ENIGMA-Relatives: The Association Between Familial Risk for Schizophrenia or Bipolar Disorder and Brain Abnormalities

Background Schizophrenia and bipolar disorder share genetic liability and some structural brain abnormalities are common to both conditions. Interestingly, imaging studies have indicated that there may be a converse pattern of brain abnormalities in first-degree relatives of schizophrenia patients (FDRs-SZ) and bipolar patients (FDRs-BD), with smaller volumes reported in FDRs-SZ and enlargements in FDRs-BD. Methods Here, we meta-analyzed global and subcortical brain measures of 6,008 individuals (1,228 FDRs-SZ, 852 FDRs-BD, 2,246 controls, 1,016 patients with schizophrenia, and 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 controls. Results FDRs-BD had significantly larger ICV (d=+0.16, q<0.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than controls (d=–0.12, q<0.05 corrected). ICV explained the enlargements of brain measures in FDRs-BD, while 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’s<–0.09, q<0.05 corrected), and third ventricle was larger (d=+0.15, q<0.05 corrected). The findings were not explained by psychopathology in the relatives or controls. Conclusions Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically an opposite effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain abnormalities in schizophrenia or bipolar disorder are distinct. As a next step, we are investigating whether IQ/educational attainment might be associated with this divergence.