The Genomics of Schizophrenia in the South African Xhosa People


Principal Investigator:

Scientific Description:

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.

Updated Aims:

Aim 1.
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.

Aim 2.
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.

Aim 3.
Identify genes enriched for damaging mutations in Xhosa-speaking individuals with schizophrenia, compared to genes harboring such mutations in Xhosa-speaking controls.

Related projects


April 4, 2018

The Genomics of Schizophrenia in the South African Xhosa People

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.
April 4, 2018

Transgenerational Effects of Maternal Stressors: Invesigating the Role of Infant Gene Expression

This collaborative project, between Emory University in the USA and the University of Cape Town (UCT) in South Africa, proposes to investigate biological mechanisms underlying the transgenerational effects of exposure to prenatal maternal psychological stress, anxiety, or depression. We propose to examine
April 4, 2018

Reprogramming of the Trypanosoma brucei Epigenome during Human Infection: Opportunities for New Therapies

. brucei is a single-celled trypanosome that occurs in extensive parts of sub-Saharan Africa, and causes African sleeping sickness. Hundreds of thousands of individuals suffer from this disease. We plan to study the way in which the epigenome of this organism is used to allow this trypanosome to continually evade the human immune system.
April 4, 2018

The Nasopharyngeal Microbiome and Respiratory Disease in African Children

Colonization of the upper part of the human respiratory tract (back of the nose and throat) by microorganisms is an important predictor for the development of pneumonia and wheezing illness (which may lead to asthma) in young children. Despite this, relatively little is known about patterns of colonization in early life, nor how these patterns influence the development of respiratory illness.
April 4, 2018

Transgenerational Epigenomics of Trauma and PTSD in Rwanda

The goal of the proposed work is to characterize the transgenerational genomic impact of genocide exposure and post-traumatic stress disorder (PTSD) in women survivors of the Rwandan genocide and their offspring. PTSD is a common and debilitating mental disorder that has a profound public health impact. Between April and June 1994, almost one million people died in the Rwandan genocide against ethnic Tutsi.
April 4, 2018

Immunoglobulin Gene Diversity in an African Population and Impact Antibody Function in HIV Infection

Antibodies are critical components of immune defense and are mediators of vaccine-elicited protection as well as autoimmunity. The heavy and light chains that comprise an antibody molecule are encoded by germline immunoglobulin (Ig) gene fragments that recombine and undergo somatic mutation thereby generating billions of specificities able to contend with a multitude of foreign antigens.
April 4, 2018

Deciphering Developmental Disorders in Africa (DDD-Africa) – Evaluating Clinical Exome Sequencing in an African Setting

Developmental disorders are severe, chronic disabilities that are systematically increasing in prevalence in low-and middle-income countries. Due to the high burden of infectious disease in many African countries, active research into rare disorders such as DD has been neglected. The genetic aetiology of DD is complex and therefore traditional diagnostic tests have a low success yield.
April 4, 2018

Clinical and Genetic Studies of Hereditary Neurological Disorders in Mali

Hereditary neurological disorders are very disabling diseases that are under-studied in Africa. Our first aim is to clinically characterize these disorders in the Malian population in order to establish a comprehensive clinical description of the diseases in this region. Our second aim is to identify gene mutations related to neurological diseases, and to explore their effects in cell culture models to further our understanding of their function and interactions and our knowledge of
April 4, 2018

Host and Microbial Genetic Determinants of febrile illness in West Africa

Febrile illnesses are among the most common causes of morbidity and mortality in tropical developing countries. While clinical diagnostics are not currently available for many of the microbes causing fevers of unknown origin (FUO), genomic tools can enable researchers to test for a wide array of known microbes