The goal of this multisite, collaborative project is to identify genes responsible for schizophrenia in the Xhosa population of South Africa. The vast majority of the genetic basis for schizophrenia has yet to be explained. Strong evidence suggests that individually rare, severely deleterious mutations are responsible for a substantial portion of cases. We hypothesize that critical genes will harbor multiple mutations leading to the disorder, with each affected individual harboring a different severe mutation. We propose a two-step approach to identify these genes. In a discovery series of 200 Xhosa individuals with schizophrenia and 200 age- and sex-matched Xhosa controls, we will sequence complete exomes and related regulatory regions to identify all rare point mutations and indels. In parallel, we will evaluate the same individuals for copy number variants (CNVs) genome-wide (Aim 1). Next, we will validate promising variants and use bioinformatic strategies to prioritize approximately 250 candidate genes most likely to be relevant to schizophrenia. We will develop custom solution pools to capture these candidate genes, and characterize their mutational spectra in an independent series of 900 Xhosa individuals with schizophrenia and 900 Xhosa controls (Aim 2). We will identify genes enriched for deleterious mutations (Aim 3). This project will be the first to use massively parallel genomic sequencing to study schizophrenia in any population of sub-Saharan African lineage. If successful, our approach will identify multiple genes important for the disorder in populations worldwide. Each of these genes will stimulate future efforts to develop more effective treatment and prevention strategies.
Lay Description: Schizophrenia is a serious mental disorder that is associated with a great deal of impairment. While there is good evidence that genetic factors contribute to schizophrenia, the exact nature of the genetic basis for this disorder remains unclear. We plan to use cutting-edge genetic methods to study schizophrenia in the Xhosa population of South Africa. Our hope is that this research will help in the identification of genes that play an important role in this disorder in other contexts, and will so ultimately contribute to the prevention and treatment of this important condition.
Ascertain, assess, and enroll 1100 individuals with schizophrenia from Xhosa-speaking populations and 1100 Xhosa-speaking controls. They are matched by age, sex, highest level of education and locality.
Using exome sequencing and related genome-wide strategies, identify all point mutations, indels and copy number variants that impact coding regions, known regulatory regions, or noncoding RNAs in genomic DNA of cases and controls.
Identify genes enriched for damaging mutations in Xhosa-speaking individuals with schizophrenia, compared to genes harboring such mutations in Xhosa-speaking controls.