De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism

Abstract

Background: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. In recent years, risk gene discovery in other complex psychiatric disorders has been achieved by studying rare de novo (DN) coding variants.

Methods: We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), comparing DN variant frequencies with 777 previously sequenced unaffected trios. We estimated the contribution of DN mutations to OCD risk and the number of genes involved. Finally, we looked for gene enrichment in other datasets and canonical pathways.

Results: DN likely gene disrupting and predicted damaging missense variants are enriched in OCD probands (rate ratio, 1.52; p = .0005) and contribute to risk. We identified 2 high-confidence risk genes, each containing 2 DN damaging variants in unrelated probands: CHD8 and SCUBE1. We estimate that 34% of DN damaging variants in OCD contribute to risk and that DN damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring DN damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly Tourette's disorder and autism spectrum disorder. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways, biological processes, and disease networks.

Conclusions: Our findings show a pathway toward systematic gene discovery in OCD via identification of DN damaging variants. Sequencing larger cohorts of OCD parent-child trios will reveal more OCD risk genes and will provide needed insights into underlying disease biology.

Keywords: Autism; CHD8; Obsessive-compulsive disorder; SCUBE1; Tourette; Whole-exome sequencing.

Figure 1 –. Study summary.

We performed whole exome sequencing on 222 OCD and 855 control parent-child trios. After quality control, 184 OCD and 777 control trios remained for subsequent analyses. Burden analyses compared the rates of de novo and inherited single nucleotide (SNVs) and insertion-deletion (indel) variants between cases and controls. Next, we used the TADA algorithm to assess the significance of gene-level recurrence of damaging variants in our OCD group, identifying two high-confidence risk genes. Exploratory network, pathway, and cross-disorder analyses were then performed using genes harboring de novo damaging variants in our OCD subjects. Finally, based on the number of de novo damaging variants in OCD versus controls, we estimated the number of genes contributing to OCD risk, and used this estimate to predict future risk gene discovery as additional OCD parent-child trios are studied by exome sequencing.

Figure 2 –. De novo damaging variants are associated with OCD risk.

(A) Bar chart comparing the rates of de novo mutation types between OCD cases (red) and controls (blue). Comparisons are between per base pair (bp) mutation rates, considering only those “callable” loci in each family and cohort that meet required sequencing depth and quality scores to support high confidence de novo variant calling. Mutation rates were compared using a one-tailed rate ratio test. Statistically significant comparisons (p<0.05) are marked with asterisks. Error bars show 95% confidence intervals. (B) For the enriched classes of de novo variants, we quantified their contribution to OCD risk in two ways. First, we estimated the percentage of observed variants carrying risk by dividing the difference in rates (estimated coding variants per individual, see Table 1 and Methods) by the rate in OCD. Second, we estimated the percentage of cases with a mutation mediating risk by subtracting the proportion of controls carrying a mutation from the proportion in OCD probands carrying a mutation.