Skip to main content
Open Access Publications from the University of California

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

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


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.


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.


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.


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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View