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Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia

Award Number: R01MH125236
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia - Project Summary Schizophrenia (SCZ) genomics has achieved unprecedented advances. A decade ago, there was perhaps one solid finding, and there are now ~270 loci that meet consensus criteria for significance and replication. As observed for other complex psychiatric disorders, the identified regions are overwhelmingly noncoding, strongly suggesting that genetic variation in gene regulatory elements is a major mechanistic contributor. Further investigation of those regulatory mechanisms is precluded by a fundamental gap in the ability to identify, characterize, and quantify brain-relevant regulatory elements, and limited understanding of how genetic variation within those elements influences their function. To address this knowledge gap, this project will comprehensively identify, characterize, quantify, and validate noncoding functional noncoding regulatory elements and variants in neuronal cells. The central hypothesis of the proposal is that noncoding variation contributes to psychiatric disorders by directly altering the function of regulatory elements in the brain. The motivation for the proposed study is that identifying regulatory mechanisms of psychiatric disorders has the potential to translate into improved diagnosis and treatment. Powered by a team with strong interdisciplinary expertise in psychiatric disorders, functional genomics, technology development, and statistical genetics, this hypothesis will be tested by completing three specific aims: 1) Comprehensive integration of diverse data types to generate hypotheses that “connect” psychiatric genetic results to specific genes; 2) perform high-throughput CRISPR epigenome editing screens to test Aim 1 hypotheses in a natural biological context; 3) Develop mechanistic understanding and validate functional noncoding SCZ risk variants using TF binding assays and iPS-derived neurons from SCZ cases with high genetic risk scores. Our approach is innovative because it uses a highly complementary and diverse set of experimental approaches to drive targeted genetic and functional investigation into regulatory mechanisms relevant for SCZ. In doing so, the proposed research provides a much-needed path forward to understand how noncoding variation contributes to complex human phenotypes.


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 = $1,359,313 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Mental Health Research Grants	000	5	3/18/2025	NON-COMPETING CONTINUATION	$1,359,313
														Subtotal = $1,359,313

Issue Date FY: 2024 ( Subtotal = $1,599,191 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Mental Health Research Grants	001	4	8/14/2024	NON-COMPETING CONTINUATION	$159,918
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Mental Health Research Grants	000	4	1/24/2024	NON-COMPETING CONTINUATION	$1,439,273
														Subtotal = $1,599,191

Issue Date FY: 2023 ( Subtotal = $1,599,191 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Mental Health Research Grants	000	3	1/26/2023	NON-COMPETING CONTINUATION	$1,599,191
														Subtotal = $1,599,191

Issue Date FY: 2022 ( Subtotal = $1,599,191 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$159,922
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	2	2/15/2022	NON-COMPETING CONTINUATION	$1,439,269
														Subtotal = $1,599,191

Issue Date FY: 2021 ( Subtotal = $1,653,935 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	1	3/24/2021	NEW	$1,653,935
														Subtotal = $1,653,935

Grand Total All Awards = $7,810,821

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Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia

Award Number: R01MH125236

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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