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 #
1U01MH105670-01
Application #
8805881
Study Section
Special Emphasis Panel (ZMH1-ERB-C (07))
Program Officer
Addington, Anjene M
Project Start
2014-09-18
Project End
2018-07-31
Budget Start
2014-09-18
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$1,376,321
Indirect Cost
$491,146
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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
Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi et al. (2017) Annotating pathogenic non-coding variants in genic regions. Nat Commun 8:236
Mori, Mari; Haskell, Gloria; Kazi, Zoheb et al. (2017) Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. Mol Genet Metab 122:189-197