Schizophrenia (SCZ) is a generally devastating neuropsychiatric illness with considerable morbidity, mortality, and personal and societal cost. Genetic factors have been strongly implicated via family and twin data, and more recently directly through genome-wide association studies (GWAS) and sequencing studies. Epigenetic modifications play a well-accepted role in a variety of medical and neurological illnesses, and are also implicated in SCZ. Somatic mosaicism is an underexplored, but potentially very important contributor to SCZ. There have been some intriguing hints that somatic mosaicism may play a role in SCZ, but assessment of this possibility awaits rigorous experiments, and that is the overarching goal of this proposal. The primary objective of our project is to identify and characterize the extent of somatic variation in post-mortem human brain samples from individuals with SCZ and controls. Following on work of members of our team, we will rigorously assess the somatic mosaicism in a large cohort of post-mortem human brains from the Common Mind Consortium, which members of our group are already analyzing for genotype, mRNA-seq and epigenome mapping. These brains are from individuals with SCZ (250) and controls (50+). We will look for retrotransposition events, copy number variants (CNVs) and single nucleotide variants (SNVs). All data will be made available to the research community through the Sage Bionetworks Synapse Platform. We have assembled the critical personnel, sample resources, technological know-how, and analytic strategies to be able to assess the role of somatic variation in the brain as well as begin to unravel SCZ biology.

Public Health Relevance

The idea that there may be changes in the actual genome present in individual neurons has been around for decades. Our project will carefully assess whether such DNA changes are present in the brain, and also determine whether individuals with schizophrenia have more of such changes as part of their pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH106891-03
Application #
9305164
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Senthil, Geetha
Project Start
2015-09-23
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Rodin, Rachel E; Walsh, Christopher A (2018) Somatic Mutation in Pediatric Neurological Diseases. Pediatr Neurol 87:20-22
Dou, Yanmei; Gold, Heather D; Luquette, Lovelace J et al. (2018) Detecting Somatic Mutations in Normal Cells. Trends Genet 34:545-557
McConnell, Michael J; Moran, John V; Abyzov, Alexej et al. (2017) Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science 356: