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Functional convergence following disruption of diverse genes associated with neurodevelopmental disorders

Award Number: R01MH123155
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/20/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Functional convergence following disruption of diverse genes associated with neurodevelopmental disorders - PROJECT SUMMARY A complex interplay of genetic variation underlies predisposition for autism spectrum disorder (ASD). There is now strong evidence from large consortia studies that mutations in genes involved in chromatin modification, transcriptional regulation, and synaptic proteins confer substantial risk for ASD; however, the extent to which these genes are interconnected and ultimately converge on a small number of functional deficits is largely unknown. A critical need therefore exists to model new gene discoveries, to directly evaluate their functional impact, and to determine their points of convergence. Innovations from our team and others in high-throughput CRISPR-engineering have now made parallelized mechanistic studies tractable, and human induced pluripotent stem cell (hiPSCs) derived neurons are well-suited to test the impact of ASD risk variants predicted to exert their influence during fetal cortical development. Here, our multi-PI proposal will undertake an ambitious, systematic isogenic loss-of-function (LoF) mechanistic screen in a compendium of 48 of the most robust ASD risk genes discovered from the largest genetic studies to date. Moreover, our exciting preliminary results suggest that transcriptional signatures shared across neuronal models of ASD genes converge on critical regulatory nodes that result in synaptic deficits. Aim 1 will characterize isogenic glutamatergic and GABAergic neurons with highly penetrant LoF mutations in 48 genes associated with ASD risk at genome-wide significant thresholds and that are expressed in neurons. These analyses will identify transcriptional and functional signatures of individual ASD genes through RNAseq and a series of high-throughput phenotyping assays in both neuronal sub-types. Aim 2 will expand our Preliminary Results to discover convergent genes downstream of ASD risk loci, characterize the synaptic consequences of the ten most compelling discoveries from individual genes and/or convergent signatures, and integrate these data to explore the druggability of the convergent networks. Our overarching goal is to define any commonalities among diverse genes, pathways and networks that underlie ASD etiology, and to dramatically expand the list of possible therapeutic targets for ASD. These studies will generate an unprecedented isogenic resource of CRISPR-edited ASD genes, and matched RNAseq and cellular phenotyping in glutamatergic and GABAergic neurons, that will be provided for open distribution to the broader community through the NIMH RUDCR resource to yield new insights into neuropsychiatric disorders.


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 = $0 )
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	5	1/13/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $846,631 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	5	3/12/2025	NON-COMPETING CONTINUATION	$719,636
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	5	9/23/2025	NON-COMPETING CONTINUATION	$126,995
														Subtotal = $846,631

Issue Date FY: 2024 ( Subtotal = $845,729 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	4	8/12/2024	NON-COMPETING CONTINUATION	$84,572
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	4	2/9/2024	NON-COMPETING CONTINUATION	$761,157
														Subtotal = $845,729

Issue Date FY: 2023 ( Subtotal = $757,807 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	3	3/27/2023	NON-COMPETING CONTINUATION	$757,807
														Subtotal = $757,807

Issue Date FY: 2022 ( Subtotal = $796,537 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	2	5/24/2022	NON-COMPETING CONTINUATION	$796,537
														Subtotal = $796,537

Issue Date FY: 2021 ( Subtotal = $873,525 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	5/20/2021	NEW	$873,525
														Subtotal = $873,525

Grand Total All Awards = $4,120,229

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Functional convergence following disruption of diverse genes associated with neurodevelopmental disorders

Award Number: R01MH123155

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/20/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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