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Network-based prediction and validation of causal schizophrenia genes and variants

Award Number: R01MH109978
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2021

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Network-based prediction and validation of causal schizophrenia genes and variants - DESCRIPTION (provided by applicant): The recent increase in GWAS discovery power for psychiatric disorders has led to the recognition of an undisputed genetic basis for schizophrenia (SZ). However, the mechanistic basis of the vast majority of these loci remains uncharacterized, hindering the ability to translate genetic findings into novel drug targets and develop new treatments for SZ patients. In this proposal, we overcome these challenges and seek to identify and characterize novel SZ driver genes and causal variants by combining computational and experimental methods, integrating systems-level information to prioritize individual genes and loci, and validating their gene- regulatory and cellular effects in 10 neuronal and 3 glial cell tyes derived from iPS cells. Aim 1: We infer gene co-expression networks and modules using multiple brain regions and developmental stages, and use them to predict schizophrenia driver genes based on their clustering in common networks/modules, and their linking to schizophrenia-associated loci using activity correlation, chromatin conformation and eQTLs. Aim 2: We search for schizophrenia-enriched modules of enhancer regions, discovered by clustering patterns of H3K27ac activity across brain regions, developmental stages, and individuals, using an iterative probabilistic framework for joint prediction of causal driver genes, variants, and regulators. Aim 3: We experimentally validate the gene- regulatory and neuronal/glial cellular phenotypes of predicted schizophrenia driver genes and variants in neuronal and glial cell lines based on targeted sequencing of heterozygous loci overlapping 800 putative driver genes and 10,000 putative causal variants, and systematic profiling of neuronal and glial phenotypes upon knockdown and knockout of 200 candidate genes and bidirectional CRISPR-Cas9 editing of 50 candidate causal variants. If successful, this ambitious proposal has the potential to reveal dozens of new target genes and variants associated with Schizophrenia, and open up new avenues for therapeutic development that may alleviate the personal and societal burden of schizophrenia in our lifetimes.


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: 2023 ( Subtotal = $0 )
2023	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	5	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$4,202 )
2022	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	005	5	8/17/2022	NON-COMPETING CONTINUATION	-$2,749
2022	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	002	5	6/29/2022	NON-COMPETING CONTINUATION	-$1,432
2022	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	003	4	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	3	6/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	004	3	6/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2017	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	2	6/29/2022	NON-COMPETING CONTINUATION	-$20
														Subtotal = -$4,202

Issue Date FY: 2021 ( Subtotal = -$612 )
2021	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	5	9/22/2021	NON-COMPETING CONTINUATION	-$612
														Subtotal = -$612

Issue Date FY: 2020 ( Subtotal = $398,193 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	5	4/9/2020	NON-COMPETING CONTINUATION	$398,193
														Subtotal = $398,193

Issue Date FY: 2019 ( Subtotal = $398,936 )
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	4	2/12/2019	NON-COMPETING CONTINUATION	$398,936
														Subtotal = $398,936

Issue Date FY: 2018 ( Subtotal = $427,188 )
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	3	5/25/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,188
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	003	3	6/14/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$252,719
2018	2017	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	2	5/25/2018	NON-COMPETING CONTINUATION	$0
2018	2017	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	002	2	6/14/2018	NON-COMPETING CONTINUATION	-$252,719
														Subtotal = $427,188

Issue Date FY: 2017 ( Subtotal = $475,347 )
2017	2017	BROAD INSTITUTE, INC., THE	7 CAMBRIDGE CTR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	2	2/9/2017	NON-COMPETING CONTINUATION	$427,812
2017	2017	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	001	2	7/25/2017	NON-COMPETING CONTINUATION	$47,535
														Subtotal = $475,347

Issue Date FY: 2016 ( Subtotal = $424,175 )
2016	2016	BROAD INSTITUTE INC	7 CAMBRIDGE CENTER	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Mental Health Research Grants	000	1	4/19/2016	NEW	$424,175
														Subtotal = $424,175

Grand Total All Awards = $2,119,026

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Network-based prediction and validation of causal schizophrenia genes and variants

Award Number: R01MH109978

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2021

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