Abstract
The susceptibility to common psychiatric disorders is largely determined by genetic factors. Knowledge of these factors may give insight into the causes of these disorders, and, more importantly, open new ways for prevention and treatment. Identifying the causal DNA variants, however, has proved to be difficult, despite considerable research efforts.
... read more
One explanation is that many genes and environmental factors are involved, which would require large study populations to detect variants with modest effects. Some variants may be involved in specific disease symptoms only, or their relative importance could differ between population subgroups. In both cases, detecting such variants would be difficult in unselected, ethnically diverse patient samples.
This thesis describes genetic studies performed on clinically well-defined, homogeneous groups of Dutch patients suffering from schizophrenia and attention-deficit hyperactivity disorder (ADHD), and presents novel techniques for efficiently performing such studies.
In a large sample of unrelated schizophrenia patients, we investigated 12 functional candidate genes involved in dopamine neurotransmission. Dopamine dysregulation has long been implicated as a causal factor in schizophrenia, since most of the effective drug treatments block dopamine receptors in the brain. In this study, which was performed using microsatellite markers and pooled DNA from patients and controls, we found no evidence however for a significant contribution to schizophrenia from any of these genes. These results suggest that if dopamine genes are involved in schizophrenia, their role must be small.
Schizophrenia has a very diverse clinical presentation and disease course in individual patients, which suggests the existence of disease subtypes with different biological causes. To investigate this possibility, we collected patients with and without the deficit form of schizophrenia. The deficit syndrome is characterized by prominent, enduring negative symptoms, such as decreased interest, social withdrawal and flattened affect. In these groups, we investigated variants in several genes that have recently been implicated in schizophrenia. We found that the neuregulin 1 and RGS4 genes were almost entirely associated with the non-deficit group, which provided genetic support for a distinct aetiology of clinically recognizable forms of schizophrenia. The PIP5K2A gene, which has previously been implicated in bipolar disorder, was strongly associated with both deficit and non-deficit schizophrenia. For several other recently reported genes, such as dysbindin (DTNBP1) and G72/G30, we were able to rule out a substantial role in Dutch schizophrenic patients.
In ADHD, genes from the dopamine system have also been regarded as candidate genes, since the most effective medication blocks the dopamine transporter. We have investigated the dopamine transporter gene (DAT1), as well as the dopamine receptor genes 4 (DRD4) and 5 (DRD5), in a large family sample of Dutch children with ADHD. We found no evidence for association of these genes with the disorder. In the same families with affected pairs of siblings, we have performed one of the first whole-genome linkage studies in ADHD. The results indicated that DNA regions on chromosomes 15q and 7p might contain genes that contribute to the disorder. On chromosome 7, we found no support for involvement of dopa decarboxylase (DDC), a functional candidate gene in the linkage region.
Besides specific genetic studies in these two disorders, two techniques are presented for the efficient screening of genetic markers. A new mathematical procedure was developed to correct the so-called stutter artefact in the analysis of microsatellite markers. This method enables the accurate and efficient estimation of microsatellite marker allele frequencies in DNA pools (combined DNA from large groups of individuals, which can be screened for differences between patients and controls). Finally, an inexpensive and efficient method was developed for analyzing single nucleotide polymorphisms (SNPs) on standard DNA sequencing equipment.
show less