The first genetic analysis of schizophrenia in an ancestral African population, the South African Xhosa, has been published. An international group of scientists conducted the research. The study of schizophrenia was carried out in the Xhosa population because Africa is the birthplace of all humans, yet ancestral African populations have rarely been the focus of genetics research. The Xhosa do not have an unusually high risk of schizophrenia.
The relative lack of genetics studies in Africa leaves a major gap in understanding human genetics. Almost 99% of human evolution took place in Africa, after the first modern humans originated and before humans migrated from Africa to Europe and Asia 50,000 to 100,000 years ago. Because of the lack of studies in Africa, many generations of human genetic history are missing from our understanding of human adaptation and of human disease.
The Xhosa trace their history to the migration of Bantu-speaking people from the Great Lakes region of eastern Africa to southern Africa centuries ago. The Xhosa now live throughout South Africa and are the largest population group of the Eastern Cape region. Schizophrenia affects approximately 1% of people in all parts of the world and is one of the leading causes of disability worldwide. This study revealed that Xhosa individuals with schizophrenia are significantly more likely to carry rare, damaging genetic mutations compared to Xhosa individuals without severe mental illness.
Many of the genes disrupted by the rare damaging mutations of these patients are involved in the organization and function of brain synapses. Synapses coordinate the communication between brain nerve cells called neurons, The organisation and firing of neuronal synapses are ultimately responsible for learning, memory and brain function. The genes and pathways identified by this research inform the understanding of schizophrenia for all human populations, and suggest potential mechanisms for the design of more effective treatments.
The project was led by Jon McClellan, professor of psychiatry, and Mary-Claire King, professor of genome sciences and of medicine, at the University of Washington School of Medicine in Seattle; Dan Stein, professor and head of psychiatry and mental health at the University of Cape Town, South Africa; and Ezra Susser, professor of epidemiology and psychiatry at the Mailman School of Public Health, Columbia University, New York. The Xhosa community participated in the development and conduct of the research.
Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.
S Gulsuner, DJ Stein, ES Susser, G Sibeko, A Pretorius, T Walsh, L Majara, MM Mndini, SG Mqulwana, OA Ntola, S Casadei, LL Ngqengelele, V Korchina, C van der Merwe, M Malan, KM Fader, M Feng, E Willoughby, D Muzny, A Baldinger, HF Andrews, RC Gur, RA Gibbs, Z Zingela, M Nagdee, RS Ramesar, MC King, JM McClellan