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Modeling the interaction of physiological and environmental stressors on common variants to psychiatric traits

Award Number: R01ES033630
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Modeling the interaction of physiological and environmental stressors on common variants to psychiatric traits - PROJECT SUMMARY Psychiatric and neurodegenerative disorders are highly heritable and debilitating brain diseases that together affect nearly fifty million Americans, caused by the complex interaction of genetic and environmental risk factors. Although genomic studies indicate that much of disease risk reflects the aggregate impact of hundreds of genetic variants, to date, a substantial proportion of both the heritable and environmental components remain unexplained. A major challenge in the field has been illuminating the pathways connecting genetic variants (the vast majority of which fall in non-coding sequences) to target genes and causal cellular phenotypes, particularly in a cell-type-specific and context-dependent manner. We previously uncovered an unexpected combinatorial effect between risk genes that was not predicted from single gene perturbations, one that concentrated on synaptic function and linked the rare and common variant genes implicated in psychiatric disease risk. Based on our preliminary analyses and the work of others, we hypothesize that impact of genetic variants and stress converge and interact to impact critical neuronal and glia functions. Here our objective is to evaluate psychiatric and neurodegenerative risk variants, investigating convergent relationships between risk variants and stress across the major cell types of the brain. To do this, we will functionally dissect the impact of genetic variants significantly associated with brain disease, exploring their regulatory impact across cell types (neurons, astrocytes, glia) and contexts (physiological and environmental stressors) (Aim 1). To extend these insights, we will explore additive effects between risk variants and stressors at the level of network expression and cellular function (Aim 2). Finally, to test the extent that these insights might result in clinically actionably information, we will the clinical consequences of gene-environment interactions across two large healthcare and population- based biobanks (Aim 3). The translational impact of our work includes potential improvements to additive polygenic risk scores, prioritization of convergent genes for mechanistic follow-up, and identification of pathways that might serve as potential therapeutic targets. Our overarching goal is to advance the field towards an era of precision medicine, whereby not just each patient’s genetic variants, but also the expected interactions between them, can be used to predict disease trajectory and potential therapeutic interventions.


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: 2026 ( Subtotal = $979,068 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	000	5	12/16/2025	NON-COMPETING CONTINUATION	$979,068
														Subtotal = $979,068

Issue Date FY: 2025 ( Subtotal = $993,652 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	000	4	11/20/2024	NON-COMPETING CONTINUATION	$993,652
														Subtotal = $993,652

Issue Date FY: 2024 ( Subtotal = $959,532 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	000	3	1/15/2024	NON-COMPETING CONTINUATION	$959,532
														Subtotal = $959,532

Issue Date FY: 2023 ( Subtotal = $931,096 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	001	2	11/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$931,096
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	003	2	5/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$665,934
2023	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Environmental Health	002	1	5/18/2023	NEW	-$665,934
2023	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Environmental Health	000	1	11/10/2022	NEW	$0
														Subtotal = $931,096

Issue Date FY: 2022 ( Subtotal = $757,349 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Environmental Health	000	1	2/9/2022	NEW	$757,349
														Subtotal = $757,349

Grand Total All Awards = $4,620,697

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Modeling the interaction of physiological and environmental stressors on common variants to psychiatric traits

Award Number: R01ES033630

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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