BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

Cardiff University Brain Research Imaging Centre Cardiff University United Kingdom

Centre for Affective Disorders Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Centre for Neuroimaging and Cognitive Genomics and National Centre for Biomedical Engineering Galway Neuroscience Centre National University of Ireland Galway Galway Ireland

Centre for Psychiatric Research Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Child and Adolescent Psychiatry Department Hospital General Universitario Gregorio Marañón Madrid Spain

Clinical Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

Clinical Translational Neuroscience Laboratory Department of Psychiatry and Human Behavior University of California Irvine Irvine California; Center for the Neurobiology of Learning and Memory University of California Irvine Irvine California

Cognitive Neuroscience Center Department of Biomedical Sciences of Cells and Systems University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Basic and Clinical Neuroscience Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom; Department of Psychology Bilkent University Ankara Turkey; Department of Psychology University of Hong Kong Hong Kong China

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

Department of Clinical Neuro and Developmental Psychology Faculty of Behaviour and Movement Sciences Vrije Universiteit Amsterdam Netherlands

Department of Experimental and Clinical Medicine Università Politecnica delle Marche Ancona Italy

Department of Forensic and Neurodevelopmental Science Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Neurosciences Health Sciences Institute Dokuz Eylül University Izmir Turkey; Department of Psychiatry Faculty of Medicine Izmir Katip Çelebi University Izmir Turkey

Department of Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Chicago Illinois

Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at Houston Houston Texas

Department of Psychiatry and Biobehavioral Sciences University of California Los Angeles Los Angeles California; Center for Neurobehavioral Genetics University of California Los Angeles Los Angeles California

Department of Psychiatry and Biobehavioral Sciences University of California Los Angeles Los Angeles California; Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California; Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Marina del Rey California

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

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada; National Institute of Mental Health Klecany Czech Republic

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

Department of Psychiatry Renaissance School of Medicine at Stony Brook University Stony Brook New York; Department of Psychiatry Faculty of Medicine Izmir Turkey; Department of Neurosciences Health Sciences Institute Dokuz Eylül University Izmir Turkey

Department of Psychiatry University Medical Center Utrecht Brain Center University Medical Center Utrecht Utrecht University Utrecht Netherlands

Department of Psychiatry University Medical Center Utrecht Brain Center University Medical Center Utrecht Utrecht University Utrecht Netherlands; Department of Child and Adolescent Psychiatry Psychology Erasmus University Medical Center Sophia Children's Hospital Rotterdam Netherlands

Department of Psychiatry University Medical Center Utrecht Brain Center University Medical Center Utrecht Utrecht University Utrecht Netherlands; Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York

Department of Psychology Georgia State University Atlanta Georgia; Neuroscience Institute Georgia State University Atlanta Georgia

Department of Psychology University of Toronto Toronto Ontario Canada; Graduate Department of Psychological Clinical Science University of Toronto Toronto Ontario Canada

Department of Psychology Yale University New Haven Connecticut United Kingdom

Division of Psychiatry Neuroscience in Mental Health Research Department University College London London United Kingdom

Division of Psychiatry Royal Edinburgh Hospital University of Edinburgh Edinburgh United Kingdom

Early Psychosis Unit Department of Psychiatry Academic Medical Center Amsterdam Netherlands

Experimental Psychopathology and Neuroimaging Department of General Psychiatry University of Heidelberg Heidelberg Germany

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Marina del Rey California

Lieber Institute for Brain Development Baltimore Maryland

Lieber Institute for Brain Development Baltimore Maryland; Department of Radiology The Johns Hopkins University School of Medicine Baltimore Maryland

MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University United Kingdom

National Institute of Mental Health Klecany Czech Republic; Department of Psychiatry 3rd Faculty of Medicine Charles University Prague Czech Republic

Neuroscience Research Australia Sydney Australia

Neuroscience Research Australia Sydney Australia; Department of Psychiatry and Behavioral Sciences University of New Mexico Albuquerque New Mexico

Norwegian Centre for Mental Disorders Research K G Jebsen Centre Institute of Clinical Medicine University of Oslo Oslo Norway; Centre for Psychiatric Research Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Norwegian Centre for Mental Disorders Research K G Jebsen Centre Institute of Clinical Medicine University of Oslo Oslo Norway; Centre for Psychiatric Research Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden; Department of Psychiatry Diakonhjemmet Hospital Oslo Norway

Norwegian Centre for Mental Disorders Research K G Jebsen Centre Institute of Clinical Medicine University of Oslo Oslo Norway; Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Olin Neuropsychiatry Research Center Institute of Living Hartford Hospital Hartford Connecticut; Department of Psychiatry Yale University School of Medicine New Haven Connecticut

Olin Neuropsychiatry Research Center Institute of Living Hartford Hospital Hartford Connecticut; Tommy Fuss Center for Neuropsychiatric Disease Research Boston Children's Hospital Boston Massachusetts; Harvard Medical School Boston Massachusetts

Psychology and Psychology 2017SGR881 Institute of Neuroscience Hospital Clínic of Barcelona Institute d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Spain

Psychosis Studies Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Research Division of Mind and Brain Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

School of Medical Sciences University of New South Wales Sydney Australia; Neuroscience Research Australia Sydney Australia

School of Psychiatry University of New South Wales Sydney Australia

Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California; Department of Psychology University of California Los Angeles Los Angeles California

SoCAT LAB Department of Psychiatry School of Medicine Ege University Bornova Izmir Turkey; Department of Psychiatry and Behavioral Sciences Mercer University School of Medicine Macon Georgia

SoCAT LAB Department of Psychiatry School of Medicine Ege University Bornova Izmir Turkey; Department of Psychiatry Renaissance School of Medicine at Stony Brook University Stony Brook New York

SoCAT LAB Department of Psychiatry School of Medicine Ege University Bornova Izmir Turkey; Department of Psychological Medicine Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom; Department of Psychiatry Cigli State Hospital Izmir Turkey

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