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1/2 An Integrative Genetic Investigation of Schizophrenia

Award Number: R01MH094091
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2011
PERIOD OF PERFORMANCE END DATE: 10/31/2017

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1/2 An Integrative Genetic Investigation of Schizophrenia - DESCRIPTION (provided by applicant): Schizophrenia is a common, severe, highly heritable psychotic disorder for which biological insights and etiological knowledge-based treatments have yet to be achieved. The vast majority of patients suffering from schizophrenia remains ill after the initial episode, suffering from chronic and severely incapacitating symptoms, and are unable to work. Genome-wide association studies (GWAS) have been successful in uncovering individual common susceptibility loci reproducibly associated with schizophrenia. However, identifying the underlying causal variants, risk genes, and etiological gene networks have proven difficult for schizophrenia, like for most other complex disorders. It is likely that many risk variants in these loci are regulatory in nature. Here, we propose to fill the gap in our biological understanding of schizophrenia etiology through an integrative genomics approach based on SNP genotype and RNAseq data from a large collection of lymphoblastoid cell lines (LCLs) derived from the Molecular Genetics of Schizophrenia case-control sample, which includes rich demographic and psychiatric information. Expression signatures will be generated at baseline and after a perturbation with dopamine, predicated on the hypothesis that cell perturbation using this pharmacologically relevant agent will reveal etiologically relevant genes which are undetectable in the unperturbed (baseline) state. We present evidence of two supporting facts: (1) Signals from expression analysis of LCLs and GWAS results converge at the major histocompatibility complex region on chromosome 6. (2) Dopamine stimulation strongly regulates the expression of many genes located in genome-wide significant GWAS loci, and in copy number variants associated with schizophrenia. Our study will capitalize on an ongoing experiment (RC2MH90030) of unstimulated (baseline) genome-wide expression profiles of LCLs from the same sample. We will identify dopamine-responsive transcripts associated with schizophrenia, analyze the underlying regulatory DNA variants (i.e., expression quantitative trait nucleotides, eQTNs), and assess the association of eQTNs with schizophrenia. We will then perform validation testing of LCL findings in neural tissues, and will functionally characterize a set of most important eQTNs. The proposed study is expected to identify new loci influencing schizophrenia risk, reveal the causal genes in already identified GWAS loci, and shed light on the underlying etiological mechanisms by establishing a connection to the mechanisms of action of antipsychotics, spearheading clinical applications in the field for diagnostic classification and treatment.


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: 2018 ( Subtotal = $0 )
2018	2015	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE SUITE 100	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	5	2/16/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE SUITE 100	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	5	5/5/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $516,034 )
2015	2015	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	5	5/16/2015	NON-COMPETING CONTINUATION	$516,034
														Subtotal = $516,034

Issue Date FY: 2014 ( Subtotal = $484,431 )
2014	2014	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	4	4/30/2014	NON-COMPETING CONTINUATION	$484,431
														Subtotal = $484,431

Issue Date FY: 2013 ( Subtotal = $447,908 )
2013	2013	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	3	5/7/2013	NON-COMPETING CONTINUATION	$447,908
														Subtotal = $447,908

Issue Date FY: 2012 ( Subtotal = $634,466 )
2012	2012	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	2	4/20/2012	NON-COMPETING CONTINUATION	$503,948
2012	2012	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	001	2	5/30/2012	SUPPLEMENT FOR EXPANSION	$130,518
														Subtotal = $634,466

Issue Date FY: 2011 ( Subtotal = $567,397 )
2011	2011	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Mental Health Research Grants	000	1	7/21/2011	NEW	$567,397
														Subtotal = $567,397

Grand Total All Awards = $2,650,236

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1/2 An Integrative Genetic Investigation of Schizophrenia

Award Number: R01MH094091

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/21/2011

PERIOD OF PERFORMANCE END DATE: 10/31/2017

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