Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia

Abstract

The symptoms of schizophrenia imply disruption to brain systems supporting higher-order cognitive activity, but whether these systems are impacted differentially against a background of diffuse cortical gray-matter deficit remains ambiguous. Some unaffected first-degree relatives of schizophrenics also manifest cortical gray-matter deficits, but it is unclear whether these changes are isomorphic with those in patients, and the answer is critical to understanding the neurobiological conditions necessary for disease expression given a predisposing genotype. Here we report three-dimensional cortical surface maps (probabilistic atlases matching subjects' anatomy point by point throughout cortex) in monozygotic (MZ) and dizygotic (DZ) twins discordant for chronic schizophrenia along with demographically matched control twins. A map encoding the average differences between schizophrenia patients and their unaffected MZ co-twins revealed deficits primarily in dorsolateral prefrontal cortex, superior temporal gyrus, and superior parietal lobule. A map encoding variation associated with genetic proximity to a patient (MZ co-twins > DZ co-twins > control twins) isolated deficits primarily in polar and dorsolateral prefrontal cortex. In each case, the statistical significance was confirmed through analysis of 10,000 Monte Carlo permutations, and the remaining cortex was shown to be significantly less affected by contrast analysis. The disease-related deficits in gray matter were correlated with measures of symptom severity and cognitive dysfunction but not with duration of illness or antipsychotic drug treatment. Genetic and disease-specific influences thus affect gray matter in partially nonoverlapping areas of predominantly heteromodal association cortex, changes that may act synergistically in producing overt behavioral features of the disorder.

Figure 1

Cortical maps showing the average magnitude (A), significance (B), and regional specificity (C) of gray-matter deficits in schizophrenic twins relative to their healthy MZ co-twins (n = 10 pairs) viewed from the right, left, and right-oblique perspectives. These maps isolate nongenetic disease-specific deficits by eliminating genetic differences between cases and controls. Disease-specific deficits are observed primarily in dorsolateral prefrontal, superior temporal, and superior parietal association areas. The significance of deficits survived correction for multiple comparisons in each of these regions bilaterally except for superior temporal gyrus in the right hemisphere. Most of the remaining cortex is significantly less affected than the average deficit in frontal cortex (C).

Figure 2

Cortical maps showing the magnitude (A), significance (B), and regional specificity (C) of liability-related gray-matter deficits viewed from the right, left, and right-oblique perspectives. “R-value” refers to the correlation between gray-matter density and genetic liability to schizophrenia, modeled as highest among unaffected MZ co-twins of probands (n = 10), intermediate among unaffected DZ co-twins of probands (n = 10), and lowest among normal control twins (n = 20, where one co-twin was chosen at random from each pair). The map reveals liability-related deficits primarily in polar and dorsolateral prefrontal regions, the significance of which survived correction for multiple comparisons. Most of the remaining cortex is significantly less affected than the average deficit in frontal cortex (C).

Figure 3

Cortical maps showing the intraclass correlations in gray matter in healthy MZ, healthy DZ, discordant MZ, and discordant DZ twin pairs (n = 10 pairs in each group). The maps for healthy twins are reproduced with permission from ref. (Copyright 2001, Nature Publishing Group) to facilitate comparison. Among the discordant pairs, the DZ correlations were uniformly low and nonsignificant throughout cortex, whereas the MZ correlations were highly significant (and significantly greater than the DZ correlations) in frontal and temporal pole, a large band of sensorimotor strip, and Wernicke's area. These results are consistent with the liability maps presented in Fig. 2 in demonstrating differential heritable influences on gray matter in these regions among twins discordant for schizophrenia. F, frontal lobe; W, Wernicke's area; S/M, sensorimotor cortex.