Publication Date

2011-06-22

Availability

Open access

Embargo Period

2011-06-22

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2011-05-27

First Committee Member

Stephan Züchner

Second Committee Member

Charles Luetje

Third Committee Member

Michael Kim

Fourth Committee Member

Julia Dallman

Abstract

Obsessive-compulsive disorder (OCD) and the spectrum of associated conditions, affect 2-4% of the population worldwide. Although heritability studies in OCD have shown a 3 - 12 times increased risk for first degree relatives, the identification of the underlying risk-conferring genetic variation using classic genetic association studies has proven to be difficult. The possibility of a larger contribution of rare genetic variants to the risk of psychiatric disorder has been suggested by several successful studies. We expect that a spectrum of risk allele frequencies exists, which includes not only common variation but also a substantial amount of rare genetic variants that contribute to OCD. This thesis is aimed at identifying and functionally characterizing rare genetic variation in the OCD spectrum. Identified statistically significant variants were scrutinized for changes related to synaptic function using high content screening and subsequent functional analyses. Identifying the genetic profile of rare variants found in the OCD spectrum cohort combined with the functional impact that these variants have has provided insight into the etiology of the OCD spectrum. With these approaches a foundation can be laid for the development of a predictive model of the OCD spectrum.

Keywords

Obsessive-Compulsive Disorder (OCD); SLIT and NTRK-like family, member 1 (SLITRK1); neurite outgrowth; rare genetic variants; psychiatric genetics; next-generation sequencing (NGS)

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