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 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 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

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 = +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.

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


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


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