Schizophrenia: a study on genetic aspects of a brain disease

Abstract

Schizophrenia is a severe and chronic psychiatric disorder with heritability estimates of 80-85%. Knowledge of the genetic factors that contribute to the risk to develop schizophrenia may provide insight into the etiology of the disorder, and, more important, may lead to new ways for treatment and prevention. This thesis encompasses various genetic studies on schizophrenia. Over 300 clinically well-defined patients with schizophrenia and over 800 comparison subjects, all of Dutch descent, participated in the studies. We carried out an association study of 12 genes involved in dopamine neurotransmission and schizophrenia. Dopamine dysregulation has long been implicated in schizophrenia since different kinds of antipsychotic medications block dopamine receptors in the brain. In this study we found no evidence for association with any of the studied genes, which suggests that these genes are not directly involved in the development of schizophrenia in our sample of Dutch patients. Three studies in this thesis are on positional candidate genes for schizophrenia, genes located in regions that previously have shown linkage to the disorder. As schizophrenia is a clinically heterogeneous disorder, we hypothesized clinical distinct subtypes of schizophrenia may have different biological origins. To investigate this hypothesis, we collected schizophrenia patients with and without the Deficit syndrome. This syndrome is characterized by prominent, enduring negative symptoms. As such, we investigated whether the positional candidate genes neuregulin 1, dysbindin (DTNBP1), G72/G30, PIP5K2A and RGS4 are differentially associated with deficit and non-deficit schizophrenia. Whereas dysbindin and G72/G30 were not inferred in the risk to develop schizophrenia (subtypes) in our Dutch population, neuregulin 1 and RGS4 were associated only with the non-deficit form of schizophrenia. PIP5K2A was associated with both the deficit and the non-deficit type of schizophrenia. This finding provides support for the assumption that different biological entities underlie the expression of different schizophrenia subtypes. Another interesting finding was that a combination of risk variants in the genes neuregulin 1, PIP5K2A and RGS4 was a highly significant predictor of the risk on schizophrenia, especially of the risk on the non-deficit subtype. Since several lines of evidence suggest that the integrity of myelin is disturbed in schizophrenia, we also investigated the association between 771 single nucleotide polymorphisms (SNPs) in 138 myelin-related genes and the disorder. Most compelling evidence for association with the disorder was found for PIK4CA, a gene involved in the phosphatidyl-inositol pathway (like PIP5K2A). Other significantly associated genes were PIK3C2G, PSAP, ARHGEF10, FGF1 and FGFR1. We also examined the relationship between SNPs in myelin-related genes and measures of brain structure volumes. Remarkably, a highly significant proportion of the SNPs that were associated with brain volume measures were SNPs in Fibroblast Growth Factor (FGF) related genes (like the above mentioned FGF1 and FGFR1 genes). This is consistent with earlier reports on FGF system genes showing an important influence on brain volume as well as the risk for developing schizophrenia. Finally, we studied the prevalence of the 22q11.2 deletion syndrome (22q11DS) in our sample of schizophrenia patients. This syndrome is associated with a very high risk (20-30%) of schizophrenia. As often quoted in literature, the prevalence of 22q11DS among schizophrenia patients is assumed to be 2% or more. We hypothesized that this prevalence is higher among patients with the Deficit syndrome, since these patients show overlap with symptoms that are found in 22q11DS patients, like social withdrawal, flat affect and lack of mental energy. However, we found no 22q11.2 deletions in a sample of 311 patients with schizophrenia, which was enriched for patients with the Deficit syndrome. Moreover, a literature review combining all available studies on the prevalence of 22q11DS among schizophrenia patients revealed that this prevalence is about 0.75%.