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Integrative Approaches to Understanding Genetic Basis of Neuropsychiatric Diseases

Award Number: R01MH110531
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/17/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Integrative Approaches to Understanding Genetic Basis of Neuropsychiatric Diseases - Project Summary Identifying the susceptibility genes and variants of neuro-psychiatric diseases will not only contribute to our understanding of these diseases, but also point to potential therapeutic targets. Genome-wide association studies (GWAS) are commonly used to study complex diseases, and have been highly successful in a range of disorder, for instance, more than 100 loci have been associated with the risk of Schizophrenia through GWAS. Nevertheless, in most cases, we do not know the biological mechanisms underlying disease associated loci, because the causal variants and genes are obscured by linkage disequilibrium (LD) and by the difficulty of interpreting functional effects of most genetic variants. The goal of this project is to develop novel statistical methods for integrative analysis of genetic data of neuropsychiatric diseases to better understand the underlying genes and biological processes. (1) We will develop a method to integrate expression QTL (eQTL) data with GWAS. Our method extends the popular Transcriptome-Wise Association Studies (TWAS). TWAS aims to discover risk genes, by effectively assessing the correlation of eQTLs of a gene with the phenotype of interest. TWAS has many advantages over standard single variant-based analysis, e.g. it reduces multiple testing burden and provides biological contexts of associations. However, current TWAS methods are susceptible to false positive findings. We will develop a rigorous statistical framework to control false discoveries by accounting for pleiotropic effects of variants. (2) Fine-mapping is the statistical approach to identifying causal variants in disease-associated loci. Current fine- mapping methods, however, are often not able to narrow down specific causal variants. Our approach is based on the observation that allelic heterogeneity (AH), i.e. many variants disrupting the same gene, is common. So we can leverage AH to identify risk genes, borrowing the statistical framework of fine-mapping. (3) Researchers have developed tools to joint analyze multiple traits to improve the power of gene discovery and to identify causal risk factors of diseases. Existing approaches, however, are often based on pair-wise analysis. We will develop a powerful statistical framework to better understand common biological processes driving genetic relationships among multiple traits. Additionally, we will develop more accurate Mendelian Randomization (MR) method to identify causal relationship among traits. (4) A key component of our effort is the development of user-friendly software that could benefit the broad psychiatric genetics community.


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 = -$70,410 )
2026	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	6	11/21/2025	NON-COMPETING CONTINUATION	-$70,410
														Subtotal = -$70,410

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	6	8/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $503,169 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	6	6/9/2022	NON-COMPETING CONTINUATION	$503,169
														Subtotal = $503,169

Issue Date FY: 2021 ( Subtotal = $495,423 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	5	5/28/2021	NON-COMPETING CONTINUATION	$495,423
2021	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	002	4	7/20/2021	COMPETING CONTINUATION	$71,288
2021	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	001	3	7/20/2021	NON-COMPETING CONTINUATION	-$71,288
														Subtotal = $495,423

Issue Date FY: 2020 ( Subtotal = $522,733 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	001	4	7/27/2020	COMPETING CONTINUATION	$522,733
2020	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	3	7/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $522,733

Issue Date FY: 2019 ( Subtotal = $559,999 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	3	2/28/2019	NON-COMPETING CONTINUATION	$559,999
														Subtotal = $559,999

Issue Date FY: 2018 ( Subtotal = $549,610 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	001	2	6/15/2018	NON-COMPETING CONTINUATION	$54,962
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	2	2/13/2018	NON-COMPETING CONTINUATION	$494,648
														Subtotal = $549,610

Issue Date FY: 2017 ( Subtotal = $577,659 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	1	5/16/2017	NEW	$577,659
														Subtotal = $577,659

Grand Total All Awards = $3,138,183

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Integrative Approaches to Understanding Genetic Basis of Neuropsychiatric Diseases

Award Number: R01MH110531

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/17/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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