The broad, long-term objective of the proposed research is to identify somatic genetic mutations that occur in brain regions of individuals with autism spectrum disorder (ASD), schizophrenia (SZ), and bipolar disorder (BD). Ultimately the discovery and characterization of somatic mutations may help us to understand the etiology of these disorders and eventually lead to improved therapeutic strategies and diagnostic markers. ASD, SZ, and BD are all commonly occurring neuropsychiatric disorders that have a large genetic basis (with estimated heritability of ~75% to 80% for each condition). However, relatively few DNA variants have been identified that have causal roles in the etiology. We hypothesize that somatic mosaicism--the occurrence of mutations in selected body regions after conception--occurs in brain and contributes to the etiology of ASD, SZ, and BD.
Specific Aim 1 is to identify the nature and extent of somatic mosaic mutations across brain and body regions in postmortem samples from apparently normal individuals. We will assess four categories of somatic variation: (1) single nucleotide variants (SNVs), (2) structural variants (SVs) including copy number variants, (3) L1 retrotransposition events, and (4) mitochondrial heteroplasmy. These types of variation will be detected using whole genome sequencing (Years 1 and 2), single molecule imaging with DNA nanochannels (Year 2), and single nucleotide polymorphism (SNP) arrays. Samples include brain regions (e.g. prefrontal cortex and cerebellum) and organs (e.g. heart and kidney). After identifying somatic variants we will perform rigorous validation.
Specific Aim 2 is to identify the nature and extent of somatic mosaicism in genomic DNA from individuals with ASD, SZ, and BD. The same approaches for discovery and validation will be applied as in Aim 1.
Specific Aim 3 is to functionally categorize somatic variants, particularly those that are predicted to disrupt the functions of genes previously implicated in those disorders. One approach is single-cell RNA-seq (to determine the consequence of the mutation on transcription, and to infer the cell type of origin of the somatic variant). Another approach uses neurons (or glia) derived from induced pluripotent stem cells (iPSCs) and stably expressing the wildtype or mutant forms of the somatic variants. These studies will help to establish the role of somatic mutation in neuropsychiatric disorders, including the functional consequences of such variation.

Public Health Relevance

The proposed research is relevant to public health because its goal is to identify genetic variants that occur in three psychiatric conditions: autism spectru disorder, schizophrenia, and bipolar disorder. We propose to characterize somatic mosaicism in which DNA in the brain selectively undergoes mutations. Thus we will better understand the etiology of those disorders, and ultimately both diagnosis and treatment may be improved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01MH106884-01A1
Application #
9022163
Study Section
Special Emphasis Panel (ZMH1-ERB-M (04))
Program Officer
Senthil, Geetha
Project Start
2015-09-22
Project End
2019-06-30
Budget Start
2015-09-22
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$619,801
Indirect Cost
$199,578
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
155342439
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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: