The present study examined the heritability of cortical thickness changes associated with schizophrenia in a large cohort of normal controls, affected patients, and unaffected siblings analyzed using sophisticated surface extraction and cortical parcellation procedures. The study demonstrated marked thickness reductions in the patient sample, most notably in frontal and temporal lobes, and provided evidence for widespread heritability of these cortical alterations. Since no significant thickness reductions were found in unaffected siblings in this large sample, reduced cortical thickness per se is unlikely to be a major neural signature of the genetic risk architecture of schizophrenia. However, this conclusion must be considered in light of the technical limitations of MRI as an anatomical research method.
Perhaps the most striking thickness effects were seen in the frontal lobe, where patients showed widespread reductions. Prefrontal cortex is one of the most consistently implicated regions in morphometric studies of schizophrenia,1–3
and previous studies of cortical thickness have likewise shown widespread thinning in this area,16,17,19
although1study (using a non–surface-based method) found no reduction among first-episode patients.52
Furthermore, unaffected siblings showed widespread relative risk for thickness reductions within the frontal lobe, consistent with reports associating schizophrenia susceptibility genes with altered prefrontal structure53
as well as studies showing intermediate prefrontally linked functional phenotypes in the first-degree relatives of patients with schizophrenia.55
The temporal lobe has likewise exhibited reduced volume in a wide range of studies, particularly in the superior temporal gyrus and medial temporal lobe.1–3
Not surprisingly, therefore, and as hypothesized, thickness was found to be reduced in a variety of temporal regions in our present data, most pronouncedly on the lateral surface, replicating previous reports of temporal thickness reductions in schizophrenia.16,17,19
Furthermore, relative risk for reduced thickness was seen in a variety of temporal regions, suggesting a role of schizophrenia risk genes in temporal lobe cortical architecture.
Intriguingly, despite the prevalence of middle temporal lobe reductions in volumetric studies of schizophrenia, 1–3,36
our sample did not show significant thickness reductions in parahippocampal gyrus or entorhinal cortex. The lack of results in this area could indicate that medial temporal volume reductions are limited to subcortical regions (hippocampus and/or amygdala). Alternatively, since thickness is not directly synonymous to volume, cortical reductions could exist in the form of reduced cortical area or some other morphometric difference, such as abnormal cytoarchitecture. Previous results in the parahippocampal gyrus have been equivocal, with at least 1 study reporting reduced thickness16
but others failing to find thinning in first-episode schizophrenia18
or over the first 5 years of childhood-onset schizophrenia.56
Beyond these a priori hypothesized regions, thickness reductions were seen in lingual gyrus, supramarginal gyrus, inferior parietal lobule, right precuneus, lateral occipital lobe, postcentral gyrus, paracentral lobule, and most of the cingulate gyrus. As with temporal and frontal lobe, many of these regions showed evidence of heritability of volume reductions. Cortical abnormalities in the cingulate might be a structural correlate of convergent reports of abnormal error-related processing in this region in schizophrenia.57
Thus, while dorsolateral prefrontal and lateral temporal regions are generally the most strongly implicated in schizophrenia, morphometric effects were not exclusive to these regions, again mirroring findings using other methods, such as regional volumes. 1,24,36
This supports the idea that the predominant functional impairment of prefrontal and medial temporal structures in schizophrenia may not be exclusively due to localized structural-functional effects, but also mediated through the extensive interconnections that these regions maintain with the rest of the brain.11,41,58
The majority of patients were treated with antipsychotic medications at the time of scanning. While supplemental analysis did not show any significant effects of medication use on cortical thickness (see the “Demographics” subsection in the “Results” section), it is impossible to fully rule out medication effects in the context of this study design. Indeed, studies in monkeys treated long-term with antipsychotic drugs have demonstrated that cortical volume is reduced by these agents.59
The Risch λ, the measure of heritability used in this study, has previously been used in a variety of schizophrenia studies, including analyses of N
and local brain volume,36
among others. In a previous study, our group used this method in an analysis of brain morphology using automated subcortical segmentations. Importantly, while this study provided evidence for heritable reductions in cortical gray matter as a whole and hippocampus in particular, it also demonstrated that marked and well-replicated phenotypes such as ventricle and dorsal striatal enlargements (the latter of which has been linked primarily to use of typical antipsychotics) did not show increased relative risk using this measure,36
illustrating that the Risch λ can be used to help dissect heritable disease-related factors from those that are environmental.36
In terms of cortical thickness, the Risch λ indeed showed evidence for heritability of thickness reductions in a wide variety of brain areas studied. Therefore, cortical thickness reduction as measured herein has a significant heritable component. Cortical thickness reductions do not necessarily reflect a loss of neurons but could also be related to a loss of local circuit connections and cortico-cortical connections through reductions in neuropil volume. This has indeed been suggested by previous postmortem studies of prefrontal cortex61
and conforms with the “dysconnectivity” concept discussed earlier. However, postmortem evidence of cortical thickness reductions is not consistent and the possibility that changes observed with MRI reflect changes that are not related to cellular elements, eg, changes in fluid compartments or vascularity, cannot be ruled out. Methodologically, one strength of the present study is the large sample assessed through a reliable semiautomated technology. Even so, the robustness of the Risch λ varies depending on the distribution of thickness values in each region and can depend on very few siblings exceeding the chosen phenotype-defining threshold. However, even using an excessively stringent limit to the most robust analyses (for the sake of example, those containing ≥20 siblings), areas of marked heritability were seen throughout the brain. These included findings in left superior and middle temporal gyrus, rostral middle frontal gyrus, inferior frontal gyrus (opercular part), banks of the superior temporal sulcus, inferior parietal lobule, and posterior cingulate and right caudal anterior cingulate, highlighting the majority of regions hypothesized at the onset of the study. While the use of parcellation labels may have obscured effects that did not conform to gyral anatomy, we feel false negatives are unlikely given the multitude of our positive findings.
Widespread heritability of cortical thickness reductions alone does not demonstrate that reduced thickness is a reflection of the risk architecture of schizophrenia, because findings like the ones presented herein could also be obtained if the siblings of healthy subjects with thin cortices were examined. To show that reduced thickness is also a marker of increased genetic risk for schizophrenia, it has to be enriched in the sample of people who are at increased genetic risk for this disease, ie, the sibling group. In our data, thickness reductions in siblings did not exceed the chosen surfacewide threshold, although smaller studies20–22
did find reductions in siblings, and in our sample, differences between the sibling and patient groups were consistently less pronounced than those between controls and patients, suggesting that siblings did occupy an intermediate position between patients and controls. Even larger samples might still uncover a significant reduction of thickness in healthy subjects at risk, or intermediate thickness reductions may be observed in subjects assessed to be at particularly high risk for the disorder.62
However, at the present time, while our data clearly show that reduced cortical thickness is heritable, our findings do not support the presence of thin cortex per se as a strong intermediate phenotype, or endophenotype, related to genetic risk for schizophrenia. This raises the question of the intermediate phenotype status of gray matter structure in schizophrenia in general. While the evidence is variable, some studies, including our own in this sample, have found heritable reductions in gray matter volume in first-degree relatives of schizophrenic patients. If it is accepted that volume can be reduced while thickness is unaltered in genetically high-risk individuals, this could indicate a reduction in cortical area, possibly as a signature of abnormal neurodevelopment, and it would be of interest to examine this feature of brain structure. If on the other hand one takes a more skeptical view of the literature regarding gray matter volume reduction, one could also conclude that gray matter structure, while heritable, lies outside the core genetic risk architecture of schizophrenia and would then be more related to peristatic and environmental effects related to illness state. In support of this latter skeptical view, significant structural differences in monozygotic twins discordant for schizophrenia are well established.63,64
Further studies should examine the effects of specifically disease-related allelic variation on cortical thickness, analogous to studies performed using regional brain volume as the phenotype,53,65–67
and investigate the effect of illness-related variables, such as treatment and duration of illness, on the phenotype in patients.