Date of Award

January 2020

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Thomas V. Fernandez


Obsessive-compulsive disorder (OCD) is a neuropsychiatric developmental disorder with known heritability (estimates ranging from 27%-80%) but poorly understood etiology. Current treatments are not fully effective in addressing chronic functional impairments and distress caused by the disorder, providing an impetus to study the genetic basis of OCD in the hopes of identifying new therapeutic targets. We previously demonstrated a significant contribution to OCD risk from likely damaging de novo germline DNA sequence variants, which arise spontaneously in the parental germ cells or zygote instead of being inherited from a parent, and we successfully used these identified variants to implicate new OCD risk genes. Recent studies have demonstrated a role for DNA copy-number variants (CNVs) in other neuropsychiatric disorders, but CNV studies in OCD have been limited. Additionally, studies of autism spectrum disorder and intellectual disability suggest a risk contribution from post-zygotic variants (PZVs) arising de novo in multicellular stages of embryogenesis, suggesting these mosaic variants can be used to study other neuropsychiatric disorders. In the studies presented here, we aim to characterize the contribution of PZVs and rare CNVs to OCD risk.

We examined whole-exome sequencing (WES) data from peripheral blood of 184 OCD trio families (unaffected parents and child with OCD) and 777 control trios that passed quality control measures. We used the bioinformatics tool MosaicHunter to identify low–allele frequency, potentially mosaic single-nucleotide variants (SNVs) in probands (OCD cases) and in control children. We then applied the XHMM tool to 101 of the OCD trio families and to the 777 control trio families, all generated with the same capture library and platform, to identify CNVs.

The rate of all single-nucleotide PZVs per base pair was not significantly different between OCD probands (4.90 x 10-9) and controls (4.93 x 10-9), rate ratio = 0.994, p = 1. The rate of likely-damaging PZVs (those altering a stop codon or splice site) also is not significantly different in OCD probands (1.45 x 10-9) than in controls (1.09 x 10-9), rate ratio = 1.33, p = 0.653.

When examining CNVs, the proportion of children with at least one rare duplication or deletion is not significantly different between OCD cases (0.869) and controls (0.796), chi-square = 2.97, p = 0.0846. However, when considering deletions separately from duplications, the proportion of children with at least one rare deletion is higher in OCD trios (0.606) than in controls (0.448), chi-square = 8.86, p = 0.00292.

Although we did not detect a higher burden of PZVs in blood in individuals with OCD, further studies may benefit from examining a larger sample of families or from looking for PZVs in other tissues. The higher rate of de novo deletions in cases vs. controls suggests they may contribute to OCD risk, but further work is needed to experimentally validate the detected CNVs. We hope to eventually use these CNVs to identify OCD risk genes that could provide jumping-off points for future studies of molecular disease mechanisms.


This is an Open Access Thesis.

Open Access

This Article is Open Access