Genetic variation and clinical variables contributing to Schizophrenia in a Founder Population from South Africa

Abstract

Thirty publications are submitted. They deal with findings of the genetic architecture of schizophrenia in an Afrikaner founder population and clinical related variables pertaining to this population.

The initial research findings supported the appropriateness of the Afrikaner population for mapping complex traits using both linkage and linkage disequilibrium (LD) approaches. Basic sample descriptors and cardinal symptoms of schizophrenia in the US and South African populations were equivalent. It was concluded that the results from our genetic study of schizophrenia in the Afrikaner sample will be applicable to other populations.

It was found that early non-psychotic childhood deviance (in the first ten years of life) distinguished a distinct subtype of schizophrenia patient, and that the form of early deviance manifested, was meaningful linked to later disease outcome; and that it may be a possible endophenotypic marker in schizophrenia but not in bipolar disorder.

Schizophrenia genetic research used linkage analysis, association studies and exome sequencing studies as it became available in the last few years. We addressed the role of the individual genes from the 22q11 locus (prototype CNV described in schizophrenia). Systematic screening of the 26 genes residing in this locus identified PRODH2, ZDHHC8, NOGO Receptor 1 (RTN4R) gene as contributing to schizophrenia risk associated with this region. Linkage genome-wide scans, using both less dense (10cM) and more dense scans (2cM), identified a locus on chromosome 1 and 13. Recent fine mapping on chromosome 13q32-34 and brain expression analysis implicates MYO16 in schizophrenia (not included in the 30 publications). For the first time a probound with a uniparental disomy (UPD) of the entire chromosome 1, was identified, which further support the involvement of chromosome 1 in schizophrenia.

We confirmed the previous reported rate of 2% frequency of 22q11 deletions in adult schizophrenia Afrikaner patients and provided a two-stage screening protocol to identify these patients in clinical practice. As more patients were recruited for this study certain comorbid conditions became obvious including marijuana use/abuse and obsessive compulsive disorder (OCD) and obsessive compulsive symptoms (OCS).

Approximately half of the male patients and a quarter of the female patients used or abused marijuana. Male users of marijuana with prominent early non-psychotic deviant behaviour in the first 10 years of life had the lowest mean age of criteria onset (18.4 years) with a poor prognosis. The prevalence of OCD/OCS in this population was 13.2% and differs from other ethnic groups in South Africa, and was associated with significant psychopathology and poor prognosis.

As the research progressed the emphasis has changed from familial cases with the disease to sporadic cases (non-familial). We offered the first clear view of the genetic landscape of schizophrenia. We found that rare de novo structural mutations at many different loci are significantly enriched and contribute to schizophrenia vulnerability in sporadic cases with the disease. We also demonstrated that genes contribute to familial schizophrenia, while new mutations are less prominent.

The study of schizophrenia in the Afrikaner founder population has helped to clear the view of the genetic landscape of schizophrenia.