czech Republic] (NIMH), University of Gothenburg (GU), Karolinska Institutet [Stockholm], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University [Hempstead], Newcastle University [Newcastle], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département Médico-Universitaire Neurosciences [Sorbonne Université] (DMU Neurosciences), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Heidelberg University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), University of East Anglia [Norwich] (UEA), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Siena = University of Siena (UNISI), Technische Universität Dresden = Dresden University of Technology (TU Dresden), University of Oxford, Bioaraba Health Research Institute, Vrije Universiteit Amsterdam [Amsterdam] (VU), Ludwig-Maximilians University [Munich] (LMU), Oslo University Hospital [Oslo], Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), GHU Paris Psychiatrie et Neurosciences, Norwegian University of Science and Technology (NTNU), Aalborg University [Denmark] (AAU), and University of Oslo (UiO)
Subjects: MESH: Pandemics, medicine.medical_specialty, Pediatrics, Bipolar disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Prevalence, Disease, infectious diseases, Communicable Diseases, Article, MESH: Communicable Disease Control, systematic review, MESH: Bipolar Disorder, Intervention (counseling), Pandemic, MESH: COVID-19, Medicine, Humans, MESH: SARS-CoV-2, Pharmacology (medical), Pandemics, Biological Psychiatry, bipolar disorder, Pharmacology, Vaccines, MESH: Humans, business.industry, SARS-CoV-2, Public health, Vaccination, COVID-19, vaccination, Mental illness, medicine.disease, MESH: Vaccines, Psychiatry and Mental health, Neurology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Communicable Disease Control, MESH: Communicable Diseases, Systematic review, Infectious diseases, Neurology (clinical), business
Abstract: Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
Published: 2022
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10. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022
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11. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Andreas J. Forstner, Martin Alda, Manolis Kogevinas, Pak C. Sham, Patrick F. Sullivan, Michele T. Pato, John R. Kelsoe, Paul A. Tooney, Steven P. Hamilton, Dorret I. Boomsma, Gerome Breen, Tracy Air, Hannelore Ehrenreich, Nakao Iwata, Jill M. Goldstein, Olav B. Smeland, Daniel R. Weinberger, Andrew McQuillin, Stuart A. Tobet, Elvira Bramon, Gabriëlla A.M. Blokland, Jing Qin Wu, Erik G. Jönsson, Peter R. Schofield, Fabian Streit, Nicholas Bass, Aarno Palotie, Brian Kelly, Cathryn M. Lewis, Srdjan Djurovic, Thomas Damm Als, Chia-Yen Chen, Bettina Konte, Joanna Hauser, Claire O'Donovan, Laura J. Scott, Hans J. Grabe, Murray J. Cairns, Rudolf Uher, Pablo Cervantes, Nicholas G. Martin, James A. Knowles, Aiden Corvin, Espen Molden, Lili Milani, Andreas Reif, Maria Grigoroiu-Serbanescu, George Kirov, Yuri Milaneschi, David St Clair, Eco J. C. de Geus, Robert Handa, Tõnu Esko, Alexander Teumer, Anders D. Børglum, Divya Mehta, Roel A. Ophoff, Susanne Lucae, Henning Tiemeier, Marion Leboyer, Ina Giegling, Alan R. Sanders, Jouke-Jan Hottenga, Pablo V. Gejman, Bernhard T. Baune, Brenda W.J.H. Penninx, Chris Cotsapas, Martin Preisig, Thomas Werge, Jakob Grove, Ingrid Melle, Jordan W. Smoller, Marcella Rietschel, Myrna M. Weissman, Preben Bo Mortensen, Philip B. Mitchell, Jolanta Lissowska, Andrew M. McIntosh, Annette M. Hartmann, Ole A. Andreassen, Lea Sirignano, John B. Vincent, Niamh Mullins, Jimmy Lee, Gonneke Willemsen, Marian L. Hamshere, Rolf Adolfsson, Mark A. Frye, Markus M. Nöthen, Jianxin Shi, Ashley L. Comes, Robin M. Murray, Patrik K. E. Magnusson, Frank Bellivier, Stéphane Jamain, Ole Mors, Sven Cichon, Uwe Völker, Fermín Mayoral, Bryan J. Mowry, Bruno Etain, James B. Potash, Beata Świątkowska, Bertram Müller-Myhsok, Mikael Landén, Tracey L. Petryshen, Franziska Degenhardt, Mark Adams, Dan Rujescu, Jose Guzman-Parra, Thomas G. Schulze, Merete Nordentoft, Joseph D. Buxbaum, Janice M. Fullerton, Brien P. Riley, Roy H. Perlis, Arne E. Vaaler, David M. Hougaard, Eli A. Stahl, Susan L. McElroy, Sabrina K. Schaupp, Martin Begemann, Sandra Van der Auwera, Todd Lencz, Joanna M. Biernacka, Agnes A. Steixner-Kumar, Douglas F. Levinson, Sathish Periyasamy, Alexander Viktorin, and Anil K. Malhotra
Subjects: Genetics, 0303 health sciences, Medizin, Locus (genetics), Genomics, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Mood, medicine, Major depressive disorder, Bipolar disorder, Gene, NKAIN2 Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.METHODSWe conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p−6) for cross-disorder GxS interaction (rs7302529,p=1.6×10−7; rs73033497,p=8.8×10−7; rs7914279,p=6.4×10−7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene locus (rs11665282;p=1.5×10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509;p=1.1×10−7) in a locus containingIDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDRCONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Published: 2022

12. Intrinsic functional connectivity, CSF biomarker profiles and their relation to cognitive function in mild cognitive impairment

Author: David Prvulovic, Johannes Pantel, Monika Scheibe, Tarik Karakaya, Jun-Suk Kang, Fabian Fusser, Silke Matura, Andreas Reif, Jan Köhler, Daniel Hartmann, Felix Ehret, and Christoph Mayer
Subjects: Male, tau Proteins, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Predictive Value of Tests, Reference Values, Risk Factors, medicine, Humans, Dementia, Cognitive Dysfunction, 0501 psychology and cognitive sciences, Cognitive decline, Correlation of Data, Biological Psychiatry, Default mode network, CSF albumin, Aged, Amyloid beta-Peptides, medicine.diagnostic_test, Resting state fMRI, business.industry, 05 social sciences, Brain, Cognition, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Peptide Fragments, Psychiatry and Mental health, Disease Progression, Biomarker (medicine), Female, Nerve Net, Functional magnetic resonance imaging, business, Neuroscience, Biomarkers, 030217 neurology & neurosurgery
Abstract: Mild cognitive impairment (MCI) often precedes Alzheimer’s Dementia (AD), and in a high proportion of individuals affected by MCI, there are already neuropathological processes ongoing that become more evident when patients progress to AD. Accordingly, there is a need for reliable biomarkers to distinguish between normal aging and incipient AD. Recent research suggests that, in addition to established biomarkers such as CSF Aß42, total tau and hyperphosphorylated tau, resting state connectivity established by functional magnetic resonance imaging might also be a feasible biomarker for prodromal stages of AD. In order to explore this possibility, we investigated resting state functional connectivity as well as cerebrospinal fluid (CSF) biomarker profiles in patients with MCI (n = 30; age 66.43 ± 7.06 years) and cognitively healthy controls (n = 38; age 66.89 ± 7.12 years). CSF Aß42, total tau and hyperphosphorylated tau concentrations were correlated with measures of cognitive performance (immediate and delayed recall, global cognition, processing speed). Moreover, MCI-related alterations in intrinsic functional connectivity within the default mode network were investigated using functional resting state MRI. As expected, MCI patients showed decreased CSF Aß42 and increased total tau concentrations. These alterations were associated with cognitive performance. However, there were no differences between MCI patients and cognitively healthy controls regarding intrinsic functional connectivity. In conclusion, our results indicate that CSF protein profiles seem to be more closely related to cognitive decline than alterations in resting state activity. Thus, resting state connectivity might not be a reliable biomarker for early stages of AD.
Published: 2019
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13. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author: Michael McCarthy, Claire O'Donovan, Urs Heilbronner, Ichiro Kusumi, Eduard Vieta, Liping Hou, Hsi-Chung Chen, Claire Slaney, Maria Grigoroiu-Serbanescu, Kazufumi Akiyama, Michael Bauer, Janusz K. Rybakowski, Frank Bellivier, Marion Leboyer, Katzutaka Shimoda, Palmiero Monteleone, Cristiana Cruceanu, Alessio Squassina, Stephanie H. Witt, Tadafumi Kato, Giovanni Severino, Alfonso Tortorella, J. Raymond DePaulo, Martin Alda, Louise Frisén, Mazda Adl, Martin Schalling, Per Hoffmann, Susan G. Leckband, Jean-Pierre Kahn, Jean-Michel Aubry, Francis J. McMahon, Sven Cichon, Alexandre Dayer, Tatyana Shekhtman, Franziska Degenhardt, James B. Potash, Bruno Etain, Joseph Frank, Antonio Benabarre, Bernhard T. Baune, Gloria Roberts, Ryota Hashimoto, Tomas Novak, Paul D. Shilling, Julia Veeh, Joanna M. Biernacka, Barbara König, Peter Falkai, Philip B. Mitchell, Urban Ösby, Esther Jiménez, Sébastien Gard, Mark A. Frye, Sarah Kittel-Schneider, Layla Kassem, Fasil Tekola-Ayele, Armin Birner, Cynthia Marie-Claire, Raffaella Ardau, Abesh Kumar Bhattacharjee, Stéphane Jamain, Julie Garnham, Guy A. Rouleau, Caterina Chillotti, Piotr M. Czerski, Thomas G. Schulze, Gustavo Turecki, Anbupalam Thalamuthu, Claudia Pisanu, Azmeraw T. Amare, Marina Mitjans, Sergi Papiol, Mario Maj, Bárbara Arias, Janice M. Fullerton, Nina Dalkner, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Francis M. Mondimore, Eva Z. Reininghaus, Fernando S. Goes, Lena Backlund, Francesc Colom, Catharina Lavebratt, Christian Simhandl, Marcella Rietschel, Micah Cearns, Mikael Landén, Norio Ozaki, Gonzalo Laje, Barbara W. Schweizer, Nirmala Akula, Andrea Pfennig, Yi-Hsiang Hsu, John R. Kelsoe, Lina Martinsson, Markus M. Nöthen, Caroline M. Nievergelt, Pavla Stopkova, Mirko Manchia, Susan L. McElroy, Peter P. Zandi, Scott R. Clark, Joanna Hauser, Andreas J. Forstner, Po-Hsiu Kuo, Andreas Reif, Maria Del Zompo, Paul Grof, Fabian Streit, Ewa Ferensztajn-Rochowiak, Pablo Cervantes, Thomas Stamm, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Schubert, K. O., Thalamuthu, A., Amare, A. T., Frank, J., Streit, F., Adl, M., Akula, N., Akiyama, K., Ardau, R., Arias, B., Aubry, J. -M., Backlund, L., Bhattacharjee, A. K., Bellivier, F., Benabarre, A., Bengesser, S., Biernacka, J. M., Birner, A., Marie-Claire, C., Cearns, M., Cervantes, P., Chen, H. -C., Chillotti, C., Cichon, S., Clark, S. R., Cruceanu, C., Czerski, P. M., Dalkner, N., Dayer, A., Degenhardt, F., Del Zompo, M., Depaulo, J. R., Etain, B., Falkai, P., Forstner, A. J., Frisen, L., Frye, M. A., Fullerton, J. M., Gard, S., Garnham, J. S., Goes, F. S., Grigoroiu-Serbanescu, M., Grof, P., Hashimoto, R., Hauser, J., Heilbronner, U., Herms, S., Hoffmann, P., Hou, L., Hsu, Y. -H., Jamain, S., Jimenez, E., Kahn, J. -P., Kassem, L., Kuo, P. -H., Kato, T., Kelsoe, J., Kittel-Schneider, S., Ferensztajn-Rochowiak, E., Konig, B., Kusumi, I., Laje, G., Landen, M., Lavebratt, C., Leboyer, M., Leckband, S. G., Maj, M., Manchia, M., Martinsson, L., Mccarthy, M. J., Mcelroy, S., Colom, F., Mitjans, M., Mondimore, F. M., Monteleone, P., Nievergelt, C. M., Nothen, M. M., Novak, T., O'Donovan, C., Ozaki, N., Osby, U., Papiol, S., Pfennig, A., Pisanu, C., Potash, J. B., Reif, A., Reininghaus, E., Rouleau, G. A., Rybakowski, J. K., Schalling, M., Schofield, P. R., Schweizer, B. W., Severino, G., Shekhtman, T., Shilling, P. D., Shimoda, K., Simhandl, C., Slaney, C. M., Squassina, A., Stamm, T., Stopkova, P., Tekola-Ayele, F., Tortorella, A., Turecki, G., Veeh, J., Vieta, E., Witt, S. H., Roberts, G., Zandi, P. P., Alda, M., Bauer, M., Mcmahon, F. J., Mitchell, P. B., Schulze, T. G., Rietschel, M., and Baune, B. T.
Subjects: Oncology, Multifactorial Inheritance, Treatment response, medicine.medical_specialty, Lithium (medication), Bipolar disorder, Poor responder, Neurosciences. Biological psychiatry. Neuropsychiatry, Lithium, DISEASE, Article, Cellular and Molecular Neuroscience, Risk Factors, Internal medicine, medicine, Humans, Manic-depressive illness, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Depressió psíquica, METAANALYSIS, Biological Psychiatry, Depression (differential diagnoses), MANIA, Depressive Disorder, Depressive Disorder, Major, Trastorn bipolar, Depression, business.industry, Major, medicine.disease, Pathway analysis, Liti, COMPARATIVE EFFICACY, Psychiatry and Mental health, Mental depression, Schizophrenia, Polygenic risk score, Esquizofrènia, Pharmacogenomics, business, RC321-571, medicine.drug
Abstract: Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
Published: 2021
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14. The German research consortium for the study of bipolar disorder (BipoLife): a magnetic resonance imaging study protocol

Author: Irina Falkenberg, Verena Schuster, Felix Bermpohl, Martin Hautzinger, Andreas Jansen, Dominik Grotegerd, Silke Matura, Jens Sommer, Christoph Vogelbacher, Andreas Reif, Karolin E. Einenkel, Christoph Mulert, Philipp Ritter, Georg Juckel, Andrea Pfennig, Catherine Hindi Attar, Udo Dannlowski, Jens Treutlein, Michael Bauer, Tilo Kircher, Vera Flasbeck, Lisa Rauer, Miriam Bopp, and Oliver Gruber
Subjects: Neurophysiology and neuropsychology, medicine.medical_specialty, Study Protocols, Bipolar disorder, BipoLife, Neurosciences. Biological psychiatry. Neuropsychiatry, Disease, MRI quality assurance, Early intervention, Neuroimaging, Early recognition, medicine, Major depression, Medical diagnosis, Intensive care medicine, Suicidal ideation, Biological Psychiatry, Protocol (science), medicine.diagnostic_test, business.industry, QP351-495, fMRI, Quality control, Magnetic resonance imaging, medicine.disease, Multicenter study, Psychiatry and Mental health, medicine.symptom, business, RC321-571
Abstract: Background Bipolar disorder is one of the most severe mental disorders. Its chronic course is associated with high rates of morbidity and mortality, a high risk of suicide and poor social and occupational outcomes. Despite the great advances over the last decades in understanding mental disorders, the mechanisms underlying bipolar disorder at the neural network level still remain elusive. This has severe consequences for clinical practice, for instance by inadequate diagnoses or delayed treatments. The German research consortium BipoLife aims to shed light on the mechanisms underlying bipolar disorders. It was established in 2015 and incorporates ten university hospitals across Germany. Its research projects focus in particular on individuals at high risk of bipolar disorder, young patients in the early stages of the disease and patients with an unstable highly relapsing course and/or with acute suicidal ideation. Methods Functional and structural magnetic resonance imaging (MRI) data was acquired across nine sites within three different studies. Obtaining neuroimaging data in a multicenter setting requires among others the harmonization of the acquisition protocol, the standardization of paradigms and the implementation of regular quality control procedures. The present article outlines the MRI imaging protocols, the acquisition parameters, the imaging paradigms, the neuroimaging quality assessment procedures and the number of recruited subjects. Discussion The careful implementation of a MRI study protocol as well as the adherence to well-defined quality assessment procedures is one key benchmark in the evaluation of the overall quality of large-scale multicenter imaging studies. This article contributes to the BipoLife project by outlining the rationale and the design of the MRI study protocol. It helps to set the necessary standards for follow-up analyses and provides the technical details for an in-depth understanding of follow-up publications.
Published: 2021

15. Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets

Author: Dirk J. Heslenfeld, Merel Postema, Paul M. Thompson, Sarah Baumeister, Tiffany M. Chaim-Avancini, Catharina A. Hartman, Sara Lera-Miguel, Patrick de Zeeuw, Sara Ambrosino, Neil A. Harrison, Marcus V. Zanetti, Philip Asherson, Joel T. Nigg, Liesbeth Reneman, David Coghill, Gustavo Sudre, Alysa E. Doyle, Francisco X. Castellanos, Tobias Banaschewski, Oscar Vilarroya, Mario Rodrigues Louzã, Kaylita Chantiluke, Annette Conzelmann, Georg G. von Polier, Lizanne J. S. Schweren, Anastasia Christakou, Klaus-Peter Lesch, Sarah Durston, Simon E. Fisher, Yuliya N. Yoncheva, Jochen Seitz, David C. Glahn, Timothy J. Silk, Norbert Skokauskas, Mark A. Bellgrove, Damien A. Fair, Geraldo F. Busatto, Georg C. Ziegler, Eric Earl, Yannis Paloyelis, Jeffery N. Epstein, Jaap Oosterlaan, Clare Kelly, Paulo Mattos, Gregor Kohls, Jan Haavik, Joseph Biederman, Janita Bralten, Neda Jahanshad, Claiton H.D. Bau, Thomas Ethofer, Paul Pauli, Cibele Edom Bandeira, Andreas Reif, Pieter J. Hoekstra, Theo G.M. van Erp, Susanne Walitza, Marie F. Høvik, Sarah Hohmann, Barbara Franke, Luisa Lázaro, Thomas Frodl, Tinatin Gogberashvili, Jonna Kuntsi, J. Antoni Ramos-Quiroga, Daniel Brandeis, Stephanie E. Novotny, Martine Hoogman, Juan Carlos Soliva Vila, Anouk Schrantee, Rosa Nicolau, Kerstin Konrad, Eileen Oberwelland Weiss, Ruth O'Gorman Tuura, Bernd Kardatzki, Felipe Almeida Picon, Hazel McCarthy, Yolanda Vives-Gilabert, Ana Cubillo, Charles B Malpas, Mara Cercignani, Astri J. Lundervold, Michael C. Stevens, Eugenio H. Grevet, Katya Rubia, Renata B. Cupertino, Philip Shaw, Georgii Karkashadze, Fernanda Tovar-Moll, Bob Oranje, Leyla Namazova-Baranova, A.A. Baranov, Andreas J. Fallgatter, Leanne Tamm, Terry L. Jernigan, Matt C. Gabel, Clyde Francks, Pedro G.P. Rosa, Stephen V. Faraone, Jan K. Buitelaar, Kerstin J. Plessen, Silvia Brem, Sarah E. Medland, Alasdair Vance, Ramona Baur-Streubel, ENIGMA ADHD Working Group, General Paediatrics, ARD - Amsterdam Reproduction and Development, Radiology and Nuclear Medicine, APH - Mental Health, APH - Personalized Medicine, ANS - Brain Imaging, ANS - Compulsivity, Impulsivity & Attention, Institut Català de la Salut, [Postema MC] Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands. [Hoogman M] Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands. [Ambrosino S] NICHE lab, Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands. [Asherson P] Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. [Banaschewski T] Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany. [Bandeira CE] Adulthood ADHD Outpatient Program (ProDAH), Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. [Ramos-Quiroga JA] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Catalonia, Spain. Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Cognitive Psychology, IBBA, Clinical Neuropsychology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Pediatric surgery, and Radiology and nuclear medicine
Subjects: Dominància cerebral, trastornos mentales::trastornos del desarrollo neurológico::trastornos generalizados del desarrollo del niño::trastorno del espectro del autismo [PSIQUIATRÍA Y PSICOLOGÍA], Autism Spectrum Disorder, Caudate nucleus, Attention-deficit, Audiology, sistema nervioso::sistema nervioso central::encéfalo [ANATOMÍA], 0302 clinical medicine, Mental Disorders::Neurodevelopmental Disorders::Attention Deficit and Disruptive Behavior Disorders::Attention Deficit Disorder with Hyperactivity [PSYCHIATRY AND PSYCHOLOGY], 130 000 Cognitive Neurology & Memory, Developmental and Educational Psychology, Brain asymmetry, Child, media_common, large-scale data, brain laterality, 05 social sciences, scale data, Brain, hyperactivity disorder, brain asymmetry, structural MRI, Mental Disorders::Neurodevelopmental Disorders::Child Development Disorders, Pervasive::Autism Spectrum Disorder [PSYCHIATRY AND PSYCHOLOGY], Magnetic Resonance Imaging, Psychiatry and Mental health, Globus pallidus, Attention&#8208, Autism spectrum disorder, Psychology, 050104 developmental & child psychology, Neuroinformatics, Adult, medicine.medical_specialty, Adolescent, media_common.quotation_subject, deficit, Nervous System::Central Nervous System::Brain [ANATOMY], Asymmetry, behavioral disciplines and activities, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Age groups, mental disorders, medicine, Humans, Attention deficit hyperactivity disorder, 0501 psychology and cognitive sciences, ddc:610, large&#8208, Other subheadings::Other subheadings::/diagnostic imaging [Other subheadings], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Otros calificadores::Otros calificadores::/diagnóstico por imagen [Otros calificadores], Cervell - Imatgeria, medicine.disease, Trastorn per dèficit d'atenció amb hiperactivitat, Attention Deficit Disorder with Hyperactivity, Pediatrics, Perinatology and Child Health, Orbitofrontal cortex, Caudate Nucleus, trastornos mentales::trastornos del desarrollo neurológico::trastornos conductuales disruptivos y déficit de atención::trastornos de déficit de atención con hiperactividad [PSIQUIATRÍA Y PSICOLOGÍA], 030217 neurology & neurosurgery
Abstract: Objective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait., Journal of Child Psychology and Psychiatry, 62 (10), ISSN:0021-9630, ISSN:1469-7610
Published: 2021
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16. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author: Arianna DiFlorio, Patrick F. Sullivan, Sebastian Zöllner, Margarita Rivera, Richard M. Myers, Stanley J. Watson, Jun Li, Anders Juréus, Sarah E. Bergen, Gonçalo R. Abecasis, Jordan W. Smoller, Michael Conlon O'Donovan, Neil Risch, Hoang T. Nguyen, Chen Jiang, Xiaoming Jia, Mehdi Pirooznia, Danielle Posthuma, Adam E. Locke, Peter P. Zandi, John B. Vincent, Niamh Mullins, Duncan Palmer, Shaun Purcell, Gerome Breen, Christina M. Hultman, Andreas Reif, Khanh K. Thai, Virginia L. Willour, Pui-Yan Kwok, Laura J. Scott, Anne U. Jackson, Michael John Owen, Fernando S. Goes, Steven A. McCarroll, James B. Potash, Mikael Landén, Jennifer L. Moran, Michele T. Pato, Hyun Min Kang, Marco P. Boks, Sinéad B. Chapman, W. Richard McCombie, Janet L. Sobell, Matthew Zawistowski, Rolf Adolfsson, Yongwen Zhuang, Michael Boehnke, René S. Kahn, Huda Akil, James T.R. Walters, Margit Burmeister, Douglas Blackwood, Cathryn M. Lewis, Eli A. Stahl, Mark N. Kvale, Melissa DelaBastide, Catherine Schaefer, Benjamin M. Neale, Giulio Genovese, Carlos N. Pato, Nicholas John Craddock, Andrew McQuillin, Shawn Levy, Aiden Corvin, Pamela Sklar, Weiqing Wang, Andrew M. McIntosh, Ling Shen, Eric T. Monson, Derek W. Morris, Douglas M. Ruderfer, Roel A. Ophoff, Peter McGuffin, Sarah Cohen-Woods, Willem H. Ouwehand, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Goes, Fernando S [0000-0001-6262-8264], Locke, Adam E [0000-0001-6227-198X], Palmer, Duncan [0000-0002-0824-0047], Wang, Weiqing [0000-0003-1565-0148], Genovese, Giulio [0000-0003-3066-5575], Jackson, Anne U [0000-0002-9672-2547], Nguyen, Hoang [0000-0001-6910-7269], Pirooznia, Mehdi [0000-0002-4210-6458], Zawistowski, Matthew [0000-0002-3005-083X], Abecasis, Gonçalo [0000-0003-1509-1825], Bergen, Sarah [0000-0002-5888-0034], Burmeister, Margit [0000-0002-1914-2434], Kwok, Pui-Yan [0000-0002-5087-3059], Li, Jun Z [0000-0001-6727-0812], Levy, Shawn E [0000-0002-1369-5740], Watson, Stanley [0000-0003-4980-5523], Blackwood, Douglas [0000-0002-4076-9346], Boehnke, Michael [0000-0002-6442-7754], Breen, Gerome [0000-0003-2053-1792], Landen, Mikael [0000-0002-4496-6451], Lewis, Cathryn [0000-0002-8249-8476], McCarroll, Steven A [0000-0002-6954-8184], McIntosh, Andrew [0000-0002-0198-4588], McQuillin, Andrew [0000-0003-1567-2240], Morris, Derek [0000-0002-3413-570X], O'Donovan, Michael [0000-0001-7073-2379], Boks, Marco [0000-0001-6163-7484], Kahn, Rene [0000-0001-5909-8004], Ouwehand, Willem [0000-0002-7744-1790], Owen, Michael [0000-0003-4798-0862], Potash, James B [0000-0002-5802-8079], Reif, Andreas [0000-0002-0992-634X], Vincent, John [0000-0003-0692-2519], Neale, Benjamin [0000-0003-1513-6077], Purcell, Shaun [0000-0002-7402-5812], Schaefer, Catherine [0000-0003-2644-055X], Stahl, Eli A [0000-0002-1192-0561], Zandi, Peter P [0000-0001-8423-2623], Scott, Laura J [0000-0002-4886-5084], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health
Subjects: Bipolar Disorder, Genome-wide association study, Biology, Medical and Health Sciences, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Clinical Research, Genetic variation, medicine, Genetics, 2.1 Biological and endogenous factors, Humans, Exome, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Molecular Biology, Gene, 030304 developmental biology, Medicinsk genetik, Psychiatry, 0303 health sciences, Prevention, Human Genome, Psychology and Cognitive Sciences, Genetic Variation, Single Nucleotide, Heritability, Biological Sciences, medicine.disease, Serious Mental Illness, Phenotype, 3. Good health, Brain Disorders, Psychiatry and Mental health, Mental Health, Schizophrenia, Medical Genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., International Bipolar Sequencing Consortium (NIMH) R01 MH 110437, Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) UO1 MH105653, Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) R01 MH 094145, Multi-ethnic GWAS of Bipolar I Disorder (NIH) R01 MH 085543, Genetic Epidemiology Research in Adult Health and Aging (GERA) RC2 AG036607, Kaiser Permanente Research Program on Genes, Environment, and Health, Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) R01 MH 087979 MH 087992, 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH095034, 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106531, 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH077139, 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106527, Dalio Foundation
Published: 2021
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17. Evidence from imaging resilience genetics for a protective mechanism against schizophrenia in the ventral visual pathway

Author: Eva Raspor, Andreas Reif, David Edmund Johannes Linden, Peter K. Hahn, Meike D. Hettwer, Thomas M. Lancaster, Wolf Singer, Nina Roth Mota, and Robert A. Bittner
Subjects: Mechanism (biology), media_common.quotation_subject, Cognition, Affect (psychology), medicine.disease, Schizophrenia, Perception, Neuroplasticity, medicine, Psychology, Resilience (network), Neuroscience, Psychosocial, media_common
Abstract: IntroductionIlluminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits.MethodUsing structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33,224 healthy subjects (UK Biobank).FindingWe observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r=0.35; p=.0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG.ConclusionOur findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and non-social visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept and schizophrenia resilience models.
Published: 2021
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18. Physical activity, physical self-perception and depression symptoms in patients with major depressive disorder: a mediation analysis

Author: Andreas Reif, Viola Oertel, Miriam Bieber, Tobias Engeroff, Semra Etyemez, David Prvulovic, Esra Görgülü, and Kirsten Zabel
Subjects: medicine.medical_specialty, Heart disease, media_common.quotation_subject, Physical fitness, education, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, ddc:150, Diabetes mellitus, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, ddc:610, Exercise, Biological Psychiatry, Depression (differential diagnoses), media_common, Depressive Disorder, Major, Mediation Analysis, business.industry, Self-esteem, General Medicine, medicine.disease, Obesity, Self Concept, Psychiatry and Mental health, Cross-Sectional Studies, Physical therapy, Major depressive disorder, business, human activities, 030217 neurology & neurosurgery, Psychopathology
Abstract: Physical inactivity is discussed as one of the most detrimental influences for lifestyle-related medical complications such as obesity, heart disease, hypertension, diabetes and premature mortality in in- and outpatients with major depressive disorder (MDD). In contrast, intervention studies indicate that moderate-to-vigorous-intensity physical activity (MVPA) might reduce complications and depression symptoms itself. Self-reported data on depression [Beck-Depression-Inventory-II (BDI-II)], general habitual well-being (FAHW), self-esteem and physical self-perception (FAHW, MSWS) were administrated in a cross-sectional study with 76 in- and outpatients with MDD. MVPA was documented using ActiGraph wGT3X + ® accelerometers and fitness was measured using cardiopulmonary exercise testing (CPET). Subgroups were built according to activity level (low PA defined as MVPA 45 min/day). Statistical analysis was performed using a Mann–Whitney U and Kruskal–Wallis test, Spearman correlation and mediation analysis. BDI-II scores and MVPA values of in- and outpatients were comparable, but fitness differed between the two groups. Analysis of the outpatient group showed a negative correlation between BDI-II and MVPA. No association of inpatient MVPA and psychopathology was found. General habitual well-being and self-esteem mediated the relationship between outpatient MVPA and BDI-II. The level of depression determined by the BDI-II score was significantly higher in the outpatient low- and moderate PA subgroups compared to outpatients with high PA. Fitness showed no association to depression symptoms or well-being. To ameliorate depressive symptoms of MDD outpatients, intervention strategies should promote habitual MVPA and exercise exceeding the duration recommended for general health (≥ 30 min/day). Further studies need to investigate sufficient MVPA strategies to impact MDD symptoms in inpatient settings. Exercise effects seem to be driven by changes of well-being rather than increased physical fitness.
Published: 2021

19. The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network

Author: Susanne Knorr, Philip Tovote, Uri E. Ramirez Pasos, Chi Wang Ip, Kathrin Grundmann-Hauser, Jens Volkmann, Andreas Reif, Thomas Ott, Robert L. Peach, Lisa Rauschenberger, Maximilian Friedrich, and Aet O'Leary
Subjects: 0301 basic medicine, Male, Deep brain stimulation, medicine.medical_treatment, Dopamine, DYT1, LFP, Neurosciences. Biological psychiatry. Neuropsychiatry, Biology, TOR1A, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Dystonia, Dopaminergic Neurons, Dopaminergic, Nerve injury, medicine.disease, Rats, 030104 developmental biology, medicine.anatomical_structure, Neurology, Hindlimb Suspension, nervous system, Peripheral nerve injury, biology.protein, Neuron, medicine.symptom, Nerve Net, Rats, Transgenic, Sciatic Neuropathy, Neuroscience, Two-hit hypothesis, 030217 neurology & neurosurgery, Parvalbumin, medicine.drug, Molecular Chaperones, RC321-571
Abstract: TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.
Published: 2021

20. The role of resources in the face of psychopathology

Author: Viola Oertel, Mira Röhm, N. Goldbach, Andreas Reif, Eva Straus, Hanna Preuss, Elisabeth Streicher, and Sabine Windmann
Subjects: Adult, Male, 050103 clinical psychology, Substance-Related Disorders, Interpersonal communication, Psychological Distress, 03 medical and health sciences, 0302 clinical medicine, Arts and Humanities (miscellaneous), Surveys and Questionnaires, medicine, Humans, Interpersonal Relations, 0501 psychology and cognitive sciences, Association (psychology), Depression (differential diagnoses), Depressive Disorder, Psychopathology, 05 social sciences, Psychological distress, Middle Aged, Resilience, Psychological, medicine.disease, Healthy Volunteers, 030227 psychiatry, Psychotherapy, Substance abuse, Clinical Psychology, Psychotic Disorders, Female, Substance use, Psychology, Intrapersonal communication, Clinical psychology
Abstract: OBJECTIVES The current study compared resource realization and psychological distress in patients with different psychiatric diagnoses and healthy individuals and examined the moderating effect of intrapersonal resources (personal strengths) and interpersonal resources (relationships) on the association between incongruence (unsatisfactory realization of personal goals) and psychological distress. METHOD In total, 218 participants (45.87% female, mean age = 39.83 years) completed standardized questionnaires at one measurement point. RESULTS Healthy individuals (n = 56) reported the most resources, followed by patients with psychotic (n = 53), substance use (n = 53), and depressive disorders (n = 56). While patients with psychotic disorders benefited from intra- and interpersonal resources, patients with depression only benefitted from intrapersonal resources. Patients with substance use disorders did not benefit from resources at all. CONCLUSIONS Depending on the diagnosis, patients evaluated their level of resources differently and benefitted in different ways. The results suggest that within psychotherapy, it might be useful to strengthen resources, especially for patients with depressive and substance use disorders.
Published: 2019
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21. KCNJ6 variants modulate reward‐related brain processes and impact executive functions in attention‐deficit/hyperactivity disorder

Author: Christoph Röser, Georg C. Ziegler, Marcel Romanos, Susanne Walitza, Andreas J. Fallgatter, Christian Jacob, Astrid Dempfle, Klaus-Peter Lesch, Ann-Christine Ehlis, Andreas Reif, Tim Hahn, Tobias J. Renner, Heike Weber, University of Zurich, Ziegler, Georg C, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
Subjects: Male, 0301 basic medicine, Brain activity and meditation, Dopamine, 2804 Cellular and Molecular Neuroscience, HYPERACTIVITY, 030105 genetics & heredity, Electroencephalography, RESPONSE CONTROL, 2738 Psychiatry and Mental Health, Executive Function, VENTRAL STRIATUM, ANTICIPATION, Genetics (clinical), Brain Mapping, SUBSTANTIA-NIGRA, medicine.diagnostic_test, Dopaminergic, Brain, ASSOCIATION, 10058 Department of Child and Adolescent Psychiatry, executive functions, Executive functions, Magnetic Resonance Imaging, Anticipation, Psychiatry and Mental health, Phenotype, Female, Adult, 2716 Genetics (clinical), 610 Medicine & health, Biology, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Reward, KCNJ6, medicine, ADHD, Humans, Attention deficit hyperactivity disorder, Family Health, THETA OSCILLATIONS, RECTIFYING K+ CHANNELS, DOPAMINERGIC-NEURONS, medicine.disease, GENE, 030104 developmental biology, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Haplotypes, Reward dependence, Attention Deficit Disorder with Hyperactivity, Mutagenesis, Case-Control Studies, 5' Untranslated Regions, Functional magnetic resonance imaging, Neuroscience
Abstract: KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)-relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, on reporter gene expression was explored in cultured cells. The KCNJ6 variants were then tested for association with ADHD and personality traits in a family-based sample (165 affected children) and an adult case-control sample (450 patients, 426 controls). Furthermore, the genotypic influence on performance in an n-back task and a cued continuous performance test (cCPT) was investigated by electroencephalography recordings. Finally, rs6517442 function was assessed by a reward anticipation paradigm using functional magnetic resonance imaging. Different haplotypes of rs7275707 and rs6517442 significantly influenced KCNJ6 gene expression proving their functional relevance on the molecular level. In the family-based children sample rs7275707 was associated with ADHD (p = .038). Moreover, rs7275707 showed association with the personality trait of Reward Dependence (p = .031). In the ADHD group, both rs7275707 and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopamine-related brain processes in ADHD risk.
Published: 2019
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22. Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder

Author: Sarah Kittel-Schneider, Katharina Domschke, Andreas Reif, Franziska Tole, Katrin Schröter, Murielle Brum, Christiane Ziegler, and Nathalie Brunkhorst-Kanaan
Subjects: Adult, Male, medicine.medical_specialty, Bipolar Disorder, 03 medical and health sciences, Patient Admission, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, mental disorders, medicine, Humans, Pharmacology (medical), Longitudinal Studies, Bipolar disorder, Promoter Regions, Genetic, Biological Psychiatry, Brain-derived neurotrophic factor, Depressive Disorder, Major, business.industry, Brain-Derived Neurotrophic Factor, Remission Induction, General Medicine, Methylation, DNA Methylation, Middle Aged, medicine.disease, Patient Discharge, 030227 psychiatry, Psychiatry and Mental health, Endocrinology, nervous system, CpG site, DNA methylation, Major depressive disorder, CpG Islands, Female, business, rs6265, Biomarkers, 030217 neurology & neurosurgery
Abstract: Preliminary evidence suggests that BDNF (brain derived neurotrophic factor) rs6265 genetic polymorphism, BDNF gene promotor methylation and BDNF serum levels might play an important role in the pathogenesis of affective disorders. As studies testing the BDNF system across molecular levels are sparse, this study aimed at investigating the BDNF val66met genotype, BDNF DNA methylation changes and peripheral BDNF serum levels in acute and remitted phases of MDD (major depressive disorder) and BD (bipolar disorder) and healthy controls. We found a significant difference of methylation levels at CpG site 1-1-1 and 3-1-1 between MDD and healthy controls (p
Published: 2019
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23. Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes

Author: Andreas Ströhle, Jan Richter, Lydia Fehm, Thomas Lang, Michael Höfler, Peter Zwanzger, Jürgen Deckert, Christiane A. Pané-Farré, Julia Mann, Tina B. Lonsdorf, Andrew T. Gloster, Tilo Kircher, Marcel Romanos, Susanne Neufang, Christoph Schartner, György A. Homola, Katharina Domschke, Georg W. Alpers, Sylvia Helbig-Lang, Alfons O. Hamm, Andreas Reif, Volker Arolt, Raffael Kalisch, Christian Büchel, Heike Weber, Maximilian J. Geiger, Alexander L. Gerlach, Michael G. Gottschalk, Paul Pauli, Thomas Fydrich, Miriam A. Schiele, Hans-Ulrich Wittchen, and Christiane Ziegler
Subjects: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Hamilton Anxiety Rating Scale, medicine.medical_treatment, behavioral disciplines and activities, Article, Arousal, lcsh:RC321-571, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Orexin Receptors, Internal medicine, Outcome Assessment, Health Care, Avoidance Learning, medicine, Humans, ddc:610, Allele, Agoraphobia, Cerebrum, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Cognitive Behavioral Therapy, business.industry, Panic disorder, Case-control study, Fear, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Cognitive behavioral therapy, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Case-Control Studies, Panic Disorder, Anxiety, Female, medicine.symptom, business, Personalized medicine, Human behaviour, Predictive markers, Molecular neuroscience, Psychiatric disorders, 030217 neurology & neurosurgery
Abstract: Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Published: 2019
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24. 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
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25. Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Author: Matthew Solomonson, Michael Conlon O'Donovan, Nancy L. Pedersen, Faith Dickerson, Eli A. Stahl, Neil Risch, Catherine Schaefer, Laura J. Scott, René S. Kahn, Duncan S. Palmer, Derek W. Morris, Claire Churchhouse, Xiaoming Jia, James T.R. Walters, Andrew M. McIntosh, Chia-Yen Chen, Michael John Owen, Arianna Di Florio, Lina Jonsson, Benjamin M. Neale, Roel A. Ophoff, Annabel Vreeker, Tarjinder Singh, Douglas Blackwood, Nicholas John Craddock, Jordan W. Smoller, Ian Jones, Weiqing Wang, Peter P. Zandi, Marco P. Boks, Fernando S. Goes, Lisa Jones, Robert H. Yolken, Mikael Landén, David Curtis, Danielle Posthuma, Andreas Reif, David St Clair, Sinéad B. Chapman, Nicholas A. Watts, Rolf Adolfsson, Adam E. Locke, Aiden Corvin, Nick Bass, Daniel P. Howrigan, and Andrew McQuillin
Subjects: Genetics, business.industry, Schizophrenia, Medicine, Risk gene, Genome-wide association study, Bipolar disorder, business, medicine.disease, Exome, Gene, GSK3B, Exome sequencing
Abstract: Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA,AKAP11emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06,P= 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.
Published: 2021
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26. Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis

Author: Sylvia Helbig-Lang, Jiaxi Lin, Gerhard Andersson, Thalia C. Eley, Katharina Domschke, Susanna Roberts, Paul Pauli, Jennifer L. Hudson, Jan Bergström, Jan Richter, Kathryn J. Lester, Alexander L. Gerlach, Alfons O. Hamm, Ulrike Lueken, Winfried Rief, Christiane Thiel, Volker Arolt, Andreas Reif, Tina B. Lonsdorf, Heike Weber, Koen Schruers, Miriam A. Schiele, Hans-Ulrich Wittchen, Evelyn Andersson, T. Lang, Christian Rück, Nils Lindefors, Per Carlbring, Georg W. Alpers, Gabriel Esquivel, Tomas Furmark, Psychiatrie & Neuropsychologie, and RS: MHeNs - R2 - Mental Health
Subjects: STRESS, medicine.medical_treatment, Anxiety, Treatment response, 0302 clinical medicine, Pharmacology (medical), Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, Panic disorder, biology, ASSOCIATION, Moderation, DEPRESSION, Anxiety Disorders, CHILDHOOD TRAUMA, Cognitive behavioral therapy, ENVIRONMENT INTERACTION, Psychiatry and Mental health, Neurology, therapygenetics, Meta-analysis, Therapygenetics, medicine.symptom, Anxiety disorder, Clinical psychology, LIFE EVENTS, CBT, 03 medical and health sciences, mental disorders, medicine, Humans, Serotonin transporter gene, Biological Psychiatry, Pharmacology, SEROTONIN TRANSPORTER GENE, Cognitive Behavioral Therapy, business.industry, therapy outcome, treatment response, medicine.disease, 030227 psychiatry, PROMOTER POLYMORPHISM 5-HTTLPR, 5-HTTLPR, biology.protein, Neurology (clinical), Therapy outcome, business, 030217 neurology & neurosurgery
Abstract: There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy. Crown Copyright (C) 2021 Published by Elsevier B.V. All rights reserved.
Published: 2021
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27. Low cardiorespiratory fitness and obesity for ADHD in childhood and adolescence: A 6‐year cohort study

Author: Barbara Franke, Stephen V. Faraone, Andreas Reif, Francisco B. Ortega, Pedro Femia, Jaanus Harro, Diva Eensoo, Evelyn Kiive, Jarek Mäestu, and Adrià Muntaner-Mas
Subjects: Male, Longitudinal study, Pediatrics, medicine.medical_specialty, Pediatric Obesity, Adolescent, Physical Therapy, Sports Therapy and Rehabilitation, body mass index, 030204 cardiovascular system & hematology, Overweight, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, mental disorders, medicine, Humans, Orthopedics and Sports Medicine, Longitudinal Studies, Risk factor, Child, 2. Zero hunger, aerobic fitness, youth, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, longitudinal study, Cardiorespiratory fitness, 030229 sport sciences, medicine.disease, Obesity, hyperactivity, Cross-Sectional Studies, Cardiorespiratory Fitness, Attention Deficit Disorder with Hyperactivity, Female, medicine.symptom, Underweight, business, Body mass index, Cohort study, Forecasting
Abstract: Contains fulltext : 231685.pdf (Publisher’s version ) (Open Access) Attention-deficit/hyperactivity disorder (ADHD) is a prevalent disorder in childhood and identifying risk factors associated with developing ADHD during childhood and adolescence is relevant from a clinical and epidemiological point of view. This work examines (a) whether overweight/obesity and low cardiorespiratory fitness (CRF) are associated with increased ADHD symptoms in childhood (cross-sectional analysis), and (b) whether overweight/obesity and low CRF levels during childhood predict increased ADHD symptoms in adolescence (longitudinal analysis). Data were examined from a longitudinal study of Estonian inhabitants who took part in the European Youth Heart Study (EYHS) in 1998 and 1999 (baseline age 9 years), who were re-evaluated 6 years later as part of the longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). CRF was determined via an incremental maximal cycle-ergometer test, overweight/obesity was based on body mass index (BMI), and the 7-point af Klinteberg Hyperactivity Scale was used to assess ADHD symptoms at both time points. In the cross-sectional analysis, children with overweight/obesity were at greater risk of ADHD symptoms compared to underweight/normal weight children, as were those unfit compared to fit children (OR = 1.92 and 95%CI = 1.02-3.55, and OR = 1.84 and 95%CI = 1.13-2.98, respectively). The cross-sectional association between BMI and ADHD symptoms was mediated by CRF (z = 2.116, 42.9%; P = .034). The longitudinal analysis showed being unfit in childhood was associated with a greater risk of increased ADHD symptoms 6 years later in adolescence (OR = 2.26 and 95%CI = 1.14-4.47), even after adjusting for baseline ADHD symptoms and BMI. Our result suggests that being unfit is an additional risk factor for increased ADHD symptoms during childhood and adolescence. The association between BMI and ADHD symptoms was mediated by CRF in the cross-sectional analysis, and no association was seen between overweight/obesity and increased ADHD symptoms.
Published: 2021
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28. ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications

Author: Jan Haavik, Helene Barone, Andreas Reif, Rune Kleppe, Nibal Betari, and Selina Cannon Homaei
Subjects: Succinic semialdehyde dehydrogenase deficiency, 0303 health sciences, Ichthyosis, business.industry, Cognitive Neuroscience, Mitochondrial disease, Maple syrup urine disease, Central Nervous System Depressants, medicine.disease, Alkaptonuria, 3. Good health, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Neuropsychology and Physiological Psychology, Monoamine neurotransmitter, Neurochemical, Attention Deficit Disorder with Hyperactivity, medicine, Humans, Phenylketonuria (PKU), business, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Neurometabolic diseases (NMDs) are typically caused by genetic abnormalities affecting enzyme functions, which in turn interfere with normal development and activity of the nervous system. Although the individual disorders are rare, NMDs are collectively relatively common and often lead to lifelong difficulties and high societal costs. Neuropsychiatric manifestations, including ADHD symptoms, are prominent in many NMDs, also when the primary biochemical defect originates in cells and tissues outside the nervous system. ADHD symptoms have been described in phenylketonuria, tyrosinemias, alkaptonuria, succinic semialdehyde dehydrogenase deficiency, X-linked ichthyosis, maple syrup urine disease, and several mitochondrial disorders, but are probably present in many other NMDs and may pose diagnostic and therapeutic challenges. Here we review current literature linking NMDs with ADHD symptoms. We cite emerging evidence that many NMDs converge on common neurochemical mechanisms that interfere with monoamine neurotransmitter synthesis, transport, metabolism, or receptor functions, mechanisms that are also considered central in ADHD pathophysiology and treatment. Finally, we discuss the therapeutic implications of these findings and propose a path forward to increase our understanding of these relationships. publishedVersion
Published: 2021

29. 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
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30. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author: Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R Johnson, Pauls Auce, Graeme J Sills, Larry W Baum, Pak C Sham, Stacey S Cherny, Colin H T Lui, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Exome sequencing, Male, Medicine (General), Neurology [D14] [Human health sciences], Gene-set, Genome-wide association study, Disease, Biology, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Whole Exome Sequencing, Epilepsy, R5-920, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Gene, Genetic association, Ultra-rare variant, Genetics, Neurologie [D14] [Sciences de la santé humaine], Burden analysis, Genetic Variation, General Medicine, medicine.disease, Ultra-rare variants, Gene-sets, Case-Control Studies, Medicine, epilepsy, Epilepsy, Generalized, Female, Genetics & genetic processes [F10] [Life sciences], Epilepsies, Partial, Human medicine, Burden analysi, Génétique & processus génétiques [F10] [Sciences du vivant], Case-Control Studie, Research Paper, Genome-Wide Association Study, Human
Abstract: EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]
Published: 2021
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31. Akute psychotische Störung als erste klinische Manifestation einer Multiplen Sklerose – eine Kasuistik

Author: Hannah Wendy, Christine Reif-Leonhard, Sharmili Edwin Thanarajah, and Andreas Reif
Subjects: medicine.medical_specialty, Neurology, business.industry, Multiple sclerosis, MEDLINE, Psychosomatic medicine, General Medicine, Clinical manifestation, Psychosomatic Medicine, Psychiatry, Psychotherapy, Neurosurgery, Psychopharmacology, medicine.disease, Psychiatry and Mental health, Acute Psychotic Episode, medicine, Neurology (clinical), business
Published: 2021

32. Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Author: Eduard Vieta, Liping Hou, Markus M. Nöthen, Martin Schalling, Thomas Stamm, Thomas G. Schulze, Norio Ozaki, Claire O'Donovan, Azmeraw T. Amare, Alessio Squassina, Alfonso Tortorella, Kazufumi Akiyama, Urs Heilbronner, Caroline M. Nievergelt, Frank Bellivier, Palmiero Monteleone, Mirko Manchia, Tadafumi Kato, Per Hoffmann, Jean-Michel Aubry, Claudia Pisanu, Pavla Stopkova, Lena Backlund, Anthony Batzler, James B. Potash, Susan L. McElroy, Jean-Pierre Kahn, Guy A. Rouleau, Bernhard T. Baune, Francis M. Mondimore, Beth Larrabee, Peter P. Zandi, Christian Simhandl, Susan G. Leckband, Andrea Pfennig, Maria Del Zompo, Francis J. McMahon, Tatyana Shekhtman, Giovanni Severino, Tomas Novak, Andreas J. Forstner, Marcella Rietschel, Paul Grof, Maria Grigoroiu-Serbanescu, Ryota Hashimoto, Nirmala Akula, Sarah Kittel-Schneider, John R. Kelsoe, Andreas Reif, Joanna M. Biernacka, Barbara W. Schweizer, Janice M. Fullerton, Sébastien Gard, Julie Garnham, Barbara König, Mark A. Frye, Michael Bauer, Po-Hsiu Kuo, Janusz K. Rybakowski, Joanna Hauser, Pablo Cervantes, Gonzalo Laje, Urban Ösby, Nina Dalkner, Ewa Ferensztajn-Rochowiak, Mikael Landén, Hsi-Chung Chen, Claire Slaney, Eva Z. Reininghaus, Katzutaka Shimoda, Esther Jiménez, Cristiana Cruceanu, Francesc Colom, Catharina Lavebratt, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Stephanie H. Witt, Sven Cichon, Bruno Etain, Layla Kassem, Caterina Chillotti, Fernando S. Goes, Franziska Degenhardt, J. Raymond DePaulo, Martin Alda, Ichiro Kusumi, Peter Falkai, Antoni Benabarre, Stéphane Jamain, Philip B. Mitchell, Raffaella Ardau, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Mario Maj, Paul D. Shilling, Mazda Adli, Louise Frisén, Brandon J. Coombes, Gustavo Turecki, Scott R. Clark, Bárbara Arias, Vincent Millischer, Michael McCarthy, Marion Leboyer, Lina Martinsson, Piotr M. Czerski, Coombes, Brandon J, Millischer, Vincent, Batzler, Anthony, Larrabee, Beth, Hou, Liping, Papiol, Sergi, Heilbronner, Ur, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Amare, Azmeraw T, Ardau, Raffaella, Arias, Barbara, Aubry, Jean-Michel, Backlund, Lena, Bauer, Michael, Baune, Bernhard T, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Cruceanu, Cristiana, Czerski, Piotr M, Dalkner, Nina, Degenhardt, Franziska, Del Zompo, Maria, Depaulo, J Raymond, Étain, Bruno, Falkai, Peter, Ferensztajn-Rochowiak, Ewa, Forstner, Andreas J, Frisen, Louise, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kato, Tadafumi, Kelsoe, John R, Kittel-Schneider, Sarah, König, Barbara, Kuo, Po-Hsiu, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan L, Mitchell, Philip B, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Nöthen, Markus M, Novák, Toma, O'Donovan, Claire, Osby, Urban, Ozaki, Norio, Pfennig, Andrea, Pisanu, Claudia, Potash, James B, Reif, Andrea, Reininghaus, Eva, Rietschel, Marcella, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Schofield, Peter R, Schubert, Klaus Oliver, Schweizer, Barbara W, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M, Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Witt, Stephanie H, Zandi, Peter P, Fullerton, Janice M, Alda, Martin, Frye, Mark A, Schulze, Thomas G, Mcmahon, Francis J, and Biernacka, Joanna M
Subjects: medicine.medical_specialty, Lithium (medication), business.industry, Bipolar disorder, General Medicine, medicine.disease, Polygenic risk scores, Attention-deficit/hyperactivity disorder, Lithium response, Adherence, medicine, Attention deficit hyperactivity disorder, Association (psychology), Psychiatry, business, Depression (differential diagnoses), 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, Research Article, medicine.drug
Abstract: Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
Published: 2021

33. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Stephan Ripke, Eduard Maron, Eco J. C. de Geus, Stefan Herms, Thomas Lang, Andreas Reif, Nina Friedrich, Volker Arolt, Susanne Moebus, Thomas Werge, Paul Pauli, Christiane Wolf, Markus M. Nöthen, Julian Hecker, Andreas Ströhle, Stacy Steinberg, Franziska Geiser, Lars Alfredsson, Heike Weber, Timo Hess, Katharina Domschke, Jessica Becker, Benedikt C. Buerfent, Martin Schalling, Georg W. Alpers, Evelyn Andersson, Thomas Fydrich, Elisabeth B. Binder, Stefanie Rambau, Darina Czamara, Alfons O. Hamm, Tomas Olsson, Hans-Ulrich Wittchen, Winfried Rief, Bertram Müller-Myhsok, Francis J. McMahon, Elias Eriksson, David M. Hougaard, Manuel Mattheisen, Rupert Conrad, Jürgen Deckert, Merete Nordentoft, Angelika Erhardt, Jens Plag, Andres Metspalu, Ingrid Kockum, Christer Allgulander, Per Hoffmann, Yuri Milaneschi, Nils Lindefors, Iiris Hovatta, Thorgeir E. Thorgeirsson, Stefanie Heilmann-Heimbach, Christiane A. Pané-Farré, Christina M. Hultman, Anders D. Børglum, Sandra Meier, David P.D. Woldbye, Johannes Schumacher, Lydia Fehm, Kari Stefansson, Alexander L. Gerlach, Hreinn Stefansson, Brenda W.J.H. Penninx, Preben Bo Mortensen, Thomas Hansen, Andreas J. Forstner, Christian Rück, Dorret I. Boomsma, Swapnil Awasthi, Ole Mors, Tilo Kircher, Patrick F. Sullivan, Catharina Lavebratt, Hamdi Mbarek, Epidemiology and Data Science, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Biological Psychology, APH - Methodology, and Functional Genomics
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Oncology, medicine.medical_specialty, Linkage disequilibrium, Medizin, Genome-wide association study, Genetic correlation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, Genetic predisposition, medicine, 1000 Genomes Project, Molecular Biology, business.industry, Heritability, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Major depressive disorder, business, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract: Panic disorder (PD) has a lifetime prevalence of 2–4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0–34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10−4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10−7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of
Published: 2021
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34. Transdiagnostic Comparison of Visual Working Memory Capacity in Bipolar Disorder and Schizophrenia

Author: Catherine V. Barnes-Scheufler, Jutta S. Mayer, Sarah Kittel-Schneider, Robert A. Bittner, Silke Matura, Andreas Reif, Lara Rösler, Viola Oertel, Caroline Passow, and Netherlands Institute for Neuroscience (NIN)
Subjects: medicine.medical_specialty, Neurology, genetic structures, Bipolar disorder, Audiology, Cognitive neuroscience, behavioral disciplines and activities, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Cognitive dysfunction, medicine, Attention, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Cognitive deficit, Working memory, Research, lcsh:QP351-495, Cognition, medicine.disease, 030227 psychiatry, Working memory capacity, Psychiatry and Mental health, lcsh:Neurophysiology and neuropsychology, Schizophrenia, Psychopharmacology, medicine.symptom, Psychology, 030217 neurology & neurosurgery
Abstract: Background Impaired working memory is a core cognitive deficit in both bipolar disorder and schizophrenia. Its study might yield crucial insights into the underpinnings of both disorders on the cognitive and neurophysiological level. Visual working memory capacity is a particularly promising construct for such translational studies. However, it has not yet been investigated across the full spectrum of both disorders. The aim of our study was to compare the degree of reductions of visual working memory capacity in patients with bipolar disorder (PBD) and patients with schizophrenia (PSZ) using a paradigm well established in cognitive neuroscience. Methods 62 PBD, 64 PSZ, and 70 healthy controls (HC) completed a canonical visual change detection task. Participants had to encode the color of four circles and indicate after a short delay whether the color of one of the circles had changed or not. We estimated working memory capacity using Pashler’s K. Results Working memory capacity was significantly reduced in both PBD and PSZ compared to HC. We observed a small effect size (r = .202) for the difference between HC and PBD and a medium effect size (r = .370) for the difference between HC and PSZ. Working memory capacity in PSZ was also significantly reduced compared to PBD with a small effect size (r = .201). Thus, PBD showed an intermediate level of impairment. Conclusions These findings provide evidence for a gradient of reduced working memory capacity in bipolar disorder and schizophrenia, with PSZ showing the strongest degree of impairment. This underscores the importance of disturbed information processing for both bipolar disorder and schizophrenia. Our results are compatible with the cognitive manifestation of a neurodevelopmental gradient affecting bipolar disorder to a lesser degree than schizophrenia. They also highlight the relevance of visual working memory capacity for the development of both behavior- and brain-based transdiagnostic biomarkers.
Published: 2020
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35. Optimizing Behavioral Paradigms to Facilitate Development of New Treatments for Anhedonia and Reward Processing Deficits in Schizophrenia and Major Depressive Disorder: Study Protocol

Author: Amy C. Bilderbeck, Andreea Raslescu, Dennis Hernaus, Anja Hayen, Daniel Umbricht, Darrel Pemberton, Jane Tiller, Birgitte Søgaard, Anke Sambeth, Therese van Amelsvoort, Andreas Reif, Georgios Papazisis, Victor Pérez, Matilde Elices, Damien Maurice, Valérie Bertaina-Anglade, Gerard R. Dawson, Stephane Pollentier, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Section Psychopharmacology, RS: FPN NPPP II, and MUMC+: MA Med Staf Spec Psychiatrie (9)
Subjects: SYMPTOMS, lcsh:RC435-571, behavioral disciplines and activities, SELF-REPORT, VALIDATION, Task (project management), ACTIVATION, Study Protocol, 03 medical and health sciences, WORKING-MEMORY, 0302 clinical medicine, reward deficits, lcsh:Psychiatry, medicine, DECISION-MAKING PARADIGMS, Set (psychology), reward processing, PSYCHOMETRIC EVALUATION, negative symptoms, Psychiatry, Protocol (science), Working memory, impaired motivation, Anhedonia, BIPOLAR DISORDER, medicine.disease, HAMILTON PLEASURE SCALE, 030227 psychiatry, schizophrenia, Clinical trial, anhedonia, Psychiatry and Mental health, Schizophrenia, depression, Major depressive disorder, medicine.symptom, Psychology, CLINICAL-TRIALS, psychological phenomena and processes, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Background: Behavioral tasks focusing on different subdomains of reward processing may provide more objective and quantifiable measures of anhedonia and impaired motivation compared with clinical scales. Typically, single tasks are used in relatively small studies to compare cases and controls in one indication, but they are rarely included in larger multisite trials. This is due to limited systematic standardization as well as the challenges of deployment in international studies and stringent adherence to the high regulatory requirements for data integrity. The Reward Task Optimization Consortium (RTOC) was formed to facilitate operational implementation of reward processing tasks, making them suitable for use in future large-scale, international, multisite drug development studies across multiple indications. The RTOC clinical study aims to conduct initial optimization of a set of tasks in patients with major depressive disorder (MDD) or schizophrenia (SZ). Methods: We will conduct a multicenter study across four EU countries. Participants (MDD = 37, SZ = 37, with ≤80 age- and gender-matched healthy volunteers) will attend a study visit comprising screening, self-report and clinically rated assessments of anhedonia and symptom severity, and three reward processing tasks; specifically, the Grip Strength Effort task, the Doors task, and the Reinforcement Learning Working Memory task. The Grip Strength Effort and Doors tasks include simultaneous electroencephalography/event-related potential recordings. Outcomes will be compared using a two-way group design of MDD and SZ with matched controls, respectively. Further analyses will include anhedonia assessment scores as covariates. Planned analyses will assess whether our findings replicate previously published data, and multisite deployment will be evaluated through assessments of quality and conduct. A subset of participants will complete a second visit, to assess test-retest reliability of the task battery. Discussion: This study will evaluate the operational deployment of three reward processing tasks to the regulatory standards required for use in drug development trials. We will explore the potential of these tasks to differentiate patients from controls and to provide a quantitative marker of anhedonia and/or impaired motivation, establishing their usefulness as endpoints in multisite clinical trials. This study should demonstrate where multifaceted reward deficits are similar or divergent across patient populations. Registration: ClinicalTrials.gov (NCT04024371).
Published: 2020
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36. Disease burden and direct medical costs of incident adult ADHD: A retrospective longitudinal analysis based on German statutory health insurance claims data

Author: Michael Karus, Melanie May, Berit Libutzki, Catharina A. Hartman, Benno Neukirch, Markus Gleitz, Andreas Reif, and Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Comorbidity, comorbidities, DIAGNOSIS, healthcare costs, German, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cost of Illness, Statutory law, Claims data, Germany, Health care, medicine, Health insurance, Attention deficit hyperactivity disorder, Humans, Longitudinal Studies, Adult ADHD (aADHD), Psychiatry, Disease burden, Retrospective Studies, Insurance, Health, business.industry, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, claims data, Health Care Costs, Middle Aged, medicine.disease, language.human_language, 3. Good health, 030227 psychiatry, Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, language, Female, medication, business, Medical costs, 030217 neurology & neurosurgery, Research Article
Abstract: Background. Adult attention-deficit/hyperactivity disorder (aADHD) is still a largely unrecognized psychiatric condition despite its strong impact on individuals’ well-being. Here, we describe the healthcare situation of individuals with incident aADHD over 4 years before and 4 years after initial administrative diagnosis. Methods. A retrospective, longitudinal cohort analysis was conducted using German claims data. The InGef database contained approximately 5 million member-records from over 60 nationwide statutory health insurances (SHI). Individuals were indexed upon initial diagnosis of aADHD. Results. Average age at diagnosis of aADHD was 35 years, and 60% of individuals were male. Comorbidities, resource use, and healthcare costs were substantial before initial diagnosis and decreased within the 4 years thereafter. Only 32% of individuals received initial ADHD medication and adherence was low. The majority received psychotherapy. Individuals with initial ADHD medication showed the highest share in comorbidities, physician visits, medication use for comorbidities, psychotherapy, and costs. Overall, healthcare costs were at over €4,000 per individual within the year of aADHD diagnosis. Conclusions. We conclude that earlier recognition of aADHD could prevent the development and aggravation of comorbid mental illnesses. At the same time, comorbid conditions may have masked (“over-shadowed”) aADHD and delayed diagnosis. The burden of disease in aADHD is high, which was noticeable especially among individuals who received initial ADHD-medication, suggesting that psychopharmacological treatment was mainly considered for the most severely ill. We conclude that measures to facilitate access of aADHD patients to clinical experts are required to improve reality of care in the outpatient setting.
Published: 2020

37. ADHD and accidents over the life span - A systematic review

Author: Henrik Larsson, Rhiannon V. McNeill, Andreas Reif, Berit Libutzki, Nathalie Brunkhorst-Kanaan, and Sarah Kittel-Schneider
Subjects: medicine.medical_treatment, CHILDREN, Comorbidity, Trajectories, Behavioral Neuroscience, 0302 clinical medicine, DEFICIT-HYPERACTIVITY DISORDER, LISDEXAMFETAMINE DIMESYLATE, YOUNG-ADULTS, ADOLESCENTS, DRIVERS, Young adult, Child, Injuries, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, Methylphenidate, 05 social sciences, 3. Good health, Substance abuse, Neuropsychology and Physiological Psychology, Research questions, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Cognitive Neuroscience, Longevity, 03 medical and health sciences, mental disorders, medicine, ADHD, Attention deficit hyperactivity disorder, Humans, 0501 psychology and cognitive sciences, 050102 behavioral science & comparative psychology, Psychiatry, SUBSTANCE USE, DRIVING-RELATED RISKS, Life span, business.industry, Atomoxetine, PERFORMANCE, medicine.disease, Stimulant, Amphetamine, Attention Deficit Disorder with Hyperactivity, Accidents, Central Nervous System Stimulants, business, 030217 neurology & neurosurgery
Abstract: Studies have demonstrated an increased risk of accidents and injuries in children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about how accident risk may alter over the lifespan. Additionally, it would be important to know if the most common types of accidents and injuries differ in ADHD patients over different age groups. Furthermore, there is increasing evidence of an ameliorating effect of ADHD medication on accident risk. Lastly, the underlying risk factors and causal mechanisms behind increased accident risk remain unclear. We therefore conducted a systematic review focusing on the above described research questions. Our results suggested that accident/injury type and overall risk changes in ADHD patients over the lifespan. ADHD medication appeared to be similarly effective at reducing accident risk in all age groups. However, studies with direct comparisons of accident/injuries and effects of medication at different age groups or in old age are still missing. Finally, comorbidities associated with ADHD such as substance abuse appear to further increase the accident/injury risk.
Published: 2020

38. Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders:Findings from the ENIGMA ADHD, ASD, and OCD working groups

Author: Pedro Moreira, Ruth O'Gorman Tuura, Mara Cercignani, Philip Aherson, Maria Jalbrzikowski, Kate D. Fitzgerald, Declan G. Murphy, Bernd Kardatzki, Christine Ecker, David F. Tolin, Fern Jaspers-Fayer, Pedro Morgado, Juan Carlos Soliva Vila, Kang Ik K. Cho, Kathrin Koch, Timothy J. Silk, Philip R. Szeszko, Thomas Frodl, Mara Parellada, Shlomi Haar, Eileen Daly, Bob Oranje, Anouk Schrantee, Leyla Namazova-Baranova, Joseph A. King, Beatriz Luna, Silvia Brem, Eric Earl, Alasdair Vance, Michela Tosetti, Christine Deruelle, Ramona Baur-Streubel, Jackie Fitzgerald, Kirsten O'Hearn, Michael C. Stevens, Yoshiyuki Hirano, J. Antoni Ramos-Quiroga, Erika L. Nurmi, Kaylita Chantiluke, Joseph O'Neill, Kerstin Kohls, Olga Puig, Devon Shook, Clodagh M. Murphy, Gustavo Sudre, Marlene Behrmann, Jaap Oosterlaan, Tinatin Gogberashvili, Lianne Schmaal, Carles Soriano-Mas, Liesbeth Hoekstra, Ignacio Martínez-Zalacaín, Noam Soreni, Marcel P. Zwiers, Paulo Mattos, Gregor Kohls, Andreas J. Fallgatter, Tiffany M. Chaim-Avancini, Alexander Baranov, S. Evelyn Stewart, Sara Dallaspezia, Gianfranco Spalletta, Jonna Kuntsi, Lizanne J. S. Schweren, Joel T. Nigg, Leanne Tamm, Premika S.W. Boedhoe, Adriana Di Martino, Jane McGrath, Marcelo C. Batistuzzo, Norbert Skokauskas, Filippo Muratori, John Piacentini, Jean-Paul Fouche, Sarah Baumeister, Alan Anticevic, Neil A. Harrison, Christine M. Freitag, Pedro G.P. Rosa, Stephen V. Faraone, Ana Cubillo, David Mataix-Cols, Yuki Sakai, Stefan Ehrlich, Eileen Oberwelland Weiss, Fabrizio Piras, Dirk J. Heslenfeld, Je-Yeon Yun, Paul Pauli, Catharina A. Hartman, Ganesan Venkatasubramanian, Janardhanan C. Narayanaswamy, Charles B Malpas, Jan C. Beucke, José M. Menchón, Egill A. Fridgeirsson, Margot J. Taylor, Mauricio Moller Martinho, H. Blair Simpson, Jan K. Buitelaar, Gerd Kvale, Ivanei E. Bramati, Aki Tsuchiyagaito, Susanne Walitza, Irene Bollettini, Jeffery N. Epstein, Anders M. Dale, Thomas Ethofer, Terry L. Jernigan, David Coghill, Rachel Marsh, Andreas Reif, Astri J. Lundervold, Pieter J. Hoekstra, Oana Georgiana Rus, Damiaan Denys, Gregory L. Wallace, Matt C. Gabel, Hazel McCarthy, Sarah Hohmann, Rosa Nicolau, Stephanie H. Ameis, Neda Jahanshad, Takashi Nakamae, Xin Feng, Emily R. Stern, Georg G. von Polier, Yanni Liu, Paulo Marques, Anushree Bose, Hao Hu, Sara Lera-Miguel, Deniz A. Gürsel, Jochen Seitz, Jos W. R. Twisk, Mario Rodrigues Louzã, Clare Kelly, Annette Conzelmann, Alysa E. Doyle, Odile A. van den Heuvel, Anthony A. James, Chris Perriello, Joost Janssen, Damien A. Fair, Norbert Kathmann, Francisco X. Castellanos, Paul D. Arnold, Oscar Vilarroya, Geraldo F. Busatto, Federica Piras, Pino Alonso, Akiko Nakagawa, Sarah Durston, Lena Schwarz, Mitul A. Mehta, Dan J. Stein, Celso Arango, Daan van Rooij, Ilan Dinstein, Anastasia Christakou, Klaus-Peter Lesch, Kerstin J. Plessen, Jennifer Fedor, Yolanda Vives-Gilabert, Ilaria Gori, Louise Gallagher, Brian P. Brennan, Yuqi Cheng, Barbara Franke, Sabin Khadka, Stephanie E. Novotny, Martine Hoogman, Georgii Karkashadze, Georg C. Ziegler, Yuliya N. Yoncheva, Rosa Calvo, Thomas Wolfers, Marcelo Q. Hoexter, Benjamin A. Ely, Masaru Kuno, Alessandra Retico, Yoshinari Abe, Geoffrey B. Hall, Tobias Banaschewski, Anatoly Anikin, Christine Lochner, Astrid Morer, Guido van Wingen, Jan Haavik, Joseph Biederman, Luisa Lázaro, Francesco Benedetti, Fengfeng Zhou, Guillaume Auzias, Daniel Brandeis, Dmitry Kapilushniy, Katya Rubia, Philip Shaw, Christian Kaufmann, Sara Calderoni, Marcus V. Zanetti, Anastasia Solovieva, Zhen Wang, Francesca Assogna, Jamie D. Feusner, Chaim Huyser, Fernanda Tovar-Moll, Theo G.M. van Erp, Y.C. Janardhan Reddy, Jun Soo Kwon, Yannis Paloyelis, Anna Calvo, Patricia Gruner, Kathrin C. Zierhut, Liesbeth Reneman, Tomohiro Nakao, Janita Bralten, Marie F. Høvik, Mark A. Bellgrove, Maarten Mennes, Paul M. Thompson, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Epidemiology and Data Science, Pediatric surgery, Radiology and nuclear medicine, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Psychiatry, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Boedhoe, Premika S W, van Rooij, Daan, Hoogman, Martine, Twisk, Jos W R, Schmaal, Lianne, Abe, Yoshinari, Alonso, Pino, Ameis, Stephanie H, Anikin, Anatoly, Anticevic, Alan, Arango, Celso, Arnold, Paul D, Asherson, Philip, Assogna, Francesca, Auzias, Guillaume, Banaschewski, Tobia, Baranov, Alexander, Batistuzzo, Marcelo C, Baumeister, Sarah, Baur-Streubel, Ramona, Behrmann, Marlene, Bellgrove, Mark A, Benedetti, Francesco, Beucke, Jan C, Biederman, Joseph, Bollettini, Irene, Bose, Anushree, Bralten, Janita, Bramati, Ivanei E, Brandeis, Daniel, Brem, Silvia, Brennan, Brian P, Busatto, Geraldo F, Calderoni, Sara, Calvo, Anna, Calvo, Rosa, Castellanos, Francisco X, Cercignani, Mara, Chaim-Avancini, Tiffany M, Chantiluke, Kaylita C, Cheng, Yuqi, Cho, Kang Ik K, Christakou, Anastasia, Coghill, David, Conzelmann, Annette, Cubillo, Ana I, Dale, Anders M, Dallaspezia, Sara, Daly, Eileen, Denys, Damiaan, Deruelle, Christine, Di Martino, Adriana, Dinstein, Ilan, Doyle, Alysa E, Durston, Sarah, Earl, Eric A, Ecker, Christine, Ehrlich, Stefan, Ely, Benjamin A, Epstein, Jeffrey N, Ethofer, Thoma, Fair, Damien A, Fallgatter, Andreas J, Faraone, Stephen V, Fedor, Jennifer, Feng, Xin, Feusner, Jamie D, Fitzgerald, Jackie, Fitzgerald, Kate D, Fouche, Jean-Paul, Freitag, Christine M, Fridgeirsson, Egill A, Frodl, Thoma, Gabel, Matt C, Gallagher, Louise, Gogberashvili, Tinatin, Gori, Ilaria, Gruner, Patricia, Gürsel, Deniz A, Haar, Shlomi, Haavik, Jan, Hall, Geoffrey B, Harrison, Neil A, Hartman, Catharina A, Heslenfeld, Dirk J, Hirano, Yoshiyuki, Hoekstra, Pieter J, Hoexter, Marcelo Q, Hohmann, Sarah, Høvik, Marie F, Hu, Hao, Huyser, Chaim, Jahanshad, Neda, Jalbrzikowski, Maria, James, Anthony, Janssen, Joost, Jaspers-Fayer, Fern, Jernigan, Terry L, Kapilushniy, Dmitry, Kardatzki, Bernd, Karkashadze, Georgii, Kathmann, Norbert, Kaufmann, Christian, Kelly, Clare, Khadka, Sabin, King, Joseph A, Koch, Kathrin, Kohls, Gregor, Konrad, Kerstin, Kuno, Masaru, Kuntsi, Jonna, Kvale, Gerd, Kwon, Jun Soo, Lázaro, Luisa, Lera-Miguel, Sara, Lesch, Klaus-Peter, Hoekstra, Liesbeth, Liu, Yanni, Lochner, Christine, Louza, Mario R, Luna, Beatriz, Lundervold, Astri J, Malpas, Charles B, Marques, Paulo, Marsh, Rachel, Martínez-Zalacaín, Ignacio, Mataix-Cols, David, Mattos, Paulo, Mccarthy, Hazel, Mcgrath, Jane, Mehta, Mitul A, Menchón, José M, Mennes, Maarten, Martinho, Mauricio Moller, Moreira, Pedro S, Morer, Astrid, Morgado, Pedro, Muratori, Filippo, Murphy, Clodagh M, Murphy, Declan G M, Nakagawa, Akiko, Nakamae, Takashi, Nakao, Tomohiro, Namazova-Baranova, Leyla, Narayanaswamy, Janardhanan C, Nicolau, Rosa, Nigg, Joel T, Novotny, Stephanie E, Nurmi, Erika L, Weiss, Eileen Oberwelland, O'Gorman Tuura, Ruth L, O'Hearn, Kirsten, O'Neill, Joseph, Oosterlaan, Jaap, Oranje, Bob, Paloyelis, Yanni, Parellada, Mara, Pauli, Paul, Perriello, Chri, Piacentini, John, Piras, Fabrizio, Piras, Federica, Plessen, Kerstin J, Puig, Olga, Ramos-Quiroga, J Antoni, Reddy, Y C Janardhan, Reif, Andrea, Reneman, Liesbeth, Retico, Alessandra, Rosa, Pedro G P, Rubia, Katya, Rus, Oana Georgiana, Sakai, Yuki, Schrantee, Anouk, Schwarz, Lena, Schweren, Lizanne J S, Seitz, Jochen, Shaw, Philip, Shook, Devon, Silk, Tim J, Simpson, H Blair, Skokauskas, Norbert, Soliva Vila, Juan Carlo, Solovieva, Anastasia, Soreni, Noam, Soriano-Mas, Carle, Spalletta, Gianfranco, Stern, Emily R, Stevens, Michael C, Stewart, S Evelyn, Sudre, Gustavo, Szeszko, Philip R, Tamm, Leanne, Taylor, Margot J, Tolin, David F, Tosetti, Michela, Tovar-Moll, Fernanda, Tsuchiyagaito, Aki, van Erp, Theo G M, van Wingen, Guido A, Vance, Alasdair, Venkatasubramanian, Ganesan, Vilarroya, Oscar, Vives-Gilabert, Yolanda, von Polier, Georg G, Walitza, Susanne, Wallace, Gregory L, Wang, Zhen, Wolfers, Thoma, Yoncheva, Yuliya N, Yun, Je-Yeon, Zanetti, Marcus V, Zhou, Fengfeng, Ziegler, Georg C, Zierhut, Kathrin C, Zwiers, Marcel P, Thompson, Paul M, Stein, Dan J, Buitelaar, Jan, Franke, Barbara, van den Heuvel, Odile A, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Adult Psychiatry, ANS - Compulsivity, Impulsivity & Attention, Graduate School, Child Psychiatry, General Paediatrics, ARD - Amsterdam Reproduction and Development, Radiology and Nuclear Medicine, APH - Personalized Medicine, and APH - Mental Health
Subjects: Male, Research Report, Obsessive-Compulsive Disorder, Frontal cortex, Systems Analysis, Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Hippocampal formation, Audiology, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, Child, Obsessive-compulsive disorder (OCD), ComputingMilieux_MISCELLANEOUS, Intelligence quotient, Psychopathology, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, ABNORMALITIES, ENIGMA, Organ Size, 3. Good health, Psychiatry and Mental health, Autism spectrum disorder, Brain size, Cohort, Female, MRI, Adult, medicine.medical_specialty, CORTEX, Adolescent, DEFICIT HYPERACTIVITY DISORDER, Human Development, Neuroimaging, behavioral disciplines and activities, Article, 03 medical and health sciences, FIELD-STRENGTH, mental disorders, medicine, MEGA-ANALYSIS, Attention deficit hyperactivity disorder, Humans, Cortical surface, Structural MRI, Attention Deficit Disorder with Hyperactivity, Cerebrum, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, medicine.disease, 030227 psychiatry, VOXEL, Autism, business, 030217 neurology & neurosurgery
Abstract: ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.
Published: 2020
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39. Site-specific phosphorylation of Huntingtin exon 1 recombinant proteins enabled by the discovery of novel kinases

Author: Andreas Reif, Anass Chiki, Ramanath Narayana Hegde, Luciano A. Abriata, Hilal A. Lashuel, and Jonathan Ricci
Subjects: Intracerebral hemorrhage, medicine.medical_specialty, education.field_of_study, Proportional hazards model, business.industry, Hazard ratio, Population, medicine.disease, Confidence interval, Internal medicine, Propensity score matching, medicine, business, education, Stroke, Cohort study
Abstract: Objectives: To examine whether preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) influenced 30-day stroke mortality. Methods: We conducted a nationwide population-based cohort study. Using medical databases, we identified all first-time stroke hospitalizations in Denmark between 2004 and 2012 (n = 100,043) and subsequent mortality. We categorized NSAID use as current (prescription redemption within 60 days before hospital admission), former, and nonuse. Current use was further classified as new or long-term use. Cox regression was used to compute hazard ratios (HRs) of death within 30 days, controlling for potential confounding through multivariable adjustment and propensity score matching. Results: The adjusted HR of death for ischemic stroke was 1.19 (95% confidence interval [CI]: 1.02–1.38) for current users of selective cyclooxygenase (COX)-2 inhibitors compared with nonusers, driven by the effect among new users (1.42, 95% CI: 1.14–1.77). Comparing the different COX-2 inhibitors, the HR was driven by new use of older traditional COX-2 inhibitors (1.42, 95% CI: 1.14–1.78) among which it was 1.53 (95% CI: 1.02–2.28) for etodolac and 1.28 (95% CI: 0.98–1.68) for diclofenac. The propensity score–matched analysis supported the association between older COX-2 inhibitors and ischemic stroke mortality. There was no association for former users. Mortality from intracerebral hemorrhage was not associated with use of nonselective NSAIDs or COX-2 inhibitors. Conclusions: Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke. Use of nonselective NSAIDs at time of admission was not associated with mortality from ischemic stroke or intracerebral hemorrhage.
Published: 2020
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40. Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

Author: Jan Haavik, Christine M. Freitag, Amaia Hervás, Estefanía Moreno, Janice M. Fullerton, Andreas Reif, Rune Kleppe, Bru Cormand, Andreas G. Chiocchetti, Eva Rojo-Francàs, Bàrbara Torrico, Nanda Rommelse, Vicent Casadó, Barbara Franke, Sadaf Ghorbani, Claudio Toma, Jan K. Buitelaar, Noèlia Fernàndez-Castillo, Ester Antón-Galindo, Isabel Rueda, Laura Pineda-Cirera, Fundació La Marató de TV3, Fundación Alicia Koplowitz, Ministerio de Economía y Competitividad (España), National Health and Medical Research Council (Australia), European Commission, Generalitat de Catalunya, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Ministerio de Educación, Cultura y Deporte (España), Ministerio de Ciencia, Innovación y Universidades (España), and Agencia Estatal de Investigación (España)
Subjects: Candidate gene, Protein family, Autism, Autisms, YWHAZ, autism, lcsh:Medicine, behavioral disciplines and activities, Article, 14-3-3 gene family, 03 medical and health sciences, transcriptomics, 0302 clinical medicine, Human genetics, mental disorders, common variants, medicine, Gene family, YWHAE, ddc:610, Transcriptomics, 14-3-3 gene family, YWHAE, YWHAZ, autism, common variants, rare variants, schizophrenia, transcriptomics, 030304 developmental biology, Genetics, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genètica humana, business.industry, Common variants, lcsh:R, rare variants, Rare variants, General Medicine, medicine.disease, 3. Good health, schizophrenia, Autism spectrum disorder, Schizophrenia, Esquizofrènia, Autisme, business, 030217 neurology & neurosurgery
Abstract: The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia., Financial support was received from Fundació La Marató de TV3 (092010), Fundación Alicia Koplowitz, AGAUR (2017SGR738, 2017SGR1497), the Spanish Ministerio de Economía y Competitividad with FEDER funds (SAF2015-68341-R, SAF2017-87629-R, RTI2018-100968-B-I00) and the Australian National Medical and Health Research Council (NHMRC) Project Grant 1063960 and 1066177, and Program Grant 1037196. The research leading to these results also received funding from the European Union H2020 Program (H2020/2014-2020) under grant agreements 667302 (CoCA) and 643051 (MiND). B. Torrico was supported by AGAUR (Generalitat de Catalunya), E. Antón-Galindo by the Ministerio de Economía y Competitividad (Spanish Government), N. Fernàndez-Castillo by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and L. Pineda-Cirera by the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/ 03867). C. Toma was supported by the European Union (Marie Curie, PIEF-GA-2009-254930) and currently is a recipient of a ‘Ramón y Cajal’ fellowship (RyC2018-024106-I) from the Spanish MINECO. J.M. Fullerton was supported by the Janette Mary O’Neil Research Fellowship.
Published: 2020
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41. An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes

Author: Alexander L. Gerlach, Volker Arolt, Christiane A. Pané-Farré, Peter Zwanzger, Jens Plag, Heike Weber, Winfried Rief, Miriam A. Schiele, Ann-Cathrine Berking, Christiane Thiel, Thomas Lang, Paul Pauli, Tilo Kircher, Thomas Fydrich, Benjamin Straube, Hans-Ulrich Wittchen, Marcel Romanos, Alfons O. Hamm, Lydia Fehm, Andreas Reif, Christian Baumann, Andreas Ströhle, Jürgen Deckert, Swantje Notzen, Katharina Domschke, Georg W. Alpers, and Raffael Kalisch
Subjects: 0301 basic medicine, Generalized anxiety disorder, Methyltransferase, media_common.quotation_subject, Single-nucleotide polymorphism, Anxiety, DNA Methyltransferase 3A, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, DNA (Cytosine-5-)-Methyltransferases, Biological Psychiatry, media_common, business.industry, Panic disorder, DNA Methylation, medicine.disease, Anxiety Disorders, Minor allele frequency, Psychiatry and Mental health, 030104 developmental biology, Phenotype, Neurology, Anxiety sensitivity, Panic Disorder, Neurology (clinical), medicine.symptom, Worry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation—DNA methyltransferases (DNMTs)—has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.
Published: 2020

42. 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
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43. Genetic variability of GLRB impact cognitive behavioral therapy response in panic disorder

Author: U. Wittchen, Alfons O. Hamm, Paul Pauli, Christiane A. Pané-Farré, Georg W. Alpers, Andreas Reif, Juergen Deckert, Thomas Fydrich, Winfried Rief, Andreas Ströhle, Heike Weber, Lydia Fehm, I Heinig, Thomas Lang, A Arolt, Tilo Kircher, and Alexander L. Gerlach
Subjects: Cognitive behavioral therapy, business.industry, Panic disorder, medicine.medical_treatment, Medicine, Genetic variability, business, medicine.disease, Clinical psychology
Published: 2020
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44. Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families

Author: Fermín Mayoral, Fabio Rivas, Jesus Haro González, Franziska Degenhardt, Julian Hecker, Fermin Perez Perez, Marcella Rietschel, Michael Bauer, Margot Albus, Markus M. Nöthen, Sascha B. Fischer, Susana Gil Flores, Francisco del Río Noriega, Mehdi Pirooznia, Stefan Herms, Jana Strohmaier, Stephanie H. Witt, Fernando S. Goes, Margitta Borrmann-Hassenbach, Anna Maaser-Hecker, Sugirthan Sivalingam, Sven Cichon, Lorena M. Schenk, Georg Auburger, Andreas Reif, Fabian Streit, María González, Francisco J. Cabaleiro Fabeiro, Peter Nürnberg, Jose Guzman-Parra, Andreas J. Forstner, Holger Thiele, Guillermo Orozco Diaz, Andrea Pfennig, Céline S. Reinbold, Johannes Schumacher, Per Hoffmann, [Forstner,AJ, Schumacher,J] Centre for Human Genetics, University of Marburg, Marburg, Germany. [Forstner,AJ, Schenk,LM, Maaser-Hecker,A, Sivalingam,S, Degenhardt,F, Schumacher,J, Herms,S, Hoffmann,P, Nöthen,MM, Cichon,S] Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. [Forstner,AJ, Fischer,SB, Reinbold,CS, Cichon,S] Department of Biomedicine, University of Basel, Basel, Switzerland. [Forstner,AJ] Department of Psychiatry (UPK), University of Basel, Basel, Switzerland. [Fischer,SB, Cichon,S] Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. [Strohmaier,J, Streit,F, Witt,SH, Rietschel,M] Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. [Strohmaier,J] SRH University Heidelberg, Academy for Psychotherapy, Heidelberg, Germany. [Reinbold,CS] Center for Lifespan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Oslo, Norway. [Hecker,J] Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [Thiele,H, Nürnberg,P] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [Guzman-Parra,J, González,MJ] Department of Mental Health, University Regional Hospital of Málaga, Institute of Biomedicine of Málaga (IBIMA), Málaga, Spain. [Orozco Diaz,G] Unidad de Gestión Clínica del Dispositivo de Cuidados Críticos y Urgencias del Distrito Sanitario Málaga - Coin- Gudalhorce, Málaga, Spain. [Auburger,G] Experimental Neurology, Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany. [Albus,M, Borrmann-Hassenbach,M]Isar Amper Klinikum München Ost, kbo, Haar, Germany. [Gil Flores,S] Department of Mental Health, University Hospital of Reina Sofia, Cordoba, Spain. [Cabaleiro Fabeiro,FJ] Department of Mental Health, Hospital of Jaén, Jaén, Spain. [del Río Noriega,F] Department of Mental Health, Hospital of Jerez de la Frontera, Jerez de la Frontera, Spain. [Perez Perez,F] Department of Mental Health, Hospital of Puerto Real, Cádiz, Spain. [Haro González,J] Department of Mental Health, Hospital Punta de Europa, Algeciras, Spain. [Rivas,F, Mayoral,F] Department of Psychiatry, Carlos Haya Regional University Hospital, Malaga, Spain. [Bauer,M, Pfennig,A] Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. [Reif,A] Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany. [Hoffmann,P, Cichon,S] Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany. [Pirooznia,M, Goes,FS] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA, The study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A/01ZX1614A to M.M.N. Forstner et al. Translational Psychiatry (2020) 10:57 Page 8 of 10 and S.C., grant 01ZX1314G/01ZX1614G to M.R.) and through ERA-NET NEURON, 'SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation' (01EW1810 to MR). The study was also supported by the German Research Foundation (DFG, grant FOR2107, RI908/11-1 and RI908/11–2 to M.R., and NO246/10-1 and NO 246/10-2 to M.M.N.), and the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation.
Subjects: Candidate gene, Bipolar Disorder, Psychiatry and Psychology::Mental Disorders::Mood Disorders::Affective Disorders, Psychotic::Bipolar Disorder [Medical Subject Headings], Neuropsiquiatría, Disease, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Germany, Exome, Exome sequencing, Genetics, 0303 health sciences, Trastorno bipolar, Predisposición genética a la enfermedad, Neuropsychiatry, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], 3. Good health, Pedigree, Psychiatry and Mental health, Schizophrenia, Phenomena and Processes::Genetic Phenomena::Inheritance Patterns::Penetrance [Medical Subject Headings], Psychiatry and Psychology::Mental Disorders::Mental Disorders Diagnosed in Childhood::Child Development Disorders, Pervasive::Autistic Disorder [Medical Subject Headings], Biology, Molecular neuroscience, Article, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Exome [Medical Subject Headings], lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Exome Sequencing, medicine, Psychiatry and Psychology::Mental Disorders::Schizophrenia and Disorders with Psychotic Features::Schizophrenia [Medical Subject Headings], Humans, Genetic Predisposition to Disease, Bipolar disorder, ddc:610, Allele, Gene, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Secuenciación del exoma completo, Whole exome sequencing, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], medicine.disease, Geographical Locations::Geographic Locations::Europe::Germany [Medical Subject Headings], Autism, 030217 neurology & neurosurgery, RGS Proteins
Abstract: Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25–38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.
Published: 2020
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45. Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures

Author: Bru Cormand, Bàrbara Torrico, Nina Roth Mota, Marieke Klein, Andreas Reif, Barbara Franke, Alejandro Arias Vasquez, Noèlia Fernàndez-Castillo, and Geert Poelmans
Subjects: Dopamine, Genome-wide association study, Bioinformatics, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Genetics research, mental disorders, medicine, Genetics, Attention deficit hyperactivity disorder, Humans, ADHD, Circadian rhythm, Obesity, Gene, 030304 developmental biology, Pharmacology, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Putamen, Dopaminergic, medicine.disease, Phenotype, Comorbidity, Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, Behavioural genetics, Obesitat, Trastorns per dèficit d'atenció amb hiperactivitat en els adults, Attention deficit disorder with hyperactivity in adults, business, Body mass index, 030217 neurology & neurosurgery, Genètica, Signal Transduction
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD–BMI and ADHD–obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD–BMI overlapping genes with brain volumes (primary GWAS data N = 10,720–10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the circadian rhythm was associated with BMI (P = 1.28 × 10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD–BMI and ADHD–obesity results. The ADHD–BMI overlapping genes were associated with putamen volume (P = 7.7 × 10−3; replication data P = 3.9 × 10−2)—a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD–obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.
Published: 2020

46. RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior

Author: Andreas Meyer-Lindenberg, Stephen V. Faraone, Noèlia Fernàndez-Castillo, Marjolein M.J. van Donkelaar, Wolfgang Retz, Barbara Franke, Mariliis Vaht, Gabriela Gan, Heike Weber, Andreas Reif, Jaanus Harro, and Bru Cormand
Subjects: 0301 basic medicine, Candidate gene, Neuroimaging, RBFOX1, Genome-wide association study, Biology, Epigenesis, Genetic, A2BP1, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Pharmacology (medical), Transcriptomics, Genetic Association Studies, Biological Psychiatry, Regulator gene, Pharmacology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Aggression, Genetic Variation, medicine.disease, Phenotype, Animal models, Psychiatry and Mental health, 030104 developmental biology, Neurology, Autism spectrum disorder, Epigenetics, RBFOX1 Gene, RNA Splicing Factors, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.
Published: 2020

47. Treating impulsivity with probiotics in adults (PROBIA) : study protocol of a multicenter, double-blind, randomized, placebo-controlled trial

Author: Vanesa Richarte, Ylva Ginsberg, János Réthelyi, István Bitter, Pol Ibañez-Jimenez, Nanda Rommelse, J. Antoni Ramos-Quiroga, Alejandro Arias-Vasquez, Gara Arteaga-Henríquez, Catharina Lavebratt, Tünde Kilencz, Silvia Karina Rosales-Ortiz, Andreas Reif, Silke Matura, and Anne Siegl
Subjects: Male, Synbiotics, Placebo-controlled study, Medicine (miscellaneous), law.invention, Placebos, Study Protocol, 0302 clinical medicine, Randomized controlled trial, law, Multicenter Studies as Topic, Pharmacology (medical), Prospective Studies, Borderline personality disorder, Randomized Controlled Trials as Topic, 0303 health sciences, lcsh:R5-920, Middle Aged, Compulsivity, 3. Good health, Aggression, Treatment Outcome, Compulsive behavior, Female, medicine.symptom, lcsh:Medicine (General), Adult, medicine.medical_specialty, Impulsivity, Adolescent, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, Double-Blind Method, Internal medicine, medicine, Humans, ADHD, 030304 developmental biology, Aged, Nutrition, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Probiotics, medicine.disease, Gastrointestinal Microbiome, Clinical trial, Attention Deficit Disorder with Hyperactivity, Impulsive Behavior, Quality of Life, Microbiome, business, Neurocognitive, 030217 neurology & neurosurgery
Abstract: Background Impulsivity and compulsivity are related to emotional and social maladjustment and often underlie psychiatric disorders. Recently, alterations in microbiota composition have been shown to have implications for brain development and social behavior via the microbiota–gut–brain axis. However, the exact mechanisms are not fully identified. Recent evidence suggests the modulatory effect of synbiotics on gut microbiota and the contribution of these agents in ameliorating symptoms of many psychiatric diseases. To date, no randomized controlled trial has been performed to establish the feasibility and efficacy of this intervention targeting the reduction of impulsivity and compulsivity. We hypothesize that supplementation with synbiotics may be an effective treatment in adults with high levels of impulsivity and/or compulsivity. Methods/design This is a prospective, multicenter, double-blind, randomized controlled trial with two arms: treatment with a synbiotic formula versus placebo treatment. The primary outcome is the response rate at the end of the placebo-controlled phase (response defined as a Clinical Global Impression–Improvement Scale score of 1 or 2 = very much improved or much improved, plus a reduction in the Affective Reactivity Index total score of at least 30% compared with baseline). A total of 180 participants with highly impulsive behavior and a diagnosis of attention deficit/hyperactivity disorder (ADHD) and/or borderline personality disorder, aged 18–65 years old, will be screened at three study centers. Secondary outcome measures, including changes in general psychopathology, ADHD symptoms, neurocognitive function, somatic parameters, physical activity, nutritional intake, and health-related quality of life, will be explored at assessments before, during, and at the end of the intervention. The effect of the intervention on genetics, microbiota, and several blood biomarkers will also be assessed. Gastrointestinal symptoms and somatic complaints will additionally be explored at 1-week follow-up. Discussion This is the first randomized controlled trial to determine the effects of supplementation with synbiotics on reducing impulsive and compulsive behavior. This clinical trial can contribute to explaining the mechanisms involved in the crosstalk between the intestinal microbiome and the brain. If effects can be established by reducing impulsive and compulsive behavior, new cost-effective treatments might become available to these patients. Trial registration ClinicalTrials.gov, NCT03495375. Registered on 26 February 2018.
Published: 2020

48. Variants of the aggression-related RBFOX1 gene in a population representative birth cohort study: aggressiveness, personality and alcohol use disorder

Author: Mariliis Vaht, Kariina Laas, Noèlia Fernàndez-Castillo, Triin Kurrikoff, Margus Kanarik, Stephen V. Faraone, Liina-Mai Tooding, Toomas Veidebaum, Barbara Franke, Andreas Reif, Bru Cormand, and Jaanus Harro
Subjects: lcsh:RC435-571, media_common.quotation_subject, Population, Alcohol use disorder, alcohol use disorder, A2BP1, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Aggressiveness, Human genetics, lcsh:Psychiatry, medicine, gender, Personality, ddc:610, neuroticism, Big Five personality traits, education, RBFOX1, 030304 developmental biology, media_common, 0303 health sciences, education.field_of_study, Extraversion and introversion, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genètica humana, business.industry, Aggression, aggressiveness, medicine.disease, Neuroticism, Psychiatry and Mental health, extraversion, Cohort, medicine.symptom, Agressivitat, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples.Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss–Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied.Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder.Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.
Published: 2020

49. Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2

Author: Niall Mortimer, William H. J. Norton, Viola Stella Palladino, Sarah Kittel-Schneider, Andreas Reif, Annette Schenck, Elisa Dalla Vecchia, and Klaus-Peter Lesch
Subjects: 0301 basic medicine, CNTNAP2, Behavioral phenotypes, Candidate gene, Mouse, Autism Spectrum Disorder, Model system, Review Article, cross-species, Receptors, G-Protein-Coupled, Mice, 0302 clinical medicine, Treatment targets, PARKINSONS-DISEASE, DEFICIT-HYPERACTIVITY DISORDER, GENOME-WIDE ANALYSIS, Autism spectrum disorder, ADGRL3, Zebrafish, Genetics (clinical), BEHAVIORAL PHENOTYPES, Human induced pluripotent stem cells, Psychiatry and Mental health, Drosophila, Psychology, PLURIPOTENT STEM-CELLS, CANDIDATE GENE, MITOCHONDRIAL DYSFUNCTION, Ubiquitin-Protein Ligases, Genome wide analysis, Nerve Tissue Proteins, COPY-NUMBER VARIATION, attention-deficit/hyperactivity disorder, behavioral disciplines and activities, Models, Biological, Cross-species, 03 medical and health sciences, mental disorders, Genetics, medicine, ANTIDEPRESSANT USE, Attention deficit hyperactivity disorder, Animals, Humans, Biological Psychiatry, mouse, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Membrane Proteins, PARK2, DOPAMINERGIC-NEURONS, medicine.disease, zebrafish, human induced pluripotent stem cells, Disease Models, Animal, Attention-deficit/hyperactivity disorder, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, Neuroscience, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 202781.pdf (Publisher’s version ) (Open Access) Animal and cellular models are essential tools for all areas of biological research including neuroscience. Model systems can also be used to investigate the pathophysiology of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this review, we provide a summary of animal and cellular models for three genes linked to ADHD and ASD in human patients - CNTNAP2, ADGRL3, and PARK2. We also highlight the strengths and weaknesses of each model system. By bringing together behavioral and neurobiological data, we demonstrate how a cross-species approach can provide integrated insights into gene function and the pathogenesis of ADHD and ASD. The knowledge gained from transgenic models will be essential to discover and validate new treatment targets for these disorders.
Published: 2018

50. Improving early recognition and intervention in people at increased risk for the development of bipolar disorder: study protocol of a prospective-longitudinal, naturalistic cohort study (Early-BipoLife)

Author: Sarah Kittel-Schneider, Irina Falkenberg, Tilo Kircher, Christoph U. Correll, Cathrin Sauer, Karolina Leopold, Georg Juckel, Michael Bauer, Andreas J. Fallgatter, Andreas Reif, Andrea Pfennig, Steffi Pfeiffer, Christina Berndt, Philipp Ritter, Martin Lambert, Thomas Stamm, Maren Rottmann-Wolf, Julia Martini, Anne Boehme, Felix Bermpohl, Andreas Jansen, and Andreas Bechdolf
Subjects: medicine.medical_specialty, Pediatrics, Neurology, Study Protocols, Bipolar disorder, Early intervention, lcsh:RC321-571, Prodrome, Early recognition, medicine, Young adult, Risk factor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Resilience, business.industry, Antecedent, Prevention, lcsh:QP351-495, medicine.disease, Psychiatry and Mental health, lcsh:Neurophysiology and neuropsychology, Protective, Cohort, Precursor, business, Psychosocial, Cohort study
Abstract: Background Bipolar disorders (BD) belong to the most severe mental disorders, characterized by an early onset and recurrent, severe episodes or a chronic course with poor psychosocial functioning in a proportion of patients. Many patients with BD experience substantial symptomatology months or even years before full BD manifestation. Adequate diagnosis and treatment is often delayed, which is associated with a worse outcome. This study aims to prospectively evaluate and improve early recognition and intervention strategies for persons at-risk for BD. Methods Early-BipoLife is a prospective-longitudinal cohort study of 1419 participants (aged 15–35 years) with at least five waves of assessment over a period of at least 2 years (baseline, 6, 12, 18 and 24 months). A research consortium of ten university and teaching hospitals across Germany conducts this study. The following risk groups (RGs) were recruited: RG I: help-seeking youth and young adults consulting early recognition centres/facilities presenting ≥ 1 of the proposed risk factors for BD, RG II: in-/outpatients with unipolar depressive syndrome, and RG III: in-/outpatients with attention-deficit/hyperactivity disorder (ADHD). The reference cohort was selected from the German representative IMAGEN cohort. Over the study period, the natural course of risk and resilience factors, early symptoms of BD and changes of symptom severity (including conversion to manifest BD) are observed. Psychometric properties of recently developed, structured instruments on potential risk factors for conversion to BD and subsyndromal symptomatology (Bipolar Prodrome Symptom Scale, Bipolar at-risk criteria, EPIbipolar) and biomarkers that potentially improve prediction are investigated. Moreover, actual treatment recommendations are monitored in the participating specialized services and compared to recently postulated clinical categorization and treatment guidance in the field of early BD. Discussion Findings from this study will contribute to an improved knowledge about the natural course of BD, from the onset of first noticeable symptoms (precursors) to fully developed BD, and about mechanisms of conversion from subthreshold to manifest BD. Moreover, these generated data will provide information for the development of evidence-based guidelines for early-targeted detection and preventive intervention for people at risk for BD.
Published: 2019

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