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1. Genetic variation in glutamatergic genes moderates the effects of childhood adversity on brain volume and IQ in treatment-resistant schizophrenia

Author: Suriati Mohamed Saini, Chad A. Bousman, Serafino G. Mancuso, Vanessa Cropley, Tamsyn E. Van Rheenen, Rhoshel K. Lenroot, Jason Bruggemann, Cynthia S. Weickert, Thomas W. Weickert, Suresh Sundram, Ian P. Everall, and Christos Pantelis
Subjects: Psychiatry, RC435-571
Published: 2023
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2. Peripheral NF-κB dysregulation in people with schizophrenia drives inflammation: putative anti-inflammatory functions of NF-κB kinases

Author: Caitlin E. Murphy, Adam K. Walker, Maryanne O’Donnell, Cherrie Galletly, Andrew R. Lloyd, Dennis Liu, Cynthia Shannon Weickert, and Thomas W. Weickert
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p
Published: 2022
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3. Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol

Author: Bodyl A. Brand, Janna N. de Boer, Sebastianus B.J. Oude Ophuis, Margot I.E. Slot, Bieke De Wilde, Kirsten C.E.E.R. Catthoor, Angelique J. Goverde, P. Roberto Bakker, Machteld C. Marcelis, Koen P. Grootens, Jurjen J. Luykx, Sophie M. Heringa, Cynthia Shannon Weickert, Iris E.C. Sommer, and Thomas W. Weickert
Subjects: Antipsychotic medication, Estrogen, Raloxifene, Randomised controlled trial, Schizophrenia, Medicine (General), R5-920
Abstract: Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.
Published: 2020
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4. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder

Author: Danny Boerrigter, Thomas W. Weickert, Rhoshel Lenroot, Maryanne O’Donnell, Cherrie Galletly, Dennis Liu, Martin Burgess, Roxanne Cadiz, Isabella Jacomb, Vibeke S. Catts, Stu G. Fillman, and Cynthia Shannon Weickert
Subjects: Cytokines, Inflammation, Periphery, Schizophrenia, Biotype, Gene expression, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Increases in pro-inflammatory cytokines are found in the brain and blood of people with schizophrenia. However, increased cytokines are not evident in all people with schizophrenia, but are found in a subset. The cytokine changes that best define this subset, termed the “elevated inflammatory biotype”, are still being identified. Methods Using quantitative RT-PCR, we measured five cytokine mRNAs (IL-1β, IL-2 IL-6, IL-8 and IL-18) from peripheral blood of healthy controls and of people with schizophrenia or schizoaffective disorder (n = 165). We used a cluster analysis of the transcript levels to define those with low and those with elevated levels of cytokine expression. From the same cohort, eight cytokine proteins (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, IFNγ and TNFα) were measured in serum and plasma using a Luminex Magpix-based assay. We compared peripheral mRNA and protein levels across diagnostic groups and between those with low and elevated levels of cytokine expression according to our transcription-based cluster analysis. Results We found an overall decrease in the anti-inflammatory IL-2 mRNA (p = 0.006) and an increase in three serum cytokines, IL-6 (p = 0.010), IL-8 (p = 0.024) and TNFα (p
Published: 2017
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5. C-Reactive Protein: Higher During Acute Psychotic Episodes and Related to Cortical Thickness in Schizophrenia and Healthy Controls

Author: Isabella Jacomb, Clive Stanton, Rohini Vasudevan, Hugh Powell, Maryanne O'Donnell, Rhoshel Lenroot, Jason Bruggemann, Ryan Balzan, Cherrie Galletly, Dennis Liu, Cynthia S. Weickert, and Thomas W. Weickert
Subjects: schizophrenia, acute psychosis, c-reactive protein, cortical thickness, inflammation, working memory, Immunologic diseases. Allergy, RC581-607
Abstract: There is increasing evidence for the role of inflammation in schizophrenia, yet the stability of increased peripheral inflammation in acute psychosis and the degree to which peripheral inflammation relates to cortical thickness, a measure of the degree of neuropathology, are unknown. In independent samples, we assessed the peripheral inflammation marker C-reactive protein (CRP) to determine the extent to which: (1) CRP was elevated and stable across admissions for acute psychosis, (2) cognition, daily function and symptom severity are characteristic of chronically ill patients with schizophrenia displaying elevated CRP, and (3) CRP levels predict cortical thickness. Study 1 assessed peripheral CRP (primary outcome) and other blood measures in 174/280 people with acute psychosis while Study 2 assessed peripheral CRP, cognition and cortical thickness (primary outcomes), symptoms, and daily function in 85/97 chronically ill patients with schizophrenia and 71/87 healthy controls. In acute psychosis, CRP and neutrophil-to-lymphocyte ratio were significantly elevated relative to a normal cutoff (with 59.8% of patients having elevated CRP) which remained elevated across admissions. CRP was significantly elevated in 43% of chronically ill patients with schizophrenia compared to 20% in controls. Elevated CRP patients displayed significantly worse working memory and CRP was inversely correlated with cortical thickness in frontal, insula, and temporal brain regions. This work supports the role of inflammation in psychotic illnesses and suggests that use of peripheral markers (e.g., CRP) in conjunction with diagnosis could be used to identify patients with more cortical neuropathology and cognitive deficits.
Published: 2018
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6. Raloxifene Improves Cognition in Schizophrenia: Spurious Result or Valid Effect?

Author: Thomas W. Weickert and Cynthia Shannon Weickert
Subjects: schizophrenia, cognition, raloxifene, selective estrogen receptor modulator, symptom severity, Psychiatry, RC435-571
Published: 2017
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7. Efficacy of Transcranial Direct Current Stimulation to Improve Insight in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Author: Ondine Adam, Martin Blay, Andre R Brunoni, Hsin-An Chang, July S Gomes, Daniel C Javitt, Do-Un Jung, Joshua T Kantrowitz, Sanne Koops, Jean-Pierre Lindenmayer, Ulrich Palm, Robert C Smith, Iris E Sommer, Leandro do Costa Lane Valiengo, Thomas W Weickert, Jérôme Brunelin, and Marine Mondino
Subjects: ANTIPSYCHOTIC MEDICATION, AUDITORY HALLUCINATIONS, SPECTRUM DISORDERS, NEGATIVE SYMPTOMS, Transcranial Direct Current Stimulation, Transcranial Magnetic Stimulation, tDCS, DOUBLE-BLIND, Psychiatry and Mental health, Treatment Outcome, DEFICITS, neuromodulation, ILLNESS AWARENESS, Schizophrenia, QUALITY, Humans, psychosis, MEDICATION ADHERENCE, CLINICAL-TRIALS, Randomized Controlled Trials as Topic
Abstract: Background and Hypothesis Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients. Study Design PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted. Study Results Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of −0.46 (95% CI [−0.78; −0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant. Conclusions Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation.
Published: 2023

8. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author: Dick Schijven, Merel C. Postema, Masaki Fukunaga, Junya Matsumoto, Kenichiro Miura, Sonja M. C. de Zwarte, Neeltje E. M. van Haren, Wiepke Cahn, Hilleke E. Hulshoff Pol, René S. Kahn, Rosa Ayesa-Arriola, Víctor Ortiz-García de la Foz, Diana Tordesillas-Gutierrez, Javier Vázquez-Bourgon, Benedicto Crespo-Facorro, Dag Alnæs, Andreas Dahl, Lars T. Westlye, Ingrid Agartz, Ole A. Andreassen, Erik G. Jönsson, Peter Kochunov, Jason M. Bruggemann, Stanley V. Catts, Patricia T. Michie, Bryan J. Mowry, Yann Quidé, Paul E. Rasser, Ulrich Schall, Rodney J. Scott, Vaughan J. Carr, Melissa J. Green, Frans A. Henskens, Carmel M. Loughland, Christos Pantelis, Cynthia Shannon Weickert, Thomas W. Weickert, Lieuwe de Haan, Katharina Brosch, Julia-Katharina Pfarr, Kai G. Ringwald, Frederike Stein, Andreas Jansen, Tilo T. J. Kircher, Igor Nenadić, Bernd Krämer, Oliver Gruber, Theodore D. Satterthwaite, Juan Bustillo, Daniel H. Mathalon, Adrian Preda, Vince D. Calhoun, Judith M. Ford, Steven G. Potkin, Jingxu Chen, Yunlong Tan, Zhiren Wang, Hong Xiang, Fengmei Fan, Fabio Bernardoni, Stefan Ehrlich, Paola Fuentes-Claramonte, Maria Angeles Garcia-Leon, Amalia Guerrero-Pedraza, Raymond Salvador, Salvador Sarró, Edith Pomarol-Clotet, Valentina Ciullo, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Gianfranco Spalletta, Stijn Michielse, Therese van Amelsvoort, Erin W. Dickie, Aristotle N. Voineskos, Kang Sim, Simone Ciufolini, Paola Dazzan, Robin M. Murray, Woo-Sung Kim, Young-Chul Chung, Christina Andreou, André Schmidt, Stefan Borgwardt, Andrew M. McIntosh, Heather C. Whalley, Stephen M. Lawrie, Stefan du Plessis, Hilmar K. Luckhoff, Freda Scheffler, Robin Emsley, Dominik Grotegerd, Rebekka Lencer, Udo Dannlowski, Jesse T. Edmond, Kelly Rootes-Murdy, Julia M. Stephen, Andrew R. Mayer, Linda A. Antonucci, Leonardo Fazio, Giulio Pergola, Alessandro Bertolino, Covadonga M. Díaz-Caneja, Joost Janssen, Noemi G. Lois, Celso Arango, Alexander S. Tomyshev, Irina Lebedeva, Simon Cervenka, Carl M. Sellgren, Foivos Georgiadis, Matthias Kirschner, Stefan Kaiser, Tomas Hajek, Antonin Skoch, Filip Spaniel, Minah Kim, Yoo Bin Kwak, Sanghoon Oh, Jun Soo Kwon, Anthony James, Geor Bakker, Christian Knöchel, Michael Stäblein, Viola Oertel, Anne Uhlmann, Fleur M. Howells, Dan J. Stein, Henk S. Temmingh, Ana M. Diaz-Zuluaga, Julian A. Pineda-Zapata, Carlos López-Jaramillo, Stephanie Homan, Ellen Ji, Werner Surbeck, Philipp Homan, Simon E. Fisher, Barbara Franke, David C. Glahn, Ruben C. Gur, Ryota Hashimoto, Neda Jahanshad, Eileen Luders, Sarah E. Medland, Paul M. Thompson, Jessica A. Turner, Theo G. M. van Erp, Clyde Francks, Neurology, and Child and Adolescent Psychiatry / Psychology
Subjects: subcortical, Neuroinformatics, Multidisciplinary, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Schizophrenia, brain imaging, cortical, asymmetry
Abstract: Contains fulltext : 291574.pdf (Publisher’s version ) (Open Access) Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Published: 2023
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9. Correction: Obesity and brain structure in schizophrenia – ENIGMA study in 3021 individuals

Author: Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Du Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadić, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Antonín Škoch, Filip Spaniel, Frederike Stein, Patrik Švancer, Diana Tordesillas-Gutiérrez, Juan Undurraga, Javier Vázquez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. van Erp, Jessica A. Turner, and Tomas Hajek
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, Molecular Biology
Published: 2023
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10. Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions

Author: Jason M. Bruggemann, Chad A. Bousman, Vaidy Swaminathan, Rhoshel K. Lenroot, Christos Pantelis, Cynthia Shannon Weickert, Vanessa Cropley, Hayley F. North, Avril Pereira, Suresh Sundram, Andrew Zalesky, and Thomas W. Weickert
Subjects: Oncology, medicine.medical_specialty, Psychosis, business.industry, Cognition, General Medicine, Neuropathology, medicine.disease, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Schizophrenia, Internal medicine, Diabetes mellitus, Cohort, medicine, Biomarker (medicine), Pharmacology (medical), Effects of sleep deprivation on cognitive performance, business, 030217 neurology & neurosurgery, Biological Psychiatry
Abstract: While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naive patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p
Published: 2021
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11. Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals

Author: Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Du Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadić, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Antonín Škoch, Filip Spaniel, Frederike Stein, Patrik Švancer, Diana Tordesillas-Gutiérrez, Juan Undurraga, Javier Vázquez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. van Erp, Jessica A. Turner, Tomas Hajek, European Commission, European Research Council, German Research Foundation, Agencia Nacional de Investigación y Desarrollo (Chile), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), and Alexander von Humboldt Foundation
Subjects: Medical and Health Sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Clinical Research, 2.1 Biological and endogenous factors, Humans, Obesity, Aetiology, Molecular Biology, Nutrition, Psychiatry, Depressive Disorder, Depressive Disorder, Major, Psychology and Cognitive Sciences, Neurosciences, Major, Brain, Biological Sciences, Serious Mental Illness, Magnetic Resonance Imaging, Brain Disorders, Psychiatry and Mental health, Mental Health, Schizophrenia, Biomedical Imaging
Abstract: Hajek, Tomas: et al., Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia., NAC et al. were supported by the Agencia Nacional de Investigación y Desarrollo, Chile, through its grants PIA ACT1414, ANID-PIA-ACT 192064, and FONDECYT regular 1200601. This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). The NUDZ and IKEM sites were supported by funding from the Ministry of Health of the Czech Republic (16-32791A, NU20-04-00393) and conceptual development of research organization (Institute for Clinical and Experimental Medicine – IKEM, IN 00023001). This work was also funded by the German Research Foundation (DFG grant FOR2107, KI588/14-1 and FOR2107, KI588/14-2 to TTJK, Marburg, Germany), as well as, the Alexander von Humboldt Foundation, EU and Deutsche Forschungsgemeinschaft (DFG), grants NE2254/1-2, NE2254/3-1, NE2254/4-1. Additional support provided by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/05028), and the Singapore Bioimaging Consortium (RP C009/2006) research grants awarded to KS. EW was supported by the European Union’s Horizon 2020 research and innovation programme (Early Cause, grant n° 848158). Funding for TWW was provided by the National Health and Medical Research Council Australia Project Grant 568807; New South Wales Health, University of New South Wales, Neuroscience Research Australia and the Schizophrenia Research Institute. GD’s research was funded by the European Research Council 677467 and Science Foundation Ireland 16/ERCS/3787. VDC was supported by NIH R01MH118695. PMT was supported by NIMH grant R01MH116147. Lastly, TH was supported by funding from the Canadian Institutes of Health Research (103703, 106469 and 142255), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to TH, Brain & Behavior Research Foundation (formerly NARSAD); 2007 Young Investigator and 2015 Independent Investigator Awards to TH.
Published: 2022
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12. The impact of smoking status on cognition and brain morphology in schizophrenia spectrum disorders

Author: Cynthia Shannon Weickert, Suresh Sundram, Jason M. Bruggemann, Andrew Zalesky, Christos Pantelis, Tamsyn E Van Rheenen, Thomas W. Weickert, Vanessa Cropley, Elysha Ringin, and Chad A. Bousman
Subjects: Cigarette Smoker, business.industry, Smoking, Brain morphometry, Australia, Brain, Cognition, Moderation, Magnetic Resonance Imaging, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Schizophrenia, Humans, Medicine, Cognitive skill, Effects of sleep deprivation on cognitive performance, Cognitive decline, business, 030217 neurology & neurosurgery, Applied Psychology, Clinical psychology, Schizophrenia spectrum
Abstract: BackgroundCigarette smoking is associated with worse cognition and decreased cortical volume and thickness in healthy cohorts. Chronic cigarette smoking is prevalent in schizophrenia spectrum disorders (SSD), but the effects of smoking status on the brain and cognition in SSD are not clear. This study aimed to understand whether cognitive performance and brain morphology differed between smoking and non-smoking individuals with SSD compared to healthy controls.MethodsData were obtained from the Australian Schizophrenia Research Bank. Cognitive functioning was measured in 299 controls and 455 SSD patients. Cortical volume, thickness and surface area data were analysed from T1-weighted structural scans obtained in a subset of the sample (n = 82 controls, n = 201 SSD). Associations between smoking status (cigarette smoker/non-smoker), cognition and brain morphology were tested using analyses of covariance, including diagnosis as a moderator.ResultsNo smoking by diagnosis interactions were evident, and no significant differences were revealed between smokers and non-smokers across any of the variables measured, with the exception of a significantly thinner left posterior cingulate in smokers compared to non-smokers. Several main effects of smoking in the cognitive, volume and thickness analyses were initially significant but did not survive false discovery rate (FDR) correction.ConclusionsDespite the general absence of significant FDR-corrected findings, trend-level effects suggest the possibility that subtle smoking-related effects exist but were not uncovered due to low statistical power. An investigation of this topic is encouraged to confirm and expand on our findings.
Published: 2021
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13. Altered levels of immune cell adhesion molecules are associated with memory impairment in schizophrenia and healthy controls

Author: Cynthia Shannon Weickert, Ryan P. Balzan, Thomas W. Weickert, Dennis Liu, Maryanne O'Donnell, Cherrie Galletly, Vibeke S. Catts, and Helen Q Cai
Subjects: 0301 basic medicine, medicine.medical_treatment, Immunology, Integrin, Inflammation, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Immune system, Cell Adhesion, Humans, Medicine, Prefrontal cortex, biology, Endocrine and Autonomic Systems, business.industry, Cell adhesion molecule, Intercellular Adhesion Molecule-1, medicine.disease, Lymphocyte Function-Associated Antigen-1, 030104 developmental biology, Cytokine, Schizophrenia, biology.protein, medicine.symptom, business, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Intracellular
Abstract: Increased cytokines and increased intercellular adhesion molecule-1 (ICAM1) found in the schizophrenia prefrontal cortex and in the blood may relate to cognitive deficits. Endothelial ICAM1 regulates immune cell trafficking into the brain by binding to integrins located on the surface of leukocytes. Whether the circulating levels of the main ICAM1 adhesion partners, lymphocyte-function associated antigen-1 (LFA1) and complement receptor 3 (CR3), both integrins, are altered in schizophrenia is unknown. Gene expressions of ICAM1, LFA1 and CR3 were measured in leukocytes from 86 schizophrenia patients and 77 controls. Participants were also administered cognitive testing to determine the extent to which cognitive ability was related to molecular measures of leukocyte adhesion. This cohort was previously stratified into inflammatory subgroups based on circulating cytokine mRNAs; thus, gene expressions were analysed by diagnosis and by inflammatory subgroups. Previously measured plasma ICAM1 protein was elevated in "high inflammation" schizophrenia compared to both "high" and "low inflammation" controls while ICAM1 mRNA was unchanged in leukocytes. LFA1 mRNA was decreased and CR3 mRNA was increased in leukocytes from people with schizophrenia compared to controls. LFA1 mRNA levels were positively correlated with working memory and elevated soluble ICAM1 was negatively correlated with verbal memory in schizophrenia. Altogether, some of the cognitive deficits in schizophrenia may be associated with altered expression of molecules that regulate immune cell trafficking.
Published: 2020
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14. Schizophrenia: Human and Animal Studies

Author: Ahmed Moustafa, Thomas W. Weickert, and Dorota Frydecka
Published: 2022
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15. 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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16. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. 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Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. 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O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards 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Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.
Subjects: LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract: Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551
Published: 2022
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17. White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs

Author: Stanley V. Catts, Chad A. Bousman, Alex Fornito, Paul Klauser, Simon T.E. Baker, Patricia T. Michie, Rhoshel K. Lenroot, Bryan J. Mowry, Carmel M. Loughland, Andrew Zalesky, Cynthia Shannon Weickert, Luca Cocchi, Vaughan J. Carr, Thomas W. Weickert, Janice M. Fullerton, Christos Pantelis, Ulrich Schall, Frans Henskens, Paul E. Rasser, and Vanessa Cropley
Subjects: Adult, Male, Adolescent, Schizoaffective disorder, Corpus callosum, Gyrus Cinguli, Corpus Callosum, White matter, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Thalamus, Neural Pathways, Fractional anisotropy, mental disorders, Connectome, medicine, Humans, Cingulum (brain), Aged, Cerebral Cortex, Regular Article, Middle Aged, medicine.disease, White Matter, 030227 psychiatry, Psychiatry and Mental health, Diffusion Tensor Imaging, medicine.anatomical_structure, Psychotic Disorders, Schizophrenia, Female, Nerve Net, Psychology, Neuroscience, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles.
Published: 2021

18. Transcriptional changes in the stress pathway are related to symptoms in schizophrenia and to mood in schizoaffective disorder

Author: D Sinclair, Cynthia Shannon Weickert, Maryanne O'Donnell, Thomas W. Weickert, Dennis Liu, Cynthia H. Lee, and Cherrie Galletly
Subjects: Adult, Male, medicine.medical_specialty, Transcription, Genetic, Schizoaffective disorder, BAG1, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, RNA, Messenger, Biological Psychiatry, Depression (differential diagnoses), Positive and Negative Syndrome Scale, business.industry, Middle Aged, medicine.disease, 030227 psychiatry, Affect, Psychiatry and Mental health, Endocrinology, Mood, Psychotic Disorders, Schizophrenia, Anxiety, Female, FKBP5, medicine.symptom, business, Stress, Psychological, 030217 neurology & neurosurgery, Signal Transduction
Abstract: Altered levels of stress-signalling transcripts have been identified in post-mortem brains of people with schizophrenia, and since stress effects may be expressed throughout the body, there should be similar changes in peripheral cells. However, the extent to which these markers are altered in peripheral white blood cells of people with schizophrenia is not known. Furthermore, how peripheral cortisol and stress-related mRNA are associated with negative symptom severity and emotional states in people with schizophrenia versus schizoaffective disorder has not been determined. Whole blood samples were collected from 86 patients with either schizophrenia or schizoaffective disorder (56 people with schizophrenia and 30 people with schizoaffective disorder), and 77 healthy controls. Total RNA was isolated, cDNA was synthesized, and stress-signalling mRNA levels (for NR3C1, FKBP5, FKBP4, PTGES3 and BAG1) were determined. Stress and symptom severity scores were measured by the Depression, Anxiety and Stress Scale, and the Positive and Negative Syndrome Scale, respectively. We found increased FKBP5 mRNA, Z(156) = 2.5, p = 0.01, decreased FKBP4 mRNA, t(155) = 3.5, p ≤ 0.001, and decreased PTGES3 mRNA, t(153) = 3.0, p ≤ 0.01, in schizophrenia and schizoaffective disorder cohorts combined compared to healthy controls. Stress-related peripheral mRNA levels were differentially correlated with negative emotional states and symptom severity in schizoaffective disorder (β's = –0.45–0.56, p's = 0.05–0.001) and schizophrenia (β's = −0.34–0.38, p's = 0.04–0.03), respectively. Therefore, molecules of the stress-signalling pathway appear to differentially contribute to clinical features of schizophrenia versus schizoaffective disorder.
Published: 2019
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19. Evidence for Network-Based Cortical Thickness Reductions in Schizophrenia

Author: Ian P. Everall, Cynthia Shannon Weickert, Eleni P. Ganella, Stephen J. Wood, Cassandra Wannan, Thomas W. Weickert, Cali F. Bartholomeusz, M. Mallar Chakravarty, Vanessa Cropley, Patrick D. McGorry, Jason M. Bruggemann, Christos Pantelis, Dennis Velakoulis, Andrew Zalesky, and Chad A. Bousman
Subjects: Adult, Male, structural covariance, Psychosis, Nerve net, Neuroimaging, Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Cerebral Cortex, structural neuroimaging, brain connectivity, cortical thickness, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, schizophrenia, Psychiatry and Mental health, Cross-Sectional Studies, medicine.anatomical_structure, Schizophrenia, Structural covariance, Cerebral cortex, Case-Control Studies, network, Female, Nerve Net, Neuroscience, 030217 neurology & neurosurgery
Abstract: Objective: Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distribution of cortical thickness reductions across the cortex, and, specifically, that cortico-cortical connectivity between loci with these reductions would be exceptionally strong and form an interconnected network. This hypothesis was tested in three cross-sectional schizophrenia cohorts: first-episode psychosis, chronic schizophrenia, and treatment-resistant schizophrenia. Methods: Structural brain images were acquired for 70 patients with first-episode psychosis, 153 patients with chronic schizophrenia, and 47 patients with treatment-resistant schizophrenia and in matching healthy control groups (N=57, N=168, and N=54, respectively). Cortical thickness was compared between the patient and respective control groups at 148 regions spanning the cortex. Structural connectivity strength between pairs of cortical regions was quantified with structural covariance analysis. Connectivity strength between regions with cortical thickness reductions was compared with connectivity strength between 5,000 sets of randomly chosen regions to establish whether regions with reductions were interconnected more strongly than would be expected by chance. Results: Significant (false discovery rate corrected) and widespread cortical thickness reductions were found in the chronic schizophrenia (79 regions) and treatment-resistant schizophrenia (106 regions) groups, with more circumscribed reductions in the first-episode psychosis group (34 regions). Cortical thickness reductions with the largest effect sizes were found in frontal, temporal, cingulate, and insular regions. In all cohorts, both the patient and healthy control groups showed significantly increased structural covariance between regions with cortical thickness reductions compared with randomly selected regions. Conclusions: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia. This finding, replicated in three distinct schizophrenia cohorts, suggests that the effect is robust and independent of illness stage.
Published: 2019
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20. Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia

Author: Cynthia Shannon Weickert, Ryan P. Balzan, Maryanne O'Donnell, Gilles J. Guillemin, Jochen Kindler, Rhoshel K. Lenroot, Thomas W. Weickert, Chai K. Lim, Cherrie Galletly, Danny Boerrigter, Jason M. Bruggemann, Dennis Liu, and Kelly R. Jacobs
Subjects: Adult, Male, medicine.medical_specialty, Kynurenine pathway, medicine.medical_treatment, Prefrontal Cortex, 610 Medicine & health, Kynurenic Acid, Article, Proinflammatory cytokine, Young Adult, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Kynurenic acid, Internal medicine, mental disorders, medicine, Humans, Attention, Neurotransmitter, Prefrontal cortex, Molecular Biology, Kynurenine, Chemistry, Middle Aged, Dorsolateral prefrontal cortex, Psychiatry and Mental health, medicine.anatomical_structure, Endocrinology, Cytokine, Schizophrenia, Cytokines, Female, Inflammation Mediators
Abstract: The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.
Published: 2019
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21. Peripheral complement is increased in schizophrenia and inversely related to cortical thickness

Author: David Lloyd, Maryanne O'Donnell, Andrew R. Lloyd, Cynthia Shannon Weickert, Helen Q Cai, Jason M. Bruggemann, Ellen Ji, Cherrie Gallety, Dennis Liu, Danny Boerrigter, Thomas W. Weickert, and Rhoshel K. Lenroot
Subjects: medicine.medical_specialty, Immunology, Inflammation, Complement factor I, Behavioral Neuroscience, Superior temporal gyrus, Transverse temporal gyrus, Internal medicine, medicine, Humans, RNA, Messenger, Cerebral Cortex, Fusiform gyrus, Endocrine and Autonomic Systems, business.industry, C4A, Complement System Proteins, medicine.disease, Magnetic Resonance Imaging, Complement system, Endocrinology, Schizophrenia, Cytokines, medicine.symptom, business
Abstract: Background There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. Method Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. Results There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. Conclusions Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows for the first time that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in schizophrenia. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.
Published: 2021

22. 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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23. Cortisol-dehydroepiandrosterone ratios are inversely associated with hippocampal and prefrontal brain volume in schizophrenia

Author: David J. Handelsman, Ellen Ji, Cynthia Shannon Weickert, Maryanne O'Donnell, Reena Desai, Cherrie Galletly, Thomas W. Weickert, Tertia D. Purves-Tyson, Rhoshel K. Lenroot, Dennis Liu, Christopher J. White, University of Zurich, and Ji, Ellen
Subjects: endocrine system, medicine.medical_specialty, Hydrocortisone, Endocrinology, Diabetes and Metabolism, Dehydroepiandrosterone, Hippocampus, 610 Medicine & health, Neuropathology, Hippocampal formation, 03 medical and health sciences, 2738 Psychiatry and Mental Health, 0302 clinical medicine, Dorsolateral Prefrontal Cortex, Endocrinology, Internal medicine, polycyclic compounds, medicine, Humans, skin and connective tissue diseases, Biological Psychiatry, business.industry, Endocrine and Autonomic Systems, Organ Size, medicine.disease, Pathophysiology, 030227 psychiatry, 1310 Endocrinology, Dorsolateral prefrontal cortex, Diabetes and Metabolism, 2712 Endocrinology, Diabetes and Metabolism, 2807 Endocrine and Autonomic Systems, Psychiatry and Mental health, medicine.anatomical_structure, Schizophrenia, Case-Control Studies, 10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics, Brain size, business, human activities, 2803 Biological Psychiatry, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery
Abstract: While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.
Published: 2021
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24. Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol

Author: Jurjen J. Luykx, Angelique J. Goverde, Iris E. C. Sommer, Sophie M. Heringa, Sebastianus B.J. Oude Ophuis, P. Roberto Bakker, Bieke De Wilde, Kirsten C.E.E.R. Catthoor, Bodyl A Brand, Machteld Marcelis, Margot I. E. Slot, Thomas W. Weickert, Janna de Boer, Koen P. Grootens, Cynthia Shannon Weickert, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Movement Disorder (MD), Clinical Cognitive Neuropsychiatry Research Program (CCNP), RS: MHeNs - R2 - Mental Health, and Psychiatrie & Neuropsychologie
Subjects: BNSS, Brief Negative Symptom scale, FSH, follicle stimulating hormone, SAE, Serious Adverse Event, SST, serum separator tube, ZNA, Ziekenhuis Netwerk Antwerpen, AF, alkaline phosphatase, law.invention, DNA, Deoxyribonucleic acid, DOUBLE-BLIND, 0302 clinical medicine, ULN, upper limit of normal, ADJUNCTIVE TREATMENT, Randomized controlled trial, law, LDL, low-density lipoprotein, iMTA-PCQ, institute for Medical Technology Assessment's Productivity Cost Questionnaire, SUSAR, Suspected Unexpected Serious Adverse Reaction, Medicine, 030212 general & internal medicine, DSMB, Data Safety Monitoring Board, Antipsychotic medication, ANOVA, analysis of variance, APTT, activated partial thrombin time, SCALE, Randomised controlled trial, education.field_of_study, lcsh:R5-920, Positive and Negative Syndrome Scale, GGzE, Geestelijke Gezondheidszorg Eindhoven, SHBG, sex hormone-binding globulin, eGFR, estimated glomerular filtration rate, General Medicine, EQ-5D-5L, Euro Quality of Life 5 Dimensions 5 Levels, UMCU, University Medical Center Utrecht, UMCG, University Medical Center Groningen, POSTMENOPAUSAL WOMEN, Selective estrogen receptor modulator, Schizophrenia, PSP, Personal and Social Performance, SMD, standard mean difference, RELIABILITY, CRP, C-reactive protein, PERSISTENT SYMPTOMS, ASAT, aspartate aminotransferase, WOCBP, Women of child bearing potential, lcsh:Medicine (General), AE, Adverse event, medicine.drug, IMCJE, International Committee of Medical Journal Editors, medicine.medical_specialty, SEX-DIFFERENCES, ICH-GCP, the International Conference on Harmonization – Good Clinical Practice, Population, HDL, high-density lipoprotein, SERM, selective estrogen receptor modulator, Placebo, Article, 03 medical and health sciences, ALAT, alanine aminotransferase, TALD, Thought And Language Disorder scale, Internal medicine, Raloxifene, β-HCG, beta-human chorionic gonadotropin, NEGATIVE SYNDROME, MINI, Mini International Neuropsychiatric Interview Plus, education, iMTA-MCQ, institute for Medical Technology Assessment's Medical Consumption Questionnaire, LHT, lithium heparin tube, psychotic disorder NOS, psychotic disorder not otherwise specified, Pharmacology, BDI, Beck's Depression Inventory, business.industry, PERFORMANCE, medicine.disease, Estrogen, ANSS, positive and negative syndrome scale, Adjunctive treatment, QALYs, Quality Adjusted Life Years, DHEA, dehydroepiandrosterone, GGZ Centraal, Psychiatric Center Geestelijke Gezondheidszorg Centraal, RvA, Reinier van Arkel Institute for Mental Health Care, COGNITION, BACS, Brief Assessment of Cognition in Schizophrenia, business, 030217 neurology & neurosurgery, SCT, sodium citrate tube
Abstract: Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.
Published: 2020

25. Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions

Author: Hayley F, North, Jason, Bruggemann, Vanessa, Cropley, Vaidy, Swaminathan, Suresh, Sundram, Rhoshel, Lenroot, Avril M, Pereira, Andrew, Zalesky, Chad, Bousman, Christos, Pantelis, Thomas W, Weickert, and Cynthia, Shannon Weickert
Subjects: Inflammation, C-Reactive Protein, Cognition, Psychotic Disorders, Schizophrenia, Humans, Magnetic Resonance Imaging, Biomarkers
Abstract: While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naïve patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p 0.006E-10). In schizophrenia, increased CRP was mildly associated with worse performance in attention, controlling for age, sex and education (R =- 0.15, p = 0.001). Further, increased CRP was associated with reduced cortical thickness in three regions related to attention: the caudal middle frontal, the pars opercularis and the posterior cingulate cortices, which remained significant after controlling for multiple comparisons (all p 0.05). Together, these findings indicate that increased peripheral inflammation is associated with deficits in cognitive function and brain structure in schizophrenia, especially reduced attention and reduced cortical thickness in associated brain regions. Using CRP as a biomarker of peripheral inflammation in persons with schizophrenia may help to identify vulnerable patients and those that may benefit from adjunctive anti-inflammatory treatments.
Published: 2020

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

Author: Niamh Mullins, Andreas J. Forstner, Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Børte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bækvad-Hansen, Nicholas Bass, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Franziska Degenhardt, Srdjan Djurovic, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, Valentina Escott-Price, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Joel Gelernter, Marianne Giørtz Pedersen, Ian R. Gizer, Scott D. Gordon, Katherine Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Per Hoffmann, Peter A. Holmans, Laura Huckins, Stéphane Jamain, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, James L. Kennedy, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Maria Koromina, Thorsten M. Kranz, Henry R. Kranzler, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Phil H. Lee, Shawn E. Levy, Catrin Lewis, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Sigurdur H. Magnusson, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Steven A. McCarroll, Nathaniel W. McGregor, Peter McGuffin, James D. McKay, Helena Medeiros, Sarah E. Medland, Vincent Millischer, Grant W. Montgomery, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, James B. Potash, Digby Quested, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, John P. Rice, Fabio Rivas, Margarita Rivera, Julian Roth, Panos Roussos, Douglas M. Ruderfer, Cristina Sánchez-Mora, Eva C. Schulte, Fanny Senner, Sally Sharp, Paul D. Shilling, Engilbert Sigurdsson, Lea Sirignano, Claire Slaney, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, Christine Søholm Hansen, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, John S. Strauss, Beata Świątkowska, Chikashi Terao, Thorgeir E. Thorgeirsson, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, James T. R. Walters, Stephanie H. Witt, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, Lea Zillich, HUNT All-In Psychiatry, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Gulja Babadjanova, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Douglas H. R. Blackwood, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley Catts, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans Henskens, Jan Hillert, Kyung Sue Hong, David M. Hougaard, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, Ian Jones, Lisa A. Jones, René S. Kahn, John R. Kelsoe, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Nicholas G. Martin, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Patricia Michie, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Ketil J. Oedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Chris Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Roy H. Perlis, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Cynthia Shannon Weickert, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Thomas W. Weickert, Thomas Werge, Naomi R. Wray, John-Anker Zwart, Joanna M. Biernacka, John I. Nurnberger, Sven Cichon, Howard J. Edenberg, Eli A. Stahl, Andrew McQuillin, Arianna Di Florio, Roel A. Ophoff, and Ole A. Andreassen
Subjects: Genetics, 0303 health sciences, Druggability, Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, medicine, Bipolar disorder, Synaptic signaling, Prefrontal cortex, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2020
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27. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Niamh, Mullins, Andreas J, Forstner, Kevin S, O'Connell, Brandon, Coombes, Jonathan R I, Coleman, Zhen, Qiao, Thomas D, Als, Tim B, Bigdeli, Sigrid, Børte, Julien, Bryois, Alexander W, Charney, Ole Kristian, Drange, Michael J, Gandal, Saskia P, Hagenaars, Masashi, Ikeda, Nolan, Kamitaki, Minsoo, Kim, Kristi, Krebs, Georgia, Panagiotaropoulou, Brian M, Schilder, Laura G, Sloofman, Stacy, Steinberg, Vassily, Trubetskoy, Bendik S, Winsvold, Hong-Hee, Won, Liliya, Abramova, Kristina, Adorjan, Esben, Agerbo, Mariam, Al Eissa, Diego, Albani, Ney, Alliey-Rodriguez, Adebayo, Anjorin, Verneri, Antilla, Anastasia, Antoniou, Swapnil, Awasthi, Ji Hyun, Baek, Marie, Bækvad-Hansen, Nicholas, Bass, Michael, Bauer, Eva C, Beins, Sarah E, Bergen, Armin, Birner, Carsten, Bøcker Pedersen, Erlend, Bøen, Marco P, Boks, Rosa, Bosch, Murielle, Brum, Ben M, Brumpton, Nathalie, Brunkhorst-Kanaan, Monika, Budde, Jonas, Bybjerg-Grauholm, William, Byerley, Murray, Cairns, Miquel, Casas, Pablo, Cervantes, Toni-Kim, Clarke, Cristiana, Cruceanu, Alfredo, Cuellar-Barboza, Julie, Cunningham, David, Curtis, Piotr M, Czerski, Anders M, Dale, Nina, Dalkner, Friederike S, David, Franziska, Degenhardt, Srdjan, Djurovic, Amanda L, Dobbyn, Athanassios, Douzenis, Torbjørn, Elvsåshagen, Valentina, Escott-Price, I Nicol, Ferrier, Alessia, Fiorentino, Tatiana M, Foroud, Liz, Forty, Josef, Frank, Oleksandr, Frei, Nelson B, Freimer, Louise, Frisén, Katrin, Gade, Julie, Garnham, Joel, Gelernter, Marianne, Giørtz Pedersen, Ian R, Gizer, Scott D, Gordon, Katherine, Gordon-Smith, Tiffany A, Greenwood, Jakob, Grove, José, Guzman-Parra, Kyooseob, Ha, Magnus, Haraldsson, Martin, Hautzinger, Urs, Heilbronner, Dennis, Hellgren, Stefan, Herms, Per, Hoffmann, Peter A, Holmans, Laura, Huckins, Stéphane, Jamain, Jessica S, Johnson, Janos L, Kalman, Yoichiro, Kamatani, James L, Kennedy, Sarah, Kittel-Schneider, James A, Knowles, Manolis, Kogevinas, Maria, Koromina, Thorsten M, Kranz, Henry R, Kranzler, Michiaki, Kubo, Ralph, Kupka, Steven A, Kushner, Catharina, Lavebratt, Jacob, Lawrence, Markus, Leber, Heon-Jeong, Lee, Phil H, Lee, Shawn E, Levy, Catrin, Lewis, Calwing, Liao, Susanne, Lucae, Martin, Lundberg, Donald J, MacIntyre, Sigurdur H, Magnusson, Wolfgang, Maier, Adam, Maihofer, Dolores, Malaspina, Eirini, Maratou, Lina, Martinsson, Manuel, Mattheisen, Steven A, McCarroll, Nathaniel W, McGregor, Peter, McGuffin, James D, McKay, Helena, Medeiros, Sarah E, Medland, Vincent, Millischer, Grant W, Montgomery, Jennifer L, Moran, Derek W, Morris, Thomas W, Mühleisen, Niamh, O'Brien, Claire, O'Donovan, Loes M, Olde Loohuis, Lilijana, Oruc, Sergi, Papiol, Antonio F, Pardiñas, Amy, Perry, Andrea, Pfennig, Evgenia, Porichi, James B, Potash, Digby, Quested, Towfique, Raj, Mark H, Rapaport, J Raymond, DePaulo, Eline J, Regeer, John P, Rice, Fabio, Rivas, Margarita, Rivera, Julian, Roth, Panos, Roussos, Douglas M, Ruderfer, Cristina, Sánchez-Mora, Eva C, Schulte, Fanny, Senner, Sally, Sharp, Paul D, Shilling, Engilbert, Sigurdsson, Lea, Sirignano, Claire, Slaney, Olav B, Smeland, Daniel J, Smith, Janet L, Sobell, Christine, Søholm Hansen, Maria, Soler Artigas, Anne T, Spijker, Dan J, Stein, John S, Strauss, Beata, Świątkowska, Chikashi, Terao, Thorgeir E, Thorgeirsson, Claudio, Toma, Paul, Tooney, Evangelia-Eirini, Tsermpini, Marquis P, Vawter, Helmut, Vedder, James T R, Walters, Stephanie H, Witt, Simon, Xi, Wei, Xu, Jessica Mei Kay, Yang, Allan H, Young, Hannah, Young, Peter P, Zandi, Hang, Zhou, Lea, Zillich, Rolf, Adolfsson, Ingrid, Agartz, Martin, Alda, Lars, Alfredsson, Gulja, Babadjanova, Lena, Backlund, Bernhard T, Baune, Frank, Bellivier, Susanne, Bengesser, Wade H, Berrettini, Douglas H R, Blackwood, Michael, Boehnke, Anders D, Børglum, Gerome, Breen, Vaughan J, Carr, Stanley, Catts, Aiden, Corvin, Nicholas, Craddock, Udo, Dannlowski, Dimitris, Dikeos, Tõnu, Esko, Bruno, Etain, Panagiotis, Ferentinos, Mark, Frye, Janice M, Fullerton, Micha, Gawlik, Elliot S, Gershon, Fernando S, Goes, Melissa J, Green, Maria, Grigoroiu-Serbanescu, Joanna, Hauser, Frans, Henskens, Jan, Hillert, Kyung Sue, Hong, David M, Hougaard, Christina M, Hultman, Kristian, Hveem, Nakao, Iwata, Assen V, Jablensky, Ian, Jones, Lisa A, Jones, René S, Kahn, John R, Kelsoe, George, Kirov, Mikael, Landén, Marion, Leboyer, Cathryn M, Lewis, Qingqin S, Li, Jolanta, Lissowska, Christine, Lochner, Carmel, Loughland, Nicholas G, Martin, Carol A, Mathews, Fermin, Mayoral, Susan L, McElroy, Andrew M, McIntosh, Francis J, McMahon, Ingrid, Melle, Patricia, Michie, Lili, Milani, Philip B, Mitchell, Gunnar, Morken, Ole, Mors, Preben Bo, Mortensen, Bryan, Mowry, Bertram, Müller-Myhsok, Richard M, Myers, Benjamin M, Neale, Caroline M, Nievergelt, Merete, Nordentoft, Markus M, Nöthen, Michael C, O'Donovan, Ketil J, Oedegaard, Tomas, Olsson, Michael J, Owen, Sara A, Paciga, Chris, Pantelis, Carlos, Pato, Michele T, Pato, George P, Patrinos, Roy H, Perlis, Danielle, Posthuma, Josep Antoni, Ramos-Quiroga, Andreas, Reif, Eva Z, Reininghaus, Marta, Ribasés, Marcella, Rietschel, Stephan, Ripke, Guy A, Rouleau, Takeo, Saito, Ulrich, Schall, Martin, Schalling, Peter R, Schofield, Thomas G, Schulze, Laura J, Scott, Rodney J, Scott, Alessandro, Serretti, Cynthia, Shannon Weickert, Jordan W, Smoller, Hreinn, Stefansson, Kari, Stefansson, Eystein, Stordal, Fabian, Streit, Patrick F, Sullivan, Gustavo, Turecki, Arne E, Vaaler, Eduard, Vieta, John B, Vincent, Irwin D, Waldman, Thomas W, Weickert, Thomas, Werge, Naomi R, Wray, John-Anker, Zwart, Joanna M, Biernacka, John I, Nurnberger, Sven, Cichon, Howard J, Edenberg, Eli A, Stahl, Andrew, McQuillin, Arianna, Di Florio, Roel A, Ophoff, and Ole A, Andreassen
Subjects: Major Histocompatibility Complex, Multifactorial Inheritance, Bipolar Disorder, Phenotype, Genome, Human, Risk Factors, Case-Control Studies, Quantitative Trait Loci, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2020

28. Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Author: Raquel E. Gur, Geor Bakker, Erick J. Canales-Rodríguez, Edith Pomarol-Clotet, Cynthia Shannon Weickert, Neda Jahanshad, Ulrich Schall, Theodore D. Satterthwaite, Vince D. Calhoun, Aleix Solanes, Frans Henskens, Antonin Skoch, Sara Llufriu, Anthony A. James, Michael Stäblein, Aurora Bonvino, Kun Yang, Cyril Höschl, Christos Pantelis, Carlos López-Jaramillo, Stefan Ehrlich, S. Sarró, Stefan Kaiser, Udo Dannlowski, Fengmei Fan, Wenhao Jiang, Paul E. Rasser, Patricia T. Michie, Julian A Pineda-Zapata, Zhiren Wang, Russell T. Shinohara, Eduard Vieta, Rodney J. Scott, Tilo Kircher, Andrea Weideman, Melissa J. Green, Nicola G. Cascella, Jason M. Bruggemann, Dominik Grotegerd, Viola Oertel, Janice M. Fullerton, Theo G.M. van Erp, Stanley V. Catts, Hong Xiang, Murray J. Cairns, Jingxu Chen, Paul M. Thompson, Adrian Preda, Elisabeth Solana, Fleur M. Howells, Godfrey D. Pearlson, Anne Uhlmann, Peter Kochunov, Christian Knöchel, Fabrizio Piras, Fude Yang, Je-Yeon Yun, Yunlong Tan, Henk Temmingh, Covadonga M. Díaz-Caneja, Peter J. McKenna, Carmel M. Loughland, Alexander Tomyshev, Kang Sim, Joost Janssen, Kaleda Vg, Ruben C. Gur, Akira Sawa, Ana M. Díaz-Zuluaga, Annabella Di Giorgio, Nerisa Banaj, Jessica A. Turner, Vanessa Cropley, Gavin Cooper, Raymond Salvador, Marc L. Seal, Rhoshel K. Lenroot, Stefan S. du Plessis, Yoichiro Takayanagi, Federica Piras, Jun Soo Kwon, Dan J. Stein, Anton Albajes-Eizagirre, David C. Glahn, Vaughan J. Carr, Thomas W. Weickert, Francesca Assogna, Lydia Fortea, Joaquim Radua, Igor Nenadic, Alessandro Bertolino, Margaret D. King, Eloy Martinez-Heras, Gianfranco Spalletta, Paul A. Tooney, Tim Hahn, Hua Guo, Stefan Borgwardt, Yann Quidé, Bryan J. Mowry, Shuping Tan, Axel Krug, Therese van Amelsvoort, Elliot Hong, Irina V. Lebedeva, David Tomecek, Daniel H. Wolf, Celso Arango, Clara Alloza, Matthias Kirschner, Dana Nguyen, Kaiser, Stefan, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), and RS: MHeNs - R2 - Mental Health
Subjects: Male, Computer science, Image Processing, Medical and Health Sciences, 0302 clinical medicine, Computer-Assisted, Image Processing, Computer-Assisted, ENIGMA Consortium collaborators, Cerebral Cortex, 05 social sciences, Brain, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Mental Health, Neurology, Schizophrenia, Biomedical Imaging, Female, Algorithms, Adult, medicine.medical_specialty, Mega-analysis, Cognitive Neuroscience, Neuroimaging, SURFACE-BASED ANALYSIS, 050105 experimental psychology, Article, Cortical thickness, lcsh:RC321-571, 03 medical and health sciences, Young Adult, Physical medicine and rehabilitation, Meta-Analysis as Topic, medicine, Humans, 0501 psychology and cognitive sciences, Cortical surface, ddc:610, Gray matter, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neurology & Neurosurgery, Volume, Psychology and Cognitive Sciences, Neurosciences, medicine.disease, Brain Disorders, Data set, 030217 neurology & neurosurgery, Diagnosis of schizophrenia
Abstract: Altres ajuts: SRB: The Australian Schizophrenia Research Bank (ASRB) was supported by the National Health and Medical Research Council of Australia (NHMRC) (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief Investigators for ASRB were Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C. We thank Loughland, C., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CP was supported by NHMRC Senior Principal Research Fellowships (IDs: 628386 & 1105825); GC was supported by the Schizophrenia Research Institute utilizing infrastructure funding from the New South Wales Ministry of Health and New South Wales Ministry of Trade and Investment (Australia); JMF was supported by NHMRC project grant (1063960) and the Janette Mary O'Neil Research Fellowship; MJG was supported by NHMRC as an R.D. Wright Biomedical Career Development Fellow (1061875). MJC was supported by NHMRC Senior Research Fellowship (1121474). CASSI: CSW is funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CIAM: The CIAM study (FMH - PI) was supported by the University Research Committee, University of Cape Town and South African funding bodies National Research Foundation and Medical Research Council. COBRE: The COBRE dataset and investigators were supported by NIH grants R01EB006841 & P20GM103472, as well as NSF grant 1539067. JT (senior author) and VDC are supported by 5R01MH094524. JMS is supported by R01 AA021771 and P50 AA022534. EONCKS: This work was supported by a New Partnership for Africa's Development (NEPAD) grant through the Department of Science and Technology of South Africa, the Medical Research Council of South Africa (grant number 65174). ESO: The ESO study was funded by NPU I - LO1611 and Ministry of Health, Czech Republic - Conceptual Development of Research Organization 00023001 (IKEM). FIDMAG/Project: This work was supported by the Catalan Government and several grants from the Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, 'Investing in your future'): Miguel Servet Research Contracts and Research Project Grants. FOR2107 Marburg: The FOR2107 Marburg study was funded by the German Research Foundation (DFG), Tilo Kircher (speaker FOR2107; DFG grant numbers KI588/14-1, KI588/14-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). FOR2107 Muenster: The FOR2107 Muenster study was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). TH was supported by grants from the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). Frankfurt: MRI was performed at the Frankfurt Brain Imaging Center, supported by the German Research Council (DFG) and the German Ministry for Education and Research (BMBF; Brain Imaging Center Frankfurt/Main, DLR 01GO0203). GIPSI: This study was supported by Colciencias PRISMA-U.T. Huilong1 & Huilong2: This study was funded by the National Natural Science Foundation of China (81761128021; 31671145; 81401115; 81401133), Beijing Municipal Science and Technology Commission grant (Z141107002514016) and Beijing Natural Science Foundation(7162087, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: This study was funded by Project Grants from the Australian National Health and Medical Research Council of Australia (NHMRC; APP630471 and APP1081603), the Macquarie University's Australian Research Council Centre of Excellence in Cognition and its Disorders (CE110001021). Johns Hopkins: Supported by National Institutes of Health Grant Nos. MH-092443, MH-094268 (Silvio O. Conte Center), MH-105660, and MH-107730; foundation grants from Stanley, RUSK/S-R, and NARSAD/Brain and Behavior Research Foundation. Madrid: Supported by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III, co-financed by ERDF Funds from the European Commission, "A way of making Europe", CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds and European Union Seventh Framework Program and H2020 Program; Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. MPRC1 & MPRC2: Support was received from NIH grants U01MH108148, 2R01EB015611, R01MH112180, R01DA027680, R01MH085646, P50MH103222 and T32MH067533, a State of Maryland contract (M00B6400091) and NSF grant (1620457). OLIN: The Olin study was supported by NIH grants R37MH43375 and R01MH074797. Oxford: The Oxford study MRC G0500092. SLF Rome: Support from the Italian Ministry of Health grants RC-12-13-14-15-16-17-18-19/A. RSCZ: RSCZ data collection was supported by RFBR 15-06-05758 grant. SCORE: This study was supported in part by grant 3232BO_119382 from the Swiss National Science Foundation. We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy Study was supported in part by grant No. SNF 3200-057216/1, ext./2, ext./3. Singapore: This study was supported by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/11003), and the Singapore Bioimaging Consortium (RP C-009/2006) research grants awarded to KS. SNUH: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant no. 2013R1A2A1A03071089 and 2017M3C7A1029610). UCISZ: The UCISZ study was supported by the National Institutes of Mental Health grant number R21MH097196 to TGMvE. UCISZ data were processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. UNIBA: The UNIBA study was supported by grant funding from the Italian Ministry of Health (PE-2011-02347951). UNIMAAS: The study was supported by Dutch Organization for Health Research and Development (ZonMw 91112002) and a personal grant to Thérèse van Amelsvoort (ZonMw-VIDI: 91712394). The data was collected in a clinical trial registered in the Dutch clinical trial registry under ID: NTR5094 (http://www.trialregister.nl). UPenn: This study was supported by the National Institute of Mental Health grants MH064045, MH 60722, MH019112, MH085096 (DHW), and R01MH112847 (RTS and TDS). Zurich: This study was supported by the Swiss National Science Foundation (105314_140351 to S.K.). Matthias Kirschner acknowledges support from the National Bank Fellowship (McGill University) and the Swiss National Foundation (P2SKP3_178175). Research reported in this publication was also supported by the following National Institutes of Health grants: U54 EB020403 to PMT, R01 MH116147, U24 RR21992, R21MH097196, and TR000153 to TGMvE, S10 OD023696 and R01EB015611 to PK, T32 AG058507and 5T32 MH073526 to CRKC, R01 MH117601 to NJ, ENIGMA's NIH Big Data to Knowledge (BD2K) initiative U54 EB020403, ENIGMA Sex Differences R01MH116147, and ENIGMA-COINSTAC: Advanced World-wide Transdiagnostic Analysis of Valence System Brain Circuits R01MH121246. A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).
Published: 2020

29. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author: Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Genetic correlation, Genome-wide association study, Mood Disorder, Bipolar disorder, Population, BF, Genomics, Major depressive disorder, Affective disorder, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Animals, ddc:610, education, Depression (differential diagnoses), Biological Psychiatry, 030304 developmental biology, Genetic association, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, Animal, business.industry, Risk Factor, medicine.disease, 3. Good health, Affective disorders, 030104 developmental biology, Mood, Mood disorders, RC0321, Biological psychiatry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.
Published: 2020
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30. Neutrophil-lymphocyte ratio - a simple, accessible measure of inflammation, morbidity and prognosis in psychiatric disorders?

Author: Dennis Liu, Thomas W. Weickert, Cherrie Galletly, Cynthia Shannon Weickert, Nicholas Myles, and Zlatan Zulfic
Subjects: Inflammation, medicine.medical_specialty, business.industry, Neutrophils, Lymphocyte, Mental Disorders, fungi, Measure (physics), Prognosis, Psychiatry and Mental health, Leukocyte Count, medicine.anatomical_structure, Inflammatory marker, Medicine, Humans, Narrative review, Lymphocytes, medicine.symptom, Morbidity, business, Psychiatry, Biomarkers
Abstract: Objective: A narrative review to describe the utility of the neutrophil-lymphocyte ratio (NLR) as an inflammatory marker in psychiatric and non-psychiatric disorders and to discuss the potential role of NLR in psychiatric research. Conclusions: NLR is inexpensive and readily available using division of two measures obtained on routine blood testing. NLR is elevated in a number of psychiatric disorders. It can predict morbidity and mortality in a wide range of non-psychiatric conditions, but this has not been confirmed in psychiatric conditions. It can be calculated in large, pre-existing datasets to investigate clinical correlates of inflammatory processes. NLR may have a future role in identifying patients with an inflammatory phenotype who could benefit from adjunctive anti-inflammatory medications.
Published: 2020

31. Exploring the moderating effects of dopaminergic polymorphisms and childhood adversity on brain morphology in schizophrenia-spectrum disorders

Author: Suresh Sundram, Thomas W. Weickert, Rhoshel K. Lenroot, Tamsyn E Van Rheenen, Jason M. Bruggemann, Cynthia Shannon Weickert, Christos Pantelis, Serafino G. Mancuso, Vanessa Cropley, Cassandra R. Hoffmann, Chad A. Bousman, and Andrew Zalesky
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Genotype, Dopamine, Neuroscience (miscellaneous), Hippocampus, Schizoaffective disorder, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, mental disorders, medicine, Humans, Radiology, Nuclear Medicine and imaging, Bipolar disorder, Polymorphism, Genetic, business.industry, Putamen, Dopaminergic, Brain morphometry, Brain, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, Dorsolateral prefrontal cortex, Psychiatry and Mental health, medicine.anatomical_structure, Adult Survivors of Child Adverse Events, Schizophrenia, Regression Analysis, Female, Gene-Environment Interaction, Schizophrenic Psychology, business, 030217 neurology & neurosurgery
Abstract: Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.
Published: 2018
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32. Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation

Author: Thomas W. Weickert, Cynthia Shannon Weickert, Vibeke S. Catts, Cherrie Galletly, Helen Q Cai, Maree J. Webster, Dennis Liu, and Maryanne O'Donnell
Subjects: 0301 basic medicine, Male, Molecular biology, Gene Expression, Occludin, 0302 clinical medicine, Prefrontal cortex, Microglia, Brain, Middle Aged, Intercellular Adhesion Molecule-1, Frontal Lobe, Psychiatry and Mental health, medicine.anatomical_structure, Frontal lobe, Schizophrenia, Blood-Brain Barrier, Encephalitis, Female, medicine.symptom, Adult, medicine.medical_specialty, Prefrontal Cortex, Inflammation, Blood–brain barrier, behavioral disciplines and activities, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Immune system, Internal medicine, mental disorders, medicine, Humans, Endothelium, business.industry, Macrophages, Endothelial Cells, medicine.disease, 030104 developmental biology, Endocrinology, Psychotic Disorders, Astrocytes, business, 030217 neurology & neurosurgery, Biomarkers, Neuroscience
Abstract: Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood–brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into “high inflammation” and “low inflammation” subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The “high inflammation” schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both “low inflammation” schizophrenia and “low inflammation” control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in “high inflammation” schizophrenia compared to both “low inflammation” schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of “high inflammation” schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.
Published: 2018

33. Probabilistic association learning in schizophrenia

Author: Thomas W. Weickert
Subjects: Cognitive Neuroscience, medicine.medical_treatment, Schizophrenia (object-oriented programming), Probabilistic logic, Hippocampus, behavioral disciplines and activities, 030227 psychiatry, 03 medical and health sciences, Behavioral Neuroscience, Psychiatry and Mental health, 0302 clinical medicine, medicine.anatomical_structure, Neuroimaging, medicine, Antipsychotic, Association (psychology), Prefrontal cortex, Psychology, 030217 neurology & neurosurgery, Parahippocampal gyrus, Cognitive psychology
Abstract: Probabilistic association learning is a form of non-declarative learning that involves the gradual acquisition of cue-outcome associations based on feedback and is dependent on frontal-striatal activity in healthy adults. Prefrontal cortex dysfunction has been established in schizophrenia; however, striatal dysfunction is often ignored or attributed to antipsychotic effects. Probabilistic association learning is typically impaired in schizophrenia. Neuroimaging studies have shown reduced frontal-striatal activity in patients with schizophrenia; although a proportion of patients with schizophrenia who can learn the probabilistic associations utilize an alternate neural network that includes the parahippocampal gyrus/hippocampus. Many studies support the hypothesis that probabilistic association learning impairment can be an intrinsic characteristic of the illness. Studies have begun to identify the molecular mechanisms underpinning probabilistic association learning deficits in schizophrenia which include the influence of dopamine, neurotrophins and estrogen.
Published: 2018
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34. Widespread Volumetric Reductions in Schizophrenia and Schizoaffective Patients Displaying Compromised Cognitive Abilities

Author: Avril Pereira, Suresh Sundram, Chad A. Bousman, Tamsyn E Van Rheenen, Thomas W. Weickert, Andrew Zalesky, Jason M. Bruggemann, Roshel K Lenroot, Christos Pantelis, Danielle Weinberg, Vanessa Cropley, Ruth Wells, and Cynthia Shannon Weickert
Subjects: Adult, Male, medicine.medical_specialty, Psychosis, Schizoaffective disorder, Audiology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, medicine, Humans, Cognitive Dysfunction, Bipolar disorder, Cerebral Cortex, business.industry, Neuropsychology, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Psychotic Disorders, Schizophrenia, Brain size, Female, Occipital lobe, business, 030217 neurology & neurosurgery, Regular Articles
Abstract: Objective Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. Method 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. Results Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. Conclusions This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.
Published: 2017
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35. Accelerated Gray and White Matter Deterioration With Age in Schizophrenia

Author: Rhoshel K. Lenroot, Cynthia Shannon Weickert, Maria A Di Biase, Andrew Zalesky, Avril Pereira, Suresh Sundram, Jason M. Bruggemann, Paul Klauser, Chad A. Bousman, Vanessa Cropley, Christos Pantelis, and Thomas W. Weickert
Subjects: Adult, Male, medicine.medical_specialty, Psychosis, Schizoaffective disorder, Audiology, computer.software_genre, Brain mapping, White matter, Young Adult, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Reference Values, Voxel, Fractional anisotropy, medicine, Humans, Gray Matter, Psychiatry, Aged, Brain Mapping, medicine.diagnostic_test, Age Factors, Neurodegenerative Diseases, Magnetic resonance imaging, Organ Size, Middle Aged, medicine.disease, White Matter, 030227 psychiatry, Psychiatry and Mental health, medicine.anatomical_structure, Psychotic Disorders, Disease Progression, Schizophrenia, Anisotropy, Female, Schizophrenic Psychology, Psychology, computer, Gray (horse), 030217 neurology & neurosurgery
Abstract: Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age.Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference.Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident.The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.
Published: 2017
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36. M62. PERIPHERAL INFLAMMATION MARKERS IDENTIFY SUBSET OF PATIENTS WITH SCHIZOPHRENIA AND RELATED PSYCHOSES WHO HAVE INTELLECTUAL DECLINE FROM PREMORBID LEVELS

Author: Cynthia Shannon Weickert, Dennis Liu, Ryan P. Balzan, Seetha Ramanathan, Rhoshel K. Lenroot, Cherrie Galletly, and Thomas W. Weickert
Subjects: Psychiatry and Mental health, Poster Session II, AcademicSubjects/MED00810, business.industry, Schizophrenia (object-oriented programming), Immunology, Medicine, Inflammation, medicine.symptom, business, Peripheral
Abstract: Background Higher inflammation has been identified in a substantial subset of both high-risk and chronically ill patients with schizophrenia and related psychoses and this may account for some of the heterogeneity of the schizophrenia. There is also much heterogeneity in cognitive deficits related to schizophrenia with some patients showing a marked decline from premorbid intellectual levels while others show little change from either normal or low intellect. However, the relationship between intellectual change with the illness onset and inflammation in schizophrenia has not been established. Methods Here, we report the assessment of two common markers of inflammation from two independent samples of generally chronically ill patients with schizophrenia and related psychoses (one sample of 73 patients versus 70 healthy controls from Sydney, NSW, Australia and one sample of 297 patients from Syracuse, NY, USA). Peripheral venous blood samples were collected from all patients and blood markers of inflammation (C-Reactive Protein, CRP, and Neutrophil to Lymphocyte Ratio, NLR) were assayed using standard procedures. Assessment of premorbid and current intellectual abilities were obtained from the Sydney cohort of patients. Results Grouping the patients and controls from the Sydney sample into those with elevated (> 3 mg/L) versus normal (< 3 mg/L) CRP levels revealed 42% of the patients versus 20% of the healthy controls had elevated CRP (Chi Square = 9.16, p = .002) and further evidence of inflammation with an elevated mean NLR of 2.5. The frequency of peripheral inflammation was confirmed by the independent sample from Syracuse in which 39% of the patients (n= 115) had an elevated NLR above a cutoff score for normal of 2.2 which was consistent with the Sydney sample. Patients from the Sydney sample who had an elevated CRP also had a significant mean 15-point IQ decline from premorbid IQ levels, whereas the patients with CRP levels within normal limits did not show a statistically significant drop in IQ from premorbid levels (mean IQ decline 7.6 points). Healthy controls with normal CRP had no IQ change (0.0 points) and healthy controls with elevated CRP has a slight, non-significant IQ decline (mean 2.3 points). Discussion Thus, our study showed supportive evidence of elevated peripheral inflammation markers in subgroups of chronically ill patients with schizophrenia from two independent samples and a link between marked intellectual decline from premorbid levels and current peripheral inflammation in one chronically ill subgroup of patients with schizophrenia suggesting a role for inflammation in the cognitive impairment of a substantial proportion (40%) of patients with schizophrenia.
Published: 2020
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37. The effects of a muscarinic receptor 1 gene variant on cortical thickness and surface area in schizophrenia

Author: Rhoshel K. Lenroot, Chad A. Bousman, Vanessa Cropley, Sean P. Carruthers, Caroline Gurvich, Jason M. Bruggemann, Susan L. Rossell, Christos Pantelis, and Thomas W. Weickert
Subjects: Adult, Male, Linkage disequilibrium, medicine.medical_specialty, Adolescent, Neuroscience (miscellaneous), Single-nucleotide polymorphism, Grey matter, Biology, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Wisconsin Card Sorting Test, Internal medicine, Genotype, medicine, Humans, Radiology, Nuclear Medicine and imaging, Gray Matter, Cerebral Cortex, Receptor, Muscarinic M1, Genetic Variation, Organ Size, Muscarinic acetylcholine receptor M1, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, medicine.anatomical_structure, Endocrinology, Cerebral cortex, Schizophrenia, Female, 030217 neurology & neurosurgery
Abstract: Individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor gene have been reported to perform less well on the Wisconsin Card Sorting Test and demonstrate reduced grey matter volume in the right precentral gyrus. We investigated if rs2067477 genotype variation influenced cortical thickness and cortical surface area in a sample of 176 schizophrenia/schizoaffective disorder patients using FreeSurfer. We were unable to detect any significant changes to either surface-based measure of brain structure across genotype. Future studies should expand the focus and include SNPs that are in linkage disequilibrium with rs2067477.
Published: 2018
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38. Reward and punishment learning in schizophrenia and bipolar disorder

Author: Eid Abohamza, Manal Ali, Ahmed A. Moustafa, and Thomas W. Weickert
Subjects: Adult, Male, Psychosis, Hamilton depression scale, Bipolar Disorder, Punishment (psychology), education, Neuropsychological Tests, behavioral disciplines and activities, Task (project management), 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Punishment, Reward, medicine, Humans, Learning, In patient, Bipolar disorder, 030304 developmental biology, 0303 health sciences, Probabilistic logic, Middle Aged, medicine.disease, Schizophrenia, Case-Control Studies, Female, Probability Learning, Psychology, psychological phenomena and processes, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Prior studies on reward learning deficits in psychiatric disorders have used probabilistic learning tasks, making it unclear whether impairment is due to the probabilistic nature of the task rather than reward processing. In this study, we tested probabilistic vs. deterministic reward and punishment learning in healthy controls and three patient groups: schizophrenia (SZ), psychotic bipolar disorder (BD), and nonpsychotic BD. Experimental results show that reward learning was impaired in patients with SZ and patients with psychotic BD in the probabilistic learning task compared to patients with nonpsychotic BD and healthy controls. In contrast, punishment learning in the probabilistic task was impaired in patients with nonpsychotic BD compared to the other patient groups and healthy controls. There were no significant differences among all groups in the deterministic learning task scores. We also found that Hamilton Depression Scale scores negatively correlated with probabilistic learning performance. Our data may suggest that reward learning impairment may be due to the nature of the task as well as subtype of BD.
Published: 2019

39. The Impact of Childhood Adversity on Cognitive Development in Schizophrenia

Author: Cynthia Shannon Weickert, Ruth Wells, Thomas W. Weickert, Vaidy Swaminathan, Vanessa Cropley, Christos Pantelis, Danielle Weinberg, Rhoshel K. Lenroot, Avril Pereira, Jason M. Bruggemann, Suresh Sundram, Andrew Zalesky, Chad A. Bousman, and Isabella Jacomb
Subjects: Adult, Male, Psychosis, media_common.quotation_subject, Human Development, Verbal abuse, behavioral disciplines and activities, Neglect, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Adverse Childhood Experiences, mental disorders, medicine, Cognitive development, Humans, Cognitive Dysfunction, Functional ability, Family history, media_common, Australia, Cognition, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Adult Survivors of Child Adverse Events, Psychotic Disorders, Schizophrenia, Female, Psychology, 030217 neurology & neurosurgery, Clinical psychology, Regular Articles
Abstract: Childhood adversity, such as physical, sexual, and verbal abuse, as well as neglect and family conflict, is a risk factor for schizophrenia. Such adversity can lead to disruptions of cognitive function during development, undermining intellectual capabilities and academic achievement. Schizophrenia is a neurodevelopmental disorder that is associated with cognitive impairments that may become evident during childhood. The Australian Schizophrenia Research Bank database comprises a large community cohort (N = 1169) in which we previously identified 3 distinct cognitive groups among people with schizophrenia: (1) Compromised, current, and estimated premorbid cognitive impairment; (2) Deteriorated, substantial decline from estimated premorbid function; and (3) Preserved, performing in the normal cognitive range without decline. The compromised group displayed the worst functional and symptom outcomes. Here, we extend our previous work by assessing the relationship among these categories of cognitive abilities and reported childhood adversity in 836 patients and healthy controls. Exploratory factor analysis of the Childhood Adversity Questionnaire revealed 3 factors (lack of parental involvement; overt abuse; family breakdown and hardship). People with schizophrenia reported significantly more childhood adversity than healthy controls on all items and factors. People with schizophrenia in the compromised group reported significantly more lack of parental involvement and family breakdown and hardship and lower socioeconomic status than those in the deteriorated group. The cognitive groups were not related to family history of psychosis. These findings identify specific social and family factors that impact cognition, highlighting the important role of these factors in the development of cognitive and functional abilities in schizophrenia.
Published: 2019

40. S33. REDUCTION IN PERIPHERAL C-REACTIVE PROTEIN LEVELS WITH CANAKINUMAB ADMINISTRATION IS RELATED TO REDUCED POSITIVE SYMPTOM SEVERITY IN PATIENTS WITH SCHIZOPHRENIA AND INFLAMMATION

Author: Adith Mohan, Rhoshel K. Lenroot, Thomas W. Weickert, Andrew R. Lloyd, Maryanne O'Donnell, Isabella Jacomb, David Brown, Denis Wakefield, Dennis Liu, Clive Stanton, Julia Lappin, Danielle Weinberg, William S. Brooks, D Pellen, Jochen Kindler, Cynthia Shannon Weickert, and Cherrie Galletly
Subjects: medicine.medical_specialty, Poster Session III, biology, business.industry, C-reactive protein, Symptom severity, Inflammation, medicine.disease, Gastroenterology, Peripheral, Psychiatry and Mental health, Canakinumab, Schizophrenia, Internal medicine, biology.protein, Medicine, In patient, medicine.symptom, business, medicine.drug
Abstract: BACKGROUND: Schizophrenia is characterized by positive and negative symptoms and cognitive deficits related to functional disability. Approved treatments targeting small molecule neurotransmitter receptors are limited in their effectiveness and often leave residual symptoms and debilitating side effects. Psychotic symptoms, cognitive deficits, and treatment response are variable in schizophrenia, highlighting heterogeneity in the etiology and presentation of the illness. There is a critical need for novel treatments targeting subgroups related to underlying biology that can be identified by biomarkers. A substantial subgroup (40%) of people with schizophrenia can be distinguished by cytokines in both peripheral blood and in brain. The cytokine interleukin 1-beta (IL-1β) mRNA and protein levels are significantly increased in serum, plasma, white blood cells, cerebrospinal fluid and brain in chronically ill patients and in first episode psychosis. Canakinumab is an approved human anti-IL-1β monoclonal antibody that interferes with the bioactivity of IL-1β and interrupts excessive immune response. However, the extent to which IL-1β blockade by canakinumab can reduce peripheral markers of an overactive immune system (e.g., high sensitivity C-reactive protein: hsCRP) and reduce psychotic symptom severity in schizophrenia is unknown. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel group trial of the monoclonal antibody canakinumab to block IL-1β in schizophrenia. Twenty-seven chronically ill patients with schizophrenia or schizoaffective disorder who had elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio) at baseline were randomized to a one-time subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive treatment to antipsychotics. Peripheral hsCRP levels were measured at baseline (prior to injection) and at 1, 4- and 8-weeks post treatment. Positive and Negative Syndrome Scale scores were assessed at baseline and at 4- and 8-weeks post treatment. RESULTS: Separate t-tests comparing canakinumab or placebo at weeks 1, 4, and 8 to baseline showed significant reductions in peripheral hsCRP levels at all time points (all p’s < .02) for canakinumab only. Separate t-tests also showed a significant reduction in positive symptom severity scores at week 8 (p = 0.05) for canakinumab and at week 4 (p = 0.02) for placebo. There was a trend for low peripheral hsCRP levels to be strongly correlated with low positive symptom severity scores (r = .57, p = .07) only at week 8 in the canakinumab group. There were no significant reductions in negative or general psychopathology symptom severity scores in either group. DISCUSSION: Blockade of the cytokine IL-1β by the monoclonal antibody canakinumab significantly reduces peripheral hsCRP serum levels and these reductions may be related to a reduction in positive symptom severity in chronically ill patients with schizophrenia. Importantly, only those patients who initially displayed elevated peripheral markers of inflammation were recruited. The effects of canakinumab on the reduction of peripheral hsCRP is potentially beneficial to general health. The relatively strong relationship between the effects of canakinumab on the biological marker hsCRP and positive symptom severity after 8 weeks of treatment supports the effect of canakinumab on positive symptom severity. Given that treatment with a monoclonal antibody is a novel and substantial advance in the potential treatment of psychotic symptom severity in schizophrenia, future studies should consider increased or top-up doses with longer follow-up to confirm the benefit of adjunctive canakinumab treatment in schizophrenia.
Published: 2019

41. Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype

Author: Jochen Kindler, Cynthia Shannon Weickert, Peter R. Schofield, Thomas W. Weickert, and Rhoshel K. Lenroot
Subjects: Adult, Male, Selective Estrogen Receptor Modulators, medicine.medical_specialty, Adolescent, Genotype, Emotions, Clinical Neurology, Prefrontal Cortex, Estrogen receptor, 610 Medicine & health, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Internal medicine, medicine, Humans, Pharmacology (medical), Raloxifene, Prefrontal cortex, Biological Psychiatry, Pharmacology, Cross-Over Studies, Raloxifene Hydrochloride, Estrogen Receptor alpha, Genetic Variation, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, 3. Good health, Inhibition, Psychological, Psychiatry and Mental health, Endocrinology, Neurology, Selective estrogen receptor modulator, Schizophrenia, Adjunctive treatment, Female, Schizophrenic Psychology, Neurology (clinical), Psychology, Estrogen receptor alpha, 030217 neurology & neurosurgery, medicine.drug
Abstract: People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippocampal activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia.
Published: 2016
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42. A quantitative review of the postmortem evidence for decreased cortical N-methyl-d-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?

Author: Vibeke S. Catts, Yan Ling Lai, Stanley V. Catts, Cyndi Shannon Weickert, and Thomas W. Weickert
Subjects: 0301 basic medicine, Mismatch negativity, Receptor expression, Neuroscience(all), Gene Expression, Prefrontal Cortex, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, medicine, Animals, Humans, RNA, Messenger, Receptor, Prefrontal cortex, General Neuroscience, Glutamate receptor, NMDA receptor, medicine.disease, Meta-analysis, 030104 developmental biology, Neuropsychology and Physiological Psychology, nervous system, Schizophrenia, Models, Animal, Evoked Potentials, Auditory, Autopsy, Glutamate, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract: Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-d-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was −0.64 (95% confidence interval: −1.08 to −0.20) for NR1 mRNA reduction and −0.44 (95% confidence interval: −0.80 to −0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models.
Published: 2016
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43. Peripheral Inflammation Markers Identify a Subset of Patients With Schizophrenia and Related Psychoses who Display Intellectual Decline From Premorbid Levels

Author: Thomas W. Weickert, Cynthia Shannon Weickert, Ryan P. Balzan, Rhoshel K. Lenroot, Cherrie Galletly, Seetha Ramanathan, and Dennis Liu
Subjects: business.industry, Schizophrenia (object-oriented programming), Immunology, medicine, Inflammation, medicine.symptom, business, Biological Psychiatry, Peripheral
Published: 2020
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44. Genetic Overlap Between Alzheimer's Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Author: Ole Kristian Drange, Olav Bjerkehagen Smeland, Alexey A. Shadrin, Per Ivar Finseth, Aree Witoelar, Oleksandr Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group, Yunpeng Wang, Sahar Hassani, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen, Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Jonathan R I Coleman, Heìleìna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Friseìn, 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, Jakob Grove, Weihua Guan, Joseì Guzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Steìphane Jamain, Jessica S Johnson, Anders Jureìus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, 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, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, 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, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Ceìline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Saìnchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, ToÞnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, Reneì S Kahn, George Kirov, Mikael Landeìn, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribaseìs, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, Pamela Sklar, APH - Mental Health, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and Complex Trait Genetics
Subjects: 0301 basic medicine, False discovery rate, Aging, genetic structures, RISK VARIANT, LOCI, Genome-wide association study, Disease, Neurodegenerative, PHOSPHATIDYLINOSITOL 3,5-BISPHOSPHATE, 0302 clinical medicine, MARK2, SCHIZOPHRENIA, 2.1 Biological and endogenous factors, Psychology, GWAS, Manic-depressive illness, Aetiology, Original Research, Psychiatric Genomics Consortium Bipolar Disorder Working Group, bipolar disorder, Genetics, Trastorn bipolar, DEMENTIA, General Neuroscience, Alzheimer's disease, 3. Good health, Cognitive Sciences, affective symptoms, Alzheimer’s disease, Biotechnology, Locus (genetics), Genomics, macromolecular substances, Biology, lcsh:RC321-571, KYNURENINE PATHWAY, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, pleiotropy, Acquired Cognitive Impairment, medicine, LITHIUM, SNP, ddc:610, Bipolar disorder, GENOME-WIDE ASSOCIATION, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, Brain Disorders, Malaltia d'Alzheimer, 030104 developmental biology, TELOMERE LENGTH, DIRECTLY PHOSPHORYLATES, cognitive symptoms, VAC14, 030217 neurology & neurosurgery, Neuroscience
Abstract: Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect). Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP. Copyright © 2019 Drange, Smeland, Shadrin, Finseth, Witoelar, Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group, Wang, Hassani, Djurovic, Dale and Andreassen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Published: 2019
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45. Reply to:New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

Author: Theo G.M. van Erp, Esther Walton, Derrek P. Hibar, Lianne Schmaal, Wenhao Jiang, David C. Glahn, Godfrey D. Pearlson, Nailin Yao, Masaki Fukunaga, Ryota Hashimoto, Naohiro Okada, Hidenaga Yamamori, Vincent P. Clark, Bryon A. Mueller, Sonja M.C. de Zwarte, Roel A. Ophoff, Neeltje E.M. van Haren, Ole A. Andreassen, Tiril P. Gurholt, Oliver Gruber, Bernd Kraemer, Anja Richter, Vince D. Calhoun, Benedicto Crespo-Facorro, Roberto Roiz-Santiañez, Diana Tordesillas-Gutiérrez, Carmel Loughland, Stanley Catts, Janice M. Fullerton, Melissa J. Green, Frans Henskens, Assen Jablensky, Bryan J. Mowry, Christos Pantelis, Yann Quidé, Ulrich Schall, Rodney J. Scott, Murray J. Cairns, Marc Seal, Paul A. Tooney, Paul E. Rasser, Gavin Cooper, Cynthia Shannon Weickert, Thomas W. Weickert, Elliot Hong, Peter Kochunov, Raquel E. Gur, Ruben C. Gur, Judith M. Ford, Fabio Macciardi, Daniel H. Mathalon, Steven G. Potkin, Adrian Preda, Fengmei Fan, Stefan Ehrlich, Margaret D. King, Lieuwe De Haan, Dick J. Veltman, Francesca Assogna, Nerisa Banaj, Pietro de Rossi, Mariangela Iorio, Fabrizio Piras, Gianfranco Spalletta, Edith Pomarol-Clotet, Sinead Kelly, Simone Ciufolini, Joaquim Radua, Robin Murray, Tiago Reis Marques, Andrew Simmons, Stefan Borgwardt, Fabienne Schönborn-Harrisberger, Anita Riecher-Rössler, Renata Smieskova, Kathryn I. Alpert, Alessandro Bertolino, Aurora Bonvino, Annabella Di Giorgio, Emma Neilson, Andrew R. Mayer, Je-Yeon Yun, Dara M. Cannon, Irina Lebedeva, Alexander S. Tomyshev, Tolibjohn Akhadov, Vasily Kaleda, Helena Fatouros-Bergman, Lena Flyckt, Pedro G.P. Rosa, Mauricio H. Serpa, Marcus V. Zanetti, Cyril Hoschl, Antonin Skoch, Filip Spaniel, David Tomecek, Andrew M. McIntosh, Heather C. Whalley, Christian Knöchel, Viola Oertel-Knöchel, Fleur M. Howells, Dan J. Stein, Henk S. Temmingh, Anne Uhlmann, Carlos Lopez-Jaramillo, Danai Dima, Joshua I. Faskowitz, Boris A. Gutman, Neda Jahanshad, Paul M. Thompson, Jessica A. Turner, Lars Farde, Simon Cervenka, Ingrid Agartz, Karin Collste, Pauliina Victorsson, Göran Engberg, Sophie Erhardt, Lilly Schwieler, Anna Malmqvist, Mikael Hedberg, Funda Orhan, Fredrik Piehl, APH - Mental Health, Adult Psychiatry, Universidad de Cantabria, Child and Adolescent Psychiatry / Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Schizophrenia (object-oriented programming), Prefrontal Cortex, BF, Neuroimaging, Mega, Severity of Illness Index, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Medical imaging, Humans, Medical physics, Disease process, Age of Onset, Child, Biological Psychiatry, Aged, Brain Diseases, medicine.diagnostic_test, Brain, Magnetic resonance imaging, Middle Aged, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, 030104 developmental biology, Case-Control Studies, Linear Models, Schizophrenia, RC0321, Female, Biological psychiatry, Psychology, 030217 neurology & neurosurgery
Abstract: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
Published: 2018
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46. Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia

Author: Dennis Liu, Cynthia Shannon Weickert, Ellen Ji, Maryanne O'Donnell, Thomas W. Weickert, Samantha J Owens, Tertia D. Purves-Tyson, Christopher J. White, and Cherrie Galletly
Subjects: medicine.medical_specialty, Original Paper, business.industry, Testosterone (patch), General Medicine, medicine.disease, Crossover study, Androgen receptor, Endocrinology, Schizophrenia, Selective estrogen receptor modulator, Polymorphism (computer science), Internal medicine, mental disorders, medicine, Raloxifene, Trinucleotide repeat expansion, business, medicine.drug
Abstract: Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.
Published: 2018

47. Increased plasma Brain-Derived Neurotrophic Factor (BDNF) levels in females with schizophrenia

Author: Cynthia Shannon Weickert, Dennis T Liu, Ryan P. Balzan, Peter F. Buckley, Rhoshel K. Lenroot, Cynthia H. Lee, Jason M. Bruggemann, Anilkumar K. Pillai, Thomas W. Weickert, and Cherrie Galletly
Subjects: Adult, Male, medicine.medical_specialty, Synaptogenesis, Regulator, behavioral disciplines and activities, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Neurotrophic factors, Internal medicine, mental disorders, medicine, Humans, Biological Psychiatry, Brain-derived neurotrophic factor, Sex Characteristics, business.industry, Brain-Derived Neurotrophic Factor, Sex related, Middle Aged, medicine.disease, 030227 psychiatry, Peripheral, Psychiatry and Mental health, Endocrinology, nervous system, Psychotic Disorders, Schizophrenia, Synaptic plasticity, Female, business, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract: Brain-Derived Neurotrophic Factor (BDNF) acts as a critical regulator of synaptogenesis and synaptic plasticity. Sex differences have been demonstrated in many aspects of schizophrenia. This study tested for sex-specific differences in peripheral BDNF levels in people with schizophrenia and healthy controls. We measured circulating plasma BDNF levels in 95 people with schizophrenia and 80 healthy controls. Plasma BDNF levels were significantly elevated in females with schizophrenia compared to males with schizophrenia and to female healthy controls. These results suggest that sex differences in peripheral BDNF levels may contribute to other sex related differences in schizophrenia.
Published: 2018

48. 107. Reduction in Peripheral C-Reactive Protein Levels With Canakinumab Administration is Related to Reduced Positive Symptom Severity in Patients With Schizophrenia and Inflammation

Author: Isabella Jacomb, William Brooks, David Brown, D Pellen, Cynthia Shannon Weickert, Dennis Liu, Thomas W. Weickert, Julia Lappin, Andrew R. Lloyd, Clive Stanton, Adith Mohan, Maryanne O'Donnell, Jochen Kindler, Danielle Weinberg, Cherrie Galletly, Denis Wakefield, and Rhoshel K. Lenroot
Subjects: medicine.medical_specialty, biology, business.industry, C-reactive protein, Symptom severity, Inflammation, medicine.disease, Gastroenterology, Peripheral, Canakinumab, Schizophrenia, Internal medicine, medicine, biology.protein, In patient, medicine.symptom, business, Biological Psychiatry, medicine.drug
Published: 2019
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49. F157. Transcriptional Changes in the Stress Pathway are Related to Symptoms in Schizophrenia and to Mood in Schizoaffective Disorder

Author: Cynthia H. Lee, Thomas W. Weickert, Maryanne O'Donnell, Cherrie Galletly, D Sinclair, Cynthia Shannon Weickert, and Dennis Liu
Subjects: medicine.medical_specialty, Mood, Schizophrenia, business.industry, Stress (linguistics), medicine, Schizoaffective disorder, Psychiatry, medicine.disease, business, Biological Psychiatry
Published: 2019
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50. 4.1 COGNITIVE RESERVE ATTENUATES AGE-RELATED COGNITIVE DECLINE IN THE CONTEXT OF ACCELERATED BRAIN AGEING IN SCHIZOPHRENIA-SPECTRUM DISORDERS: EVIDENCE FOR ACTIVE COMPENSATION

Author: Jason M. Bruggemann, Andrew Zalesky, Vanessa Cropley, Birgitte Fagerlund, Rhoshel K. Lenroot, Cynthia Shannon Weickert, Christos Pantelis, Suresh Sundram, Cassandra Wannan, Thomas W. Weickert, Tamsyn E Van Rheenen, and Chad A. Bousman
Subjects: Plenary/Symposia, Active compensation, Psychiatry and Mental health, Age-related cognitive decline, Ageing, Context (language use), Psychology, Schizophrenia spectrum, Clinical psychology, Cognitive reserve
Abstract: BACKGROUND: In schizophrenia, relative stability in the magnitude of fluid cognitive deficits across age and illness duration is inconsistent with evidence of accelerated deterioration in brain regions known to support these functions. These discrepant brain-cognition outcomes may be explained by variability in cognitive reserve (CR), which in neurological disorders has been shown to enable resilience against brain pathology and minimize its impact on cognitive or clinical indicators of illness. METHODS: Age-related changes in fluid reasoning, working memory and frontal brain volume, area and thickness were mapped using regression analysis in 214 individuals with schizophrenia or schizoaffective disorder and 168 healthy controls. In patients, these changes were modelled as a function of CR. RESULTS: Patients showed exaggerated age-related decline in brain structure, but not fluid cognition compared to controls. In the patient group, no moderation of age-related brain structural change by CR was evident. However, age-related cognitive change was moderated by CR, such that only patients with low CR showed evidence of exaggerated fluid reasoning decline that paralleled the exaggerated age-related deterioration of underpinning brain structures seen in all patients. CONCLUSIONS: In schizophrenia-spectrum illness, CR may negate ageing effects on fluid cognition by conferring resilience against pathologically exaggerated structural brain deterioration through some form of compensation. CR may represent an important modifier that could explain inconsistencies in brain structure - cognition outcomes evident in the extant literature.
Published: 2019
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