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

UC Irvine

UC Irvine Previously Published Works bannerUC Irvine

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
For improved accessibility of PDF content, download the file to your device.
Current View