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

Sonja M C de Zwarte; Rachel M Brouwer; Ingrid Agartz; Martin Alda; André Aleman; Kathryn I Alpert; Carrie E Bearden; Alessandro Bertolino; Catherine Bois; Aurora Bonvino; Elvira Bramon; Elizabeth E L Buimer; Wiepke Cahn; Dara M Cannon; Tyrone D Cannon; Xavier Caseras; Josefina Castro-Fornieles; Qiang Chen; Yoonho Chung; Elena De la Serna; Annabella Di Giorgio; Gaelle E Doucet; Mehmet Cagdas Eker; Susanne Erk; Scott C Fears; Sonya F Foley; Sophia Frangou; Andrew Frankland; Janice M Fullerton; David C Glahn; Vina M Goghari; Aaron L Goldman; Ali Saffet Gonul; Oliver Gruber; Lieuwe de Haan; Tomas Hajek; Emma L Hawkins; Andreas Heinz; Manon H J Hillegers; Hilleke E Hulshoff Pol; Christina M Hultman; Martin Ingvar; Viktoria Johansson; Erik G Jönsson; Fergus Kane; Matthew J Kempton; Marinka M G Koenis; Miloslav Kopecek; Lydia Krabbendam; Bernd Krämer; Stephen M Lawrie; Rhoshel K Lenroot; Machteld Marcelis; Jan-Bernard C Marsman; Venkata S Mattay; Colm McDonald; Andreas Meyer-Lindenberg; Stijn Michielse; Philip B Mitchell; Dolores Moreno; Robin M Murray; Benson Mwangi; Pablo Najt; Emma Neilson; Jason Newport; Jim van Os; Bronwyn Overs; Aysegul Ozerdem; Marco M Picchioni; Anja Richter; Gloria Roberts; Aybala Saricicek Aydogan; Peter R Schofield; Fatma Simsek; Jair C Soares; Gisela Sugranyes; Timothea Toulopoulou; Giulia Tronchin; Henrik Walter; Lei Wang; Daniel R Weinberger; Heather C Whalley; Nefize Yalin; Ole A Andreassen; Christopher R K Ching; Theo G M van Erp; Jessica A Turner; Neda Jahanshad; Paul M Thompson; René S Kahn; Neeltje E M van Haren

doi:10.1016/j.biopsych.2019.03.985

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

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

Authors

Sonja M C de Zwarte¹, Rachel M Brouwer², Ingrid Agartz³, Martin Alda⁴, André Aleman⁵, Kathryn I Alpert⁶, Carrie E Bearden⁷, Alessandro Bertolino⁸, Catherine Bois⁹, Aurora Bonvino⁸, Elvira Bramon¹⁰, Elizabeth E L Buimer², Wiepke Cahn², Dara M Cannon¹¹, Tyrone D Cannon¹², Xavier Caseras¹³, Josefina Castro-Fornieles¹⁴, Qiang Chen¹⁵, Yoonho Chung¹², Elena De la Serna¹⁴, Annabella Di Giorgio¹⁶, Gaelle E Doucet¹⁷, Mehmet Cagdas Eker¹⁸, Susanne Erk¹⁹, Scott C Fears²⁰, Sonya F Foley²¹, Sophia Frangou¹⁷, Andrew Frankland²², Janice M Fullerton²³, David C Glahn²⁴, Vina M Goghari²⁵, Aaron L Goldman¹⁵, Ali Saffet Gonul²⁶, Oliver Gruber²⁷, Lieuwe de Haan²⁸, Tomas Hajek⁴, Emma L Hawkins⁹, Andreas Heinz¹⁹, Manon H J Hillegers²⁹, Hilleke E Hulshoff Pol², Christina M Hultman³⁰, Martin Ingvar³¹, Viktoria Johansson³⁰, Erik G Jönsson³², Fergus Kane³³, Matthew J Kempton³³, Marinka M G Koenis³⁴, Miloslav Kopecek³⁵, Lydia Krabbendam³⁶, Bernd Krämer²⁷, Stephen M Lawrie⁹, Rhoshel K Lenroot³⁷, Machteld Marcelis³⁸, Jan-Bernard C Marsman⁵, Venkata S Mattay³⁹, Colm McDonald¹¹, Andreas Meyer-Lindenberg⁴⁰, Stijn Michielse³⁸, Philip B Mitchell²², Dolores Moreno⁴¹, Robin M Murray³³, Benson Mwangi⁴², Pablo Najt¹¹, Emma Neilson⁹, Jason Newport⁴³, Jim van Os³⁸, Bronwyn Overs⁴⁴, Aysegul Ozerdem⁴⁵, Marco M Picchioni⁴⁶, Anja Richter²⁷, Gloria Roberts²², Aybala Saricicek Aydogan⁴⁷, Peter R Schofield²³, Fatma Simsek⁴⁸, Jair C Soares⁴², Gisela Sugranyes¹⁴, Timothea Toulopoulou⁴⁹, Giulia Tronchin¹¹, Henrik Walter¹⁹, Lei Wang⁶, Daniel R Weinberger¹⁵, Heather C Whalley⁹, Nefize Yalin⁵⁰, Ole A Andreassen⁵¹, Christopher R K Ching⁵², Theo G M van Erp⁵³, Jessica A Turner⁵⁴, Neda Jahanshad⁵⁵, Paul M Thompson⁵⁵, René S Kahn⁵⁶, Neeltje E M van Haren²⁹

Affiliations

¹ Department of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. Electronic address: [email protected].
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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Twin Study

MeSH terms

Adult
Bipolar Disorder* / genetics
Bipolar Disorder* / pathology
Brain / pathology*
Cohort Studies
Female
Genetic Predisposition to Disease*
Humans
Male
Middle Aged
Schizophrenia* / genetics
Schizophrenia* / pathology
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding