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Biol Psychiatry. 2019 Oct 1;86(7):545-556. doi: 10.1016/j.biopsych.2019.03.985. Epub 2019 Jun 13.

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

Author information

1
Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. Electronic address: s.m.c.dezwarte@umcutrecht.nl.
2
Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
3
Norwegian Centre for Mental Disorders Research (NORMENT), 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.
4
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; National Institute of Mental Health, Klecany, Czech Republic.
5
Cognitive Neuroscience Center, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
6
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
7
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.
8
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
9
Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, United Kingdom.
10
Division of Psychiatry, Neuroscience in Mental Health Research Department, University College London, London, United Kingdom.
11
Centre for Neuroimaging and Cognitive Genomics and National Centre for Biomedical Engineering (NCBES), Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
12
Department of Psychology, Yale University, New Haven, Connecticut, United Kingdom.
13
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, United Kingdom.
14
Psychology and Psychology, 2017SGR881, Institute of Neuroscience, Hospital Clínic of Barcelona, Institute d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Spain.
15
Lieber Institute for Brain Development, Baltimore, Maryland.
16
Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy.
17
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
18
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.
19
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.
20
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.
21
Cardiff University Brain Research Imaging Centre, Cardiff University, United Kingdom.
22
School of Psychiatry, University of New South Wales, Sydney, Australia.
23
School of Medical Sciences, University of New South Wales, Sydney, Australia; Neuroscience Research Australia, Sydney, Australia.
24
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.
25
Department of Psychology, University of Toronto, Toronto, Ontario, Canada; Graduate Department of Psychological Clinical Science, University of Toronto, Toronto, Ontario, Canada.
26
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.
27
Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, University of Heidelberg, Heidelberg, Germany.
28
Early Psychosis Unit, Department of Psychiatry, Academic Medical Center, Amsterdam, Netherlands.
29
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.
30
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
31
Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
32
Norwegian Centre for Mental Disorders Research (NORMENT), 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.
33
Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
34
Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
35
National Institute of Mental Health, Klecany, Czech Republic; Department of Psychiatry, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
36
Department of Clinical, Neuro and Developmental Psychology, Faculty of Behaviour and Movement Sciences, Vrije Universiteit, Amsterdam, Netherlands.
37
Neuroscience Research Australia, Sydney, Australia; Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, New Mexico.
38
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht University, Maastricht, Netherlands.
39
Lieber Institute for Brain Development, Baltimore, Maryland; Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
40
Clinical Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
41
Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón (IiSGM), School of Medicine, Universidad Complutense, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
42
Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas.
43
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
44
Neuroscience Research Australia, Sydney, Australia.
45
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.
46
Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
47
Department of Neurosciences, Health Sciences Institute, Dokuz Eylül University, Izmir, Turkey; Department of Psychiatry, Faculty of Medicine, Izmir Katip Çelebi University, Izmir, Turkey.
48
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.
49
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.
50
Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
51
Norwegian Centre for Mental Disorders Research (NORMENT), K.G. Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
52
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.
53
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.
54
Department of Psychology, Georgia State University, Atlanta, Georgia; Neuroscience Institute, Georgia State University, Atlanta, Georgia.
55
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California.
56
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.

Abstract

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.

KEYWORDS:

Bipolar disorder; Familial risk; Imaging; Meta-analysis; Neurodevelopment; Schizophrenia

PMID:
31443932
DOI:
10.1016/j.biopsych.2019.03.985
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