Resumen
An overview is given on the genetics of schizophrenia in an Afrikaner founder population. This research has been done over a period of ten years. Founder populations hold tremendous promise for mapping genes for complex traits, as they offer less genetic and environmental heterogeneity and greater potential for genealogical research. Not all founder populations are equally valuable, however. The Afrikaner population meets several criteria that make it an ideal population for mapping complex traits. These include founding by a small number of initial founders that likely allowed for a relatively restricted set of mutations and a large current population size that allows identification of a sufficient number of cases. Since a large number of patients was traced to an original founder couple, the genealogical data of the research support the hypothesis that a substantial portion of the schizophrenia cases the researchers have identified will share the same or a small number of susceptibility alleles. Results further show that genetic variation at the 22q11 locus enhances the risk to develop schizophrenia. More than one gene in this region can independently or synergistically increase the risk of schizophrenia in non-deleted patients. In three independent samples, evidence was provided for a contribution of the PRODH/DGCR6 locus in 22q11 associated schizophrenia. One of these samples was from South Africa as part of an ongoing collection of schizophrenia patients of Afrikaner origin. An unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene was uncovered. Several of the pseudo gene-like variants identified, resulted in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. The results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotype and provide further insight into the genomic instability of this region. It was shown in an independent sample of Afrikaner schizophrenia patients that the frequency of 22q11 deletion syndrome was 2%, as suggested in earlier studies. Early deviant behaviour before 10 years of age was the most important factor related to the onset of illness. Early deviant childhood behaviour was grouped into three clusters: social functioning impairment cluster, mood/anxiety cluster and cognitive impairment cluster. Some of these factors are important in male schizophrenia patients and maybe used as endophenotypic markers. The LRRTM1 gene is implicated in the paternal transmission of schizophrenia. This gene may be implicated in the development of specific forebrain structures. It influences neuronal differentiation and connections. Male users of cannabis suffering from schizophrenia; with prominent early deviant behaviour have the lowest age of onset of illness, namely 18.4 years. Approximately half of the male schizophrenia patients and a quarter of the female schizophrenia patients used or abused cannabis. These figures are high and make cannabis use/abuse an important part of the management strategy of these patients. It was stated that in male patients with a specific subtype of schizophrenia (where early deviant behaviour was present) the use of cannabis triggers an illness with earlier onset and a poor prognosis. The prevalence of obsessive-compulsive disorder and obsessive-compulsive symptoms in Afrikaner patients suffering from schizophrenia was 13.25%. This finding differs from those in another ethnic group in South Africa suggesting the possible role of genetic and cultural factors in the prevalence of co-morbid OCD/OCS in this patient population. The most common obsession reported was contamination followed by religious obsession. The most common compulsion was checking behaviour. Clinical characteristics of Afrikaner schizophrenia and schizo-affective disorder patients with and without co-morbid OCD/OCS are the same; both groups were associated with significant psychopathology and a poor prognosis.