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pathQTL: Integrative Multi-Omics Causal Inference of Molecular Mechanisms Leading to Neuropsychiatric Illness

Award Number: R01MH118349
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/10/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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pathQTL: Integrative Multi-Omics Causal Inference of Molecular Mechanisms Leading to Neuropsychiatric Illness - Project Summary A multitude of common genetic variants influencing risk for neuropsychiatric disorders (e.g., schizophrenia, major depressive disorder, and Alzheimer’s disease) have recently been identified and replicated, providing a foothold into the causes of these disorders. The critical next step in neuropsychiatric genetics is to move from a risk locus in the genome to an understanding of how this genetic variation influences molecules, cells, and circuits of the brain, leading to complex disorders. Many datasets, including those generated by our own labs, have established direct links between genotype and human brain traits at multiple levels of biology (molecular: chromatin accessibility, expression; cellular: morphology; circuit: gross brain structure), termed quantitative trait loci (QTLs). Here, we will integrate QTLs across multiple levels of biology in order to statistically prioritize causal pathways by which genetic variation creates risk for complex neuropsychiatric disorders. Causal modeling goes well beyond previous co-localization work, as it allows the prioritization of expensive functional validation experiments for cellular or molecular changes that are a cause of the disorder, rather than those that are a consequence or independent of the disorder. It additionally allows inference of key experimental parameters including cell-type and developmental time period. Finally, causal inference when combined across multiple levels of biology and multiple disorder risk loci allows for assessment of convergence at a biological level, cell-type, or developmental time period, which is critical information for therapeutic targeting. We will leverage the computational and statistical frameworks of Bayesian probabilistic networks and causal inference in a new framework that utilizes association summary statistics, as well-powered multi-level data collected on the same individuals is almost always infeasible. Subsequently, we will experimentally validate the molecular predictions of our model using epigenetic engineering in primary human neural progenitor cells, and in turn revising the computational models. Prioritizing causal molecular pathways of disorder associated variants, and identifying the relevant cell-type and developmental stage will increase the success rate of validation experiments and shed light on mechanisms of neuropsychiatric disorders in an unbiased manner.


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: 2024 ( Subtotal = -$4,224 )
2024	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	5	4/12/2024	NON-COMPETING CONTINUATION	-$4,224
														Subtotal = -$4,224

Issue Date FY: 2023 ( Subtotal = $471,846 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	5	2/4/2023	NON-COMPETING CONTINUATION	$47,185
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	5	11/18/2022	NON-COMPETING CONTINUATION	$424,661
														Subtotal = $471,846

Issue Date FY: 2022 ( Subtotal = $468,892 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	4	1/13/2022	NON-COMPETING CONTINUATION	$422,002
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	4	5/23/2022	NON-COMPETING CONTINUATION	$46,890
														Subtotal = $468,892

Issue Date FY: 2021 ( Subtotal = $471,846 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	3	4/14/2021	NON-COMPETING CONTINUATION	$47,185
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	3	12/15/2020	NON-COMPETING CONTINUATION	$424,661
														Subtotal = $471,846

Issue Date FY: 2020 ( Subtotal = $496,679 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	2	12/6/2019	NON-COMPETING CONTINUATION	$447,011
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	2	3/11/2020	NON-COMPETING CONTINUATION	$49,668
														Subtotal = $496,679

Issue Date FY: 2019 ( Subtotal = $493,569 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	1	9/24/2019	NEW	$0
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	1	12/10/2018	NEW	$493,569
														Subtotal = $493,569

Grand Total All Awards = $2,398,608

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pathQTL: Integrative Multi-Omics Causal Inference of Molecular Mechanisms Leading to Neuropsychiatric Illness

Award Number: R01MH118349

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/10/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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