The goal of this international collaborative project is to identify genes responsible for schizophrenia in the Xhosa population of South Africa. The three participating sites are Columbia University, New York (Ezra Susser, PI), University of Washington, Seattle (Mary- Claire King, Jack McClellan, Tom Walsh, MPIs), and University of Cape Town, South Africa (Dan Stein, PI). The vast majority of the genetic basis for schizophrenia has yet to be explained. We hypothesize that genes and pathways important to schizophrenia will harbor different, severe disease-causing mutations in different affected individuals. Given the genetic diversity of African populations, we expect to find genes for schizophrenia that have not yet emerged from studies of other populations. This project will also foster the development of gene discovery research for neuropsychiatric disorders in Africa. In 1100 Xhosa individuals with schizophrenia and 1100 age and gender-matched Xhosa controls, we will compare profiles of exomes, flanking regulatory sites, and noncoding RNAs (obtained by exome sequencing) and profiles of structural genomic variants (obtained by arrayCGH). Both rare/private variants and ancient African alleles will be identified and evaluated. Genes enriched for deleterious mutations in individuals with schizophrenia compared to controls will be defined as candidates. Variant profiles of candidate genes will be assessed in NIMH sequence databases derived from schizophrenia studies of other populations. This project will be the first to use modern genomic sequencing approaches to study schizophrenia in a population of sub-Saharan African lineage. If successful, our approach will identify genes important for the disorder in populations worldwide. These genes will stimulate future efforts to develop more effective treatment and prevention strategies.

Public Health Relevance

We will use exome sequencing and arrayCGH to identify candidate genes responsible for schizophrenia in the Xhosa population of South Africa. This project will be the first to use large- scale genomic sequencing in a sub-Saharan African population to find causal genes for schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-GGG-H (02))
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Koester, Susan E
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Yu, Cassie; McClellan, Jon (2016) Genetics of Substance Use Disorders. Child Adolesc Psychiatr Clin N Am 25:377-85
Rippey, Caitlin; Walsh, Tom; Gulsuner, Suleyman et al. (2013) Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. Am J Hum Genet 93:697-710
Gulsuner, Suleyman; Walsh, Tom; Watts, Amanda C et al. (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154:518-29