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Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci

Award Number: R01MH125246
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci - PROJECT SUMMARY Serious mental illness (SMI) that includes schizophrenia (SCZ) and bipolar disorder (BD) are common, complex and debilitating psychiatric disorders that together affect over 2% of the population and carry considerable morbidity, mortality, and personal and societal cost. Over the last decade, large-scale genome wide association studies (GWAS) have identified hundreds of loci contributing to the risk of SCZ and BD. Advancing these statistical associations to causal mechanisms for SMIs is very challenging due to incomplete understanding of the non-coding regulatory mechanisms in the human brain tissue and the local correlation of risk variants. Therefore, a systematic analysis that performs fine-mapping to jointly identify and validate a credible set of causal variants in SMI and molecular features that includes transcripts and regulatory sequences, in relevant tissues and cell types is a critical next step. The overarching goal of our proposal is to leverage genomics and multiscale functional omics (gene expression and epigenome regulation) data and perform fine mapping to detect and validate causal variants, transcripts and regulatory sequences in SMI. In Aim 1, we will perform large-scale trans- ancestry GWAS of SCZ and BD to expand the current repertoire of risk (and resilience) loci and refine the credible sets of causal variants underlying genome-wide significant associations. In Aim 2, we will integrate putative causal variants with multiscale functional omics data from human brain tissue that capture gene expression and epigenome regulation at the bulk, cell type-specific and single cell level to identify credible sets of transcripts and regulatory sequences. In Aim 3, we will functionally validate putative causal variants and regulatory sequences, by using novel approaches that combine massively parallel reporter assays and genome editing in excitatory and inhibitory neurons derived from human induced pluripotent stem cells. Our computational and experimental aims bridge the gap between the fine-mapping of causal variants, the molecular gene- regulatory effects of risk variants on enhancer activity and gene expression and their biological effects at the cellular level. If successful, our project can elucidate the genes, pathways, and mechanisms underlying SCZ and BD, and provide new insights and avenues for therapeutic development.


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 = $1,067,884 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	5	11/20/2024	NON-COMPETING CONTINUATION	$1,067,884
														Subtotal = $1,067,884

Issue Date FY: 2024 ( Subtotal = $1,259,821 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	4	7/5/2024	NON-COMPETING CONTINUATION	$125,983
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	4	10/25/2023	NON-COMPETING CONTINUATION	$1,133,838
														Subtotal = $1,259,821

Issue Date FY: 2023 ( Subtotal = $1,002,134 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	3	2/6/2023	NON-COMPETING CONTINUATION	$100,214
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	3	11/2/2022	NON-COMPETING CONTINUATION	$901,920
														Subtotal = $1,002,134

Issue Date FY: 2022 ( Subtotal = $815,483 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	2	12/15/2021	NON-COMPETING CONTINUATION	$733,934
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$81,549
														Subtotal = $815,483

Issue Date FY: 2021 ( Subtotal = $851,306 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	1	3/29/2021	NEW	$0
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	1	12/31/2020	NEW	$851,306
														Subtotal = $851,306

Grand Total All Awards = $4,996,628

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Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci

Award Number: R01MH125246

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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