Structural brain measures are employed as endophenotypes in the search for schizophrenia susceptibility genes. We analyzed two independent structural imaging datasets with voxel-based morphometry and with source-based morphometry, a multivariate, independent components analysis, to determine the stability and heritability of regional gray matter concentration abnormalities in schizophrenia. The samples comprised 209 and 102 patients with schizophrenia and 208 and 96 healthy volunteers, respectively. The second sample additionally included non-ill siblings of participants with and without schizophrenia. A standard voxel-based analysis showed reproducible regional gray matter deficits in the affected participants compared with unrelated, unaffected controls in both datasets: patients showed significant gray matter concentration deficits in cortical frontal, temporal, and insular lobes. Source-based morphometry (SBM) was applied to the gray matter images of the entire sample to determine the effects of diagnosis on networks of covarying structures. The SBM analysis extracted 24 significant sets of covarying regions (components). Four of these components showed significantly lower gray matter concentrations in patients (p < .05). We determined the familiality of the observed SBM components based on 66 sibling pairs (25 discordant for schizophrenia). Two components, one including the medial frontal, insular, inferior frontal, and temporal lobes, and the other including the posterior occipital lobe, showed significant familiality (p < .05). We conclude that structural brain deficits in schizophrenia are replicable, and that SBM can extract unique familial and likely heritable components. SBM provides a useful data reduction technique that can provide measures that may serve as endophenotypes for schizophrenia.
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