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, 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

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.

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.
Figure 1.
(A) Cohen’s d effect sizes comparing relatives and patients with bipolar disorder (BD) (blue) and relatives and patients with schizophrenia (SZ) (red) with control subjects for global brain measures, (B) controlled for intracranial volume (ICV). *Nominally significant effect sizes (p < .05, uncorrected); **q < .05, corrected.
Figure 2.
Figure 2.
(A) Cohen’s d effect sizes comparing relatives and patients with bipolar disorder (BD) (blue) and relatives and patients with schizophrenia (SZ) (red) with controls for subcortical volumes, (B) controlled for intracranial volume. *Nominally significant effect sizes (p < .05, uncorrected); **q < .05, corrected.

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