Sunday, August 10, 2025 8/10/2025

1/3-Schizophrenia Genetics and Brain Somatic Mosaicism

Award Number: U01MH106893
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2015
PERIOD OF PERFORMANCE END DATE: 01/31/2021

Group Awards By:

View Award Description

1/3-Schizophrenia Genetics and Brain Somatic Mosaicism - DESCRIPTION (provided by applicant): Schizophrenia (SCZD) is a debilitating and typically incurable neuropsychiatric disease that affects 1% of the human population. Disease symptoms, which include hallucinations, paranoia, and impaired cognition, are thought to arise from impairments in neuronal connectivity and plasticity, but etiology of these defects remains unclear. Multiple lines of evidence suggest a strong genetic component to SCZD. Thus, identifying genetic variants associated with SCZD may provide critical tools for understanding and treating the disease. Indeed, recent genome wide association studies have identified >100 loci that are associated with SCZD, but these genetic variants account for only a small percentage of disease incidence. One potential explanation for this unsatisfying result is that SCZD risk alleles are not inherited through the germline, but instead arise through somatic mutations within neurons of affected individuals. Perhaps it is the propensity for somatic mosaicism that is inherited in patients with SCZD. It is now clear that somatic mosaicism of DNA sequence is much more common than previously thought (i.e., all cells within an individual do not contain the same genome), and that this phenomenon is particularly prevalent in the brain. These genomic differences may contribute to the diversity of neuronal function. However, dysregulation of processes that generate or control somatic mosaicism may lead to disease-related genomic instability. Our hypothesis, therefore, is that somatic mosaicism in neurons or their progenitors are a major contributor to SCZD pathogenesis. Aim 1 will use single-cell genomic sequencing techniques to identify somatic copy number variants (CNVs) in neuronal and non-neuronal cell types from patients with SCZD or neurotypic controls. These analyses will focus on the frontal cortex and hippocampus, two brain regions associated with SCZD pathogenesis. Results will determine whether somatic CNVs are overrepresented in SCZD brains, and whether SCZD risk alleles are disproportionately affected by these CNVs. Aim 2 will characterize somatic retrotransposon insertions within these same cell types, asking whether the frequency or location of retrotransposition events is altered in neurons from patients with SCZD compared with controls. A total of 8000 neurons will be analyzed in Aims 1 and 2, making this the most comprehensive analysis of neuronal somatic mosaicism to date. In Aim 3, genomic variants most overrepresented in patients with SCZD (identified in Aims 1 and 2) will be engineered into hESCs for functional validation tests. It has been shown that cultured neurons derived from patients with SCZD exhibit reduced levels of connectivity and have underdeveloped neurites compared with controls. Similar analyses will be performed using isogenic and mosaic cultures of neurons derived from engineered hESCs. Results from these studies will determine whether the level, pattern, or type of somatic mosaicism is altered in SCZD neurons, and potentially identify genes and gene networks most affected by these changes. Identifying causal disease factors will provide new therapeutic targets and move us closer to finding a cure for this devastating disease.


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 = $0 )
2024	2019	THE LIEBER INSTITUTE	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	5	2/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $696,225 )
2019	2019	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	5	4/11/2019	NON-COMPETING CONTINUATION	$696,225
														Subtotal = $696,225

Issue Date FY: 2018 ( Subtotal = $696,225 )
2018	2018	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	4	8/18/2018	NON-COMPETING CONTINUATION	$696,225
														Subtotal = $696,225

Issue Date FY: 2017 ( Subtotal = $785,025 )
2017	2017	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	001	3	7/12/2017	NON-COMPETING CONTINUATION	$78,503
2017	2017	LIEBER INSTITUTE, INC.	855 N WOLFE ST	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	3	3/31/2017	NON-COMPETING CONTINUATION	$706,522
														Subtotal = $785,025

Issue Date FY: 2016 ( Subtotal = $1,029,456 )
2016	2016	LIEBER INSTITUTE INC	855 NORTH WOLFE STREET	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	2	2/9/2016	NON-COMPETING CONTINUATION	$861,767
2016	2016	LIEBER INSTITUTE INC	855 NORTH WOLFE STREET	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	001	2	6/21/2016	SUPPLEMENT FOR EXPANSION	$167,689
2016	2016	LIEBER INSTITUTE INC	855 NORTH WOLFE STREET	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	002	2	6/23/2016	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,029,456

Issue Date FY: 2015 ( Subtotal = $724,867 )
2015	2015	LIEBER INSTITUTE INC	855 NORTH WOLFE STREET	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	4/17/2015	NEW	$724,867
														Subtotal = $724,867

Grand Total All Awards = $3,931,798

Top

All Categories

About

Search

Reports

Data Submission

Award Information

1/3-Schizophrenia Genetics and Brain Somatic Mosaicism

Award Number: U01MH106893

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/20/2015

PERIOD OF PERFORMANCE END DATE: 01/31/2021

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer