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3/3 Genomics of Schizophrenia in the South African Xhosa

Award Number: U01MH125053
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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3/3 Genomics of Schizophrenia in the South African Xhosa - PROJECT DESCRIPTION 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: 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 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $524,661 )
2025	2025	UNIVERSITY OF CAPE TOWN	LOVERS WALK	CAPE TOWN				ZAF	Mental Health Research Grants	000	5	12/12/2024	NON-COMPETING CONTINUATION	$524,661
														Subtotal = $524,661

Issue Date FY: 2024 ( Subtotal = $772,930 )
2024	2024	UNIVERSITY OF CAPE TOWN	LOVERS WALK	CAPE TOWN				ZAF	Mental Health Research Grants	001	4	7/16/2024	NON-COMPETING CONTINUATION	$77,292
2024	2024	UNIVERSITY OF CAPE TOWN	LOVERS WALK	CAPE TOWN				ZAF	Mental Health Research Grants	000	4	3/1/2024	NON-COMPETING CONTINUATION	$695,638
														Subtotal = $772,930

Issue Date FY: 2023 ( Subtotal = $752,229 )
2023	2023	UNIVERSITY OF CAPE TOWN	LOVERS WALK	CAPE TOWN				ZAF	Mental Health Research Grants	000	3	3/2/2023	NON-COMPETING CONTINUATION	$752,229
														Subtotal = $752,229

Issue Date FY: 2022 ( Subtotal = $777,438 )
2022	2022	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH				ZAF	Mental Health Research Grants	001	2	6/3/2022	NON-COMPETING CONTINUATION	$77,743
2022	2022	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH				ZAF	Mental Health Research Grants	000	2	2/7/2022	NON-COMPETING CONTINUATION	$699,695
														Subtotal = $777,438

Issue Date FY: 2021 ( Subtotal = $708,041 )
2021	2021	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH				ZAF	Mental Health Research Grants	001	1	9/8/2021	NEW	$0
2021	2021	UNIVERSITY OF CAPE TOWN	LOVERS WALK	RONDEBOSCH				ZAF	Mental Health Research Grants	000	1	4/2/2021	NEW	$708,041
														Subtotal = $708,041

Grand Total All Awards = $3,535,299

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3/3 Genomics of Schizophrenia in the South African Xhosa

Award Number: U01MH125053

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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