Elsevier

Biological Psychiatry

Volume 63, Issue 5, 1 March 2008, Pages 475-483
Biological Psychiatry

Original Article
Heritability of Brain Morphology Related to Schizophrenia: A Large-Scale Automated Magnetic Resonance Imaging Segmentation Study

https://doi.org/10.1016/j.biopsych.2007.06.006Get rights and content

Background

Schizophrenia is a devastating psychiatric disorder with a strong genetic component that has been related to a number of structural brain alterations. Currently available data on the heritability of these structural changes are inconsistent.

Methods

To examine heritability of morphological alterations in a large sample, we used a novel and validated fully-automated whole brain segmentation technique to study disease-related variability and heritability in anatomically defined regions of interest in 221 healthy control subjects, 169 patients with schizophrenia, and 183 unaffected siblings.

Results

Compared with healthy control subjects, patients showed a bilateral decrease in hippocampal and cortical gray matter volume and increases in bilateral dorsal striatum and right lateral ventricle. No significant volumetric differences were found in unaffected siblings compared with normal control subjects in any structure. Post hoc analysis of the dorsal striatum showed the volumetric increase to be widespread, including caudate, putamen, and globus pallidus. With Risch’s λ (λs), we found strong evidence for heritability of reduced cortical volume and moderate evidence for hippocampal volume, whereas abnormal striatal and ventricle volumes showed no sign of heritability. Additional exploratory analyses were performed on amygdala, thalamus, nucleus accumbens, ventral diencephalon, and cerebral and cerebellar cortex and white matter. Of these regions, patients showed increased volume in ventral diencephalon and cerebellum.

Conclusions

These findings support evidence of genetic control of brain volume even in adults, particularly of hippocampal and neocortical volume and of cortical volumetric reductions being familial, but do not support measures of subcortical volumes per se as representing intermediate biologic phenotypes.

Section snippets

Participants

Two hundred twenty-one healthy volunteers, 169 patients with schizophrenia, and 183 unaffected siblings of patients with schizophrenia were included in this study (Table 1). This sample largely overlapped with the one used in our VBM study (22) but was not identical, because the two methods involved separate processing streams and quality control subjects and a few images met quality criteria for only one method (see Imaging and Preprocessing section). Subjects were recruited nationwide in an

Demographics

Table 1 shows demographic information separately for each diagnostic group, which were altogether representative of participants in this case-control study. To ensure there were no confounding age or gender interactions, preliminary GLM models were performed including gender-diagnosis and age-diagnosis interactions. No significant interactions were found in dorsal striatum, cortical GM, or hippocampus, although age-diagnosis was significant in the left lateral (p = .021) and third (p < .002)

Discussion

The present study assessed volume changes and heritability of brain morphological phenotypes associated with schizophrenia with a large sample of patients with schizophrenia, unaffected siblings, and healthy volunteers. A sophisticated, fully-automated method was used to process structural brain images and divide them into a number of cortical and subcortical structures. The results provide confirmatory evidence for several widely reported morphological phenotypes in schizophrenia, demonstrate

Conclusions

The results of this study support several commonly reported volumetric differences associated with schizophrenia, including reductions in hippocampal and total cortical GM volume, ventricular enlargement, and widespread volumetric increases in dorsal striatum. Although no volumetric differences were observed between unaffected siblings and normal control subjects in these regions, evidence for heritability of reduced GM volume as a schizophrenia-associated biologic trait was found in both

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