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.

Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

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 GWAS Consortium (8,690 schizophrenia patients and 11,831 controls, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (“risk”) scores (PSSs) in an independent sample of 152 schizophrenia patients and 142 healthy controls with available structural MRI scans. Results In the entire group, the PSS was significantly associated with total brain volume (R2=0.048, p=1.6×10−4) and white matter volume (R2=0.051, p=8.6×10−5) equally in patients and controls. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n=2,020) was much smaller than the entire set of SNPs that modulated disease status (n=14,751). From the set of 2,020 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.

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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.

Our results do not support the validity of schizophrenia subtypes. Schizophrenia can be distinguished from brief psychotic disorder and psychotic disorder not otherwise specified. These findings may fuel the actual DSM-V discussion.

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