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, Andre 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 SernaAnnabella 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. Jonsson, Fergus Kane, Matthew J. Kempton, Marinka M. G. Koenis, Miloslav Kopecek, Lydia Krabbendam, Bernd Kraemer, 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, Rene S. Kahn, Neeltje E. M. van Haren

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 = +10.16, 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.

Original languageEnglish
Pages (from-to)545-556
Number of pages12
JournalBiological Psychiatry
Issue number7
Publication statusPublished - 1 Oct 2019


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

Cite this