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.

Advanced Computing and e Science Instituto de Física de Cantabria Universidad de Cantabria Consejo Superior de Investigaciones Científicas Santander 39005 Spain

Arkin Institute for Mental Health Amsterdam 1033 NN The Netherlands

Beijing Huilongguan Hospital Peking University Huilongguan Clinical Medical School Beijing 100096 P R China

Benito Menni Complex Assistencial en Salut Mental Barcelona 08830 Spain

Bjørknes College Oslo 0456 Norway

Campbell Family Mental Health Institute Centre for Addiction and Mental Health Toronto M5S 2S1 Canada

Center for Biomedical Image Computing and Analytics Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104

Center for Mind Brain and Behavior Marburg 35032 Germany

Center for Psychiatric Neuroscience Feinstein Institute for Medical Research Manhasset NY 11030

Center for the Neurobiology of Learning and Memory University of California Irvine Irvine CA 92697

Centre for Brain and Mental Health Research University of Newcastle Newcastle 2308 Australia

Centre for Psychiatry Research Department of Clinical Neuroscience Karolinska Institutet and Stockholm Health Care Services Region Stockholm Stockholm 113 64 Sweden

Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos 3 Madrid 28029 Spain

Chongqing University Three Gorges Hospital Chongqing 404188 P R China

Ciber del Área de Salud Mental Instituto de Salud Carlos 3 Madrid 28029 Spain

Clinical Translational Neuroscience Laboratory Department of Psychiatry and Human Behavior University of California Irvine Irvine CA 92697

Core Facility Brainimaging Faculty of Medicine Philipps Universität Marburg Marburg 35032 Germany

Department of Basic Medical Science Neuroscience and Sense Organs University of Bari Aldo Moro Bari 70121 Italy

Department of Brain and Cognitive Sciences Seoul National University College of Natural Sciences Seoul 08826 Republic of Korea

Department of Child and Adolescent Psychiatry Eating Disorder Treatment and Research Center Technische Universität Dresden Faculty of Medicine University Hospital C G Carus Dresden 01307 Germany

Department of Child and Adolescent Psychiatry Institute of Psychiatry and Mental Health Hospital General Universitario Gregorio Marañón Madrid 28009 Spain

Department of Child and Adolescent Psychiatry Psychology Erasmus University Medical Center Sophia Children's Hospital Rotterdam 3015 CN The Netherlands

Department of Child and Adolescent Psychiatry Technische Universität Dresden Dresden 01187 Germany

Department of Education Psychology Communication University of Bari Aldo Moro Bari 70121 Italy

Department of General Psychiatry Section for Experimental Psychopathology and Neuroimaging Heidelberg University Heidelberg 69115 Germany

Department of Human Genetics Radboud University Medical Center Nijmegen 6525 GA The Netherlands

Department of Medical Sciences Psychiatry Uppsala University Uppsala 751 85 Sweden

Department of Medicine and Psychiatry School of Medicine University of Cantabria Santander 39011 Spain

Department of Neurology Alzheimer Center Amsterdam Amsterdam Neuroscience Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam 1081 HZ The Netherlands

Department of Neurology Perelman School of Medicine Philadelphia PA 19104

Department of Neuropsychiatry Seoul National University Hospital Seoul 08826 Republic of Korea

Department of Neuroscience and Physiology Upstate Medical University Syracuse NY 13210

Department of Pathology of Mental Diseases National Center of Neurology and Psychiatry National Institute of Mental Health Tokyo 187 8551 Japan

Department of Physiology and Pharmacology Karolinska Institutet Stockholm 171 65 Sweden

Department of Psychiatric Research Diakonhjemmet Hospital Oslo 0373 Norway

Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences University of California San Francisco CA 94143

Department of Psychiatry and Human Behavior University of California Irvine Irvine CA 92697

Department of Psychiatry and Mental Health Faculty of Health Sciences University of Cape Town Cape Town 7935 South Africa

Department of Psychiatry and Neuropsychology School for Mental Health and Neuroscience Maastricht University Medical Centre Maastricht University Maastricht 6229 ER The Netherlands

Department of Psychiatry and Neuroscience University of New Mexico Albuquerque NM 87106

Department of Psychiatry and Psychotherapy Philipps Universität Marburg Marburg 35039 Germany

Department of Psychiatry and Psychotherapy University of Lübeck Lübeck 23562 Germany

Department of Psychiatry Boston Children's Hospital and Harvard Medical School Boston MA 02115

Department of Psychiatry Dalhousie University Halifax B3H 2E2 Canada

Department of Psychiatry Division of Adult Psychiatry Geneva University Hospitals Geneva 1202 Switzerland

Department of Psychiatry Faculty of Medicine and Health Sciences Stellenbosch University Stellenbosch 7505 South Africa

Department of Psychiatry Icahn School of Medicine at Mount Sinai New York NY 10029

Department of Psychiatry Instituto de Investigación Marqués de Valdecilla University Hospital Marqués de Valdecilla Santander 39008 Spain

Department of Psychiatry Jeonbuk National University Medical School Jeonju 54896 Republic of Korea

Department of Psychiatry Marqués de Valdecilla University Hospital Instituto de Investigación Sanitaria Valdecilla School of Medicine University of Cantabria Santander 39011 Spain

Department of Psychiatry Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt am Main 60528 Germany

Department of Psychiatry Psychotherapy and Psychosomatics Psychiatric University Hospital Zurich Zurich 8008 Switzerland

Department of Psychiatry Radboud University Medical Center Nijmegen 6525 GA The Netherlands

Department of Psychiatry Research Group in Psychiatry Faculty of Medicine Universidad de Antioquia Medellín 050010 Colombia

Department of Psychiatry School of Medicine University of Sevilla University Hospital Virgen del Rocío Consejo Superior de Investigaciones Científicas Instituto de Biomedicina de Sevilla Sevilla 41013 Spain

Department of Psychiatry Seoul National University College of Medicine Seoul 08826 Republic of Korea

Department of Psychiatry University Medical Center Utrecht Brain Center University Medical Center Utrecht Utrecht University Utrecht 3584 CG The Netherlands

Department of Psychiatry University of Maryland School of Medicine Baltimore MD 21201

Department of Psychiatry University of Oxford Oxford OX3 7JX United Kingdom

Department of Psychiatry University of Toronto Toronto M5T 1R8 Canada

Department of Psychiatry University Psychiatric Clinics University of Basel Basel 4002 Switzerland

Department of Psychiatry Zucker School of Medicine at Northwell Hofstra New York NY 11549

Department of Psychological Medicine Institute of Psychiatry Psychology and Neuroscience King's College London London SE5 8AF United Kingdom

Department of Psychology University of Oslo Oslo 0373 Norway

Department of Psychosis Studies Institute of Psychiatry Psychology and Neuroscience King's College London London SE5 8AF United Kingdom

Department of Radiology Instituto de Investigación Marqués de Valdecilla Marqués de Valdecilla University Hospital Santander 39011 Spain

Department of Radiology Perelman School of Medicine Philadelphia PA 19104

Department of Women's and Children's Health Uppsala University Uppsala 752 37 Sweden

Division of Cerebral Integration National Institute for Physiological Sciences Okazaki 444 8585 Japan

Division of Mental Health and Addiction Oslo University Hospital Oslo 0372 Norway

Division of Psychiatry Centre for Clinical Brain Sciences University of Edinburgh Edinburgh EH16 4SB United Kingdom

Division of Psychiatry Research Zucker Hillside Hospital Northwell Health New York NY 11004

Division of Psychological and Social Medicine and Developmental Neurosciences Translational Developmental Neuroscience Section Technische Universität Dresden University Hospital C G Carus Dresden 01307 Germany

Donders Institute for Brain Cognition and Behaviour Radboud University Nijmegen 6500 HB The Netherlands

Early Psychosis Department Department of Psychiatry Amsterdam UMC Amsterdam 1105 AZ The Netherlands

Edith Collins Centre Sydney Local Health District Sydney 2050 Australia

Experimental Psychopathology and Psychotherapy Department of Psychology University of Zurich Zurich 8050 Switzerland

FIDMAG Germanes Hospitalàries Research Foundation Barcelona 08035 Spain

Hunter Medical Research Institute Newcastle 2305 Australia

Hunter New England Mental Health Service Newcastle 2305 Australia

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Los Angeles CA 90033

Institute for Translational Psychiatry Westfälische Wilhelms Universität Münster Münster 48149 Germany

Instituto de Investigación Sanitaria Gregorio Marañón Madrid 28009 Spain

KG Jebsen Center for Neurodevelopmental Disorders University of Oslo Oslo 0450 Norway

Laboratory of Neuro Imaging School of Medicine University of Southern California Los Angeles CA 90033

Laboratory of Neuroimaging and Multimodal Analysis Mental Health Research Center Moscow 115522 Russian Federation

Laboratory of Neuropsychiatry Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation Rome 00179 Italy

Language and Genetics Department Max Planck Institute for Psycholinguistics Nijmegen 6525 XD The Netherlands

Lifespan Brain Institute University of Pennsylvania and Children's Hospital of Philadelphia Philadelphia PA 19104

Long Beach VA Health Care System Long Beach CA 90822

Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne Melbourne 3053 Australia

Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Houston TX 77030

Mental Health Research Networking Center Madrid 28029 Spain

Mental Health Service Veterans Affairs San Francisco Healthcare System San Francisco CA 94121

Montreal Neurological Institute McGill University Montreal H3A 2B4 Canada

MR Unit Department of Diagnostic and Interventional Radiology Institute for Clinical and Experimental Medicine Prague 140 21 Czech Republic

National Institute of Mental Health Klecany 250 67 Czech Republic

Neuroscience Institute University of Cape Town Cape Town 7935 South Africa

Neuroscience Research Australia Sydney 2031 Australia

Norwegian Centre for Mental Disorders Research Institute of Clinical Medicine University of Oslo Oslo 0450 Norway

Olin Neuropsychiatry Research Center Institute of Living Hartford CT 06102

PRC for Health Behaviour Hunter Medical Research Institute Newcastle 2305 Australia

Priority Research Centre for Stroke and Brain Injury University of Newcastle Newcastle 2308 Australia

Psychiatric Genetics QIMR Berghofer Medical Research Institute Brisbane 4006 Australia

Psychiatry Unit Bari University Hospital Bari 70121 Italy

Psychology Department and Neuroscience Institute Georgia State University Atlanta GA 30303

Queensland Brain Institute The University of Queensland Brisbane 4072 Australia

Queensland Centre for Mental Health Research The University of Queensland Brisbane 4076 Australia

Research Institute of Clinical Medicine Jeonbuk National University Biomedical Research Institute Jeonbuk National University Hospital Jeonju 54896 Republic of Korea

SA MRC Unit on Risk and Resilience in Mental Disorders University of Cape Town Cape Town 7505 South Africa

San Francisco VA Medical Center University of California San Francisco CA 94121

School of Biomedical Science and Pharmacy Faculty of Health and Medicine University of Newcastle Newcastle 2308 Australia

School of Medicine and Public Health University of Newcastle Newcastle 2308 Australia

School of Medicine The University of Queensland Brisbane 4006 Australia

School of Medicine Universidad Complutense Madrid 28040 Spain

School of Psychiatry University of New South Wales Sydney 2033 Australia

School of Psychological Sciences University of Newcastle Newcastle 2308 Australia

School of Psychology University of Auckland Auckland 1010 New Zealand

Specialty of Addiction Medicine Central Clinical School Faculty of Medicine and Health University of Sydney Sydney 2006 Australia

Stellenbosch University Genomics of Brain Disorders Research Unit South African Medical Research Council Cape Town 7505 South Africa

The Mental Illness Research Education and Clinical Centers James J Peters VA Medical Center New York NY 10468

The Mind Research Network Albuquerque NM 87106

Tri Institutional Center for Translational Research in Neuroimaging and Data Science Georgia State University Georgia Institute of Technology and Emory University Atlanta GA 30303

West Region Institute of Mental Health Singapore 539747 Singapore

Yong Loo Lin School of Medicine National University of Singapore Singapore 119228 Singapore

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