Genetic schizophrenia risk variants jointly modulate total brain and white matter volume.

BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 × 10(-4)) and white matter volume (R2 = .051, p = 8.6 × 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

Tract-based diffusion tensor imaging in patients with schizophrenia and their non-psychotic siblings.

Structural brain abnormalities have consistently been found in patients with schizophrenia. Diffusion tensor imaging (DTI) has been shown to be a useful method to measure white matter (WM) integrity in this illness, but findings in the earlier disease stages are inconclusive. Moreover, the relationship between WM microstructure and the familial risk for developing schizophrenia remains unresolved. From 126 patients with schizophrenia, 123 of their non-psychotic siblings and 109 healthy control subjects, DTI images were acquired on a 1.5 T MRI scanner. Mean fractional anisotropy (FA) was compared along averaged WM tracts, computed for the genu, splenium, left and right uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, fornix, arcuate fasciculus, and inferior longitudinal fasciculus. Fractional anisotropy (FA) was assessed for its unique environmental and familial (possibly heritable) aspects associated with schizophrenia, using structural equation modeling for these white matter tracts. The results of this study show that young adult (mean age 26.7 years) patients with schizophrenia did not differ in mean FA from healthy controls along WM fibers; siblings of patients showed higher mean FA in the left and right arcuate fasciculus as compared to patients and controls. With increasing age, an excessive decline in mean FA was found in patients as compared to siblings and healthy controls in the genu, left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left inferior longitudinal fasciculus. Moreover, symptom severity was negatively correlated to mean FA in the arcuate fasciculus bilaterally in patients with schizophrenia. In young adult patients with schizophrenia integrity of individual tract-based (corticocortical) fibers can (still) be within normal limits. However, changes in the arcuate fasciculus may be relevant to (the risk to develop) psychosis, while a general and widespread loss of fiber integrity may be related to illness progression.

Genetic Risk and Outcome of Psychosis (GROUP), a multi-site longitudinal cohort study focused on gene-environment interaction: objectives, sample characteristics, recruitment and assessment methods.

OBJECTIVE: A longitudinal focus on gene-environment vulnerability and resilience in both patients, their unaffected family members and non-related controls offers the opportunity to elucidate etiological and pathogenetic factors influencing the onset and course of psychotic disorders. The current paper delineates the objectives, sample characteristics, recruitment and assessment procedures of the Genetic Risk and Outcome of Psychoses (GROUP) study. METHODS: A naturalistic longitudinal cohort study with assessments at baseline, after three and six years of follow-up. The study is conducted by a consortium of four university psychiatric centres, with their affiliated mental health care institutions in the Netherlands covering more than 7.5 million inhabitants. Extensive assessment of genetic factors, environmental factors, (endo)phenotypes, and outcome. RESULTS: At baseline, 1120 patients, 1057 siblings, 919 parents and 590 healthy controls were included. CONCLUSION: The GROUP study will contribute to insight in risk and protective factors in the aetiology of non-affective psychotic disorders, and in the variation in their course and outcome.

Focal and global brain measurements in siblings of patients with schizophrenia.

BACKGROUND: It remains unclear whether structural brain abnormalities in schizophrenia are caused by genetic and/or disease-related factors. Structural brain abnormalities have been found in nonpsychotic first-degree relatives of patients with schizophrenia, but results are inconclusive. This large magnetic resonance imaging study examined brain structures in patients with schizophrenia, their nonpsychotic siblings, and healthy control subjects using global and focal brain measurements. METHODS: From 155 patients with schizophrenia, their 186 nonpsychotic siblings, and 122 healthy controls (including 25 sibling pairs), whole-brain scans were obtained. Segmentations of total brain, gray matter (GM), and white matter of the cerebrum, lateral and third ventricle, and cerebellum volumes were obtained. For each subject, measures of cortical thickness and GM density maps were estimated. Group differences in volumes, cortical thickness, and GM density were analyzed using Structural Equation Modeling, hence controlling for familial dependency of the data. RESULTS: Patients with schizophrenia, but not their nonpsychotic siblings, showed volumetric differences, cortical thinning, and reduced GM density as compared with control subjects. CONCLUSIONS: This study did not reveal structural brain abnormalities in nonpsychotic siblings of patients with schizophrenia compared with healthy control subjects using multiple imaging methods. Therefore, the structural brain abnormalities observed in patients with schizophrenia are for the largest part explained by disease-related factors.

Brain volumes in relatives of patients with schizophrenia: a meta-analysis.

CONTEXT: Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. OBJECTIVE: To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. DATA SOURCES: A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. STUDY SELECTION: Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. DATA EXTRACTION: For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors (H.B.M.B. and A.A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. DATA SYNTHESIS: Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d = 0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d = 0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d = 0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. CONCLUSION: Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.