Obsessive-compulsive disorder (OCD) is one of the most common and incapacitating psychiatric disorders. Currently, the cause of OCD is unknown, and while treatments are available, there is no specific cure. Therefore, understanding the molecular and genetic mechanisms leading to OCD will be critical for the development of effective treatments. This is a collaborative proposal to study OCD at the molecular and patient levels. Thus far, human genetic studies in OCD have neither identified a genetic locus with a major effect using linkage studies nor found common variants associated with the condition using GWAS studies. Given the technological advances that permit large-scale sequencing, there is now the opportunity to detect putative rare functional mutations for this genetically complex condition. In this application, we propose to directly test the hypothesis that rare variants influence this disease by using cutting-edge next generation whole-genome sequencing technologies. The efficiency of identifying variants relevant for OCD will be increased by sequencing the 150 cases in large, multiplex families that are most likely to exhibit a rare mutation. Variants will be prioritized using a Bayesian multi-variant liability regression model based upon their frequency in normal controls, their functional annotation, their conservation, their enrichment in cases, and their genomic location with regard to linkage peaks and GWAS signals. The multiplex families in the study will be recontacted and assessed to identify additional relatives who had not passed through the age of risk at the time of the initial family assessment. Identifying additional affecteds will improve the sensitivity of the linkage analysis in each family, this enhancing the prioritization of variants. Subsequently, 8,000 candidate variants will be genotyped in an independent sample of 800 unrelated OCD cases and 750 controls, as well as two relatives in each multiplex family, using a large-scale iSelect chip, to identify potentially causative variants. Additionally, implicated genes will be sequenced using the MiSeq platform to identify cases with different causal variants within the same genes. If successful, these studies will open up the field for neurobiology and human genetic studies of OCD and will provide insight for new strategies to develop more effective treatments for OCD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH097971-04
Application #
8877315
Study Section
Special Emphasis Panel (ZRG1-GGG-H (02))
Program Officer
Addington, Anjene M
Project Start
2013-08-15
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
4
Fiscal Year
2015
Total Cost
$379,011
Indirect Cost
$137,254
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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