The overarching goal of this study is the development of a framework to identify causal regulatory mutations in patients with serious neuropsychiatric presentations through the paired analyses of whole genome sequence and high resolution RNA sequence data from both accessible primary cells (PBMC and buccal cells) and reprogrammed neuronal cells from the same patients. The latter constitutes a particularly exciting opportunity as it will allow us to assay gene expression during different developmental stages of previously inaccessible cell types of much greater relevance to patient phenotype than the circulating cells DNA studies are customarily performed on. Specifically, we will interpret the effects of the regulatory variants in different developmental stages of the reprogrammed neuronal and other cells of interest with a comparison to the PBMC and buccal cells helping to interpret the specificity or generality of the relevant effects in different tissues. These analyses will focus nt only on mapping cis- and trans-acting eQTLs, but will also deploy new variant prioritization schemes that integrate knowledge of regulatory regions of the genome through ENCODE and related efforts as well as population genetic data. While an explicit aim of the work is to identif regulatory variants influencing risk of schizophrenia and autism, we emphasize that this work has primarily the broader goal of the development of appropriate frameworks for the eventual identification of such mutations, which inevitably will require substantially larger sample sizes that currently feasible to facilitate systematic discovery.

Public Health Relevance

This project will establish a paradigm by which rare, non-coding DNA variation can begin to be robustly evaluated for a role in severe neurodevelopmental and Mendelian disease. This in turn may lead to the development of specific tests to improve the diagnosis of such disorders and may point to novel therapeutic targets to improve treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH105669-03
Application #
9116306
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Addington, Anjene M
Project Start
2014-09-18
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
Fan, Linlin Z; Nehme, Ralda; Adam, Yoav et al. (2018) All-optical synaptic electrophysiology probes mechanism of ketamine-induced disinhibition. Nat Methods 15:823-831
Nehme, Ralda; Zuccaro, Emanuela; Ghosh, Sulagna Dia et al. (2018) Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission. Cell Rep 23:2509-2523
Sanders, Stephan J; Neale, Benjamin M; Huang, Hailiang et al. (2017) Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nat Neurosci 20:1661-1668
Gymrek, Melissa; Willems, Thomas; Reich, David et al. (2017) Interpreting short tandem repeat variations in humans using mutational constraint. Nat Genet 49:1495-1501