The goal of this international collaborative project, in response to PAR-20-027, is to characterize the genetic
architecture of schizophrenia in the Xhosa population of South Africa. The three participating sites have
already successfully established the infrastructure necessary to undertake the aims of this proposal. The three
sites are University of Washington, Seattle (Mary-Claire King, Jack McClellan, Tom Walsh, MPIs); Columbia
University, New York (Ezra Susser, PI); and University of Cape Town, South Africa (Dan Stein, PI).
African populations harbor far more genetic variation than out-of-Africa populations, facilitating discovery of
associations between genotypes and phenotypes. Our initial study (Gulsuner at al., Science, 2020) was the
first large-scale genetic study of schizophrenia in an ancestral African population. We discovered that Xhosa
individuals with schizophrenia (cases) are enriched for rare damaging mutations in genes intolerant to such
mutations. The effect was particularly strong for damaging mutations in genes involved in synaptic functioning.
These results extend understanding of schizophrenia genetics, specifically supporting an oligogenic severe
alleles model and a role for rare damaging mutations in genes critical to synaptic signaling and plasticity.
For this project, we propose to enroll an additional 1250 cases and 1250 age- and gender-matched controls, all
Xhosa-speaking, bringing our total study population to 5425 participants. We will apply new genomic
technology to identify previously undetectable classes of mutations likely to be implicated in schizophrenia. The
genomic structure of Xhosa cases and controls will be characterized using whole genome sequencing (wgs),
both short–read Illumina wgs to identify conventional classes of mutations and (in a subset of participants with
existing cell lines) long-read PacBio wgs to identify structural variants of all types, mobile transposable
elements, and repeat expansions. In addition, SAX v2, the African-variation-enriched SNP array developed for
this project by Affymetrix, will be used to identify copy number variants (CNVs).
Africa is the single most informative continent for understanding the human genome and human disorders with
worldwide impact. African populations provide the most complete human reference genomes for screening
candidate risk alleles for any phenotype. The whole-genome sequencing strategies used in this project allow
the comparison of all classes of damaging mutations between cases and controls, including the detection of
case-specific copy number variation and repeat expansions, while also providing a resource for human
genomics research worldwide.