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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

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      Linked Article

      • Don’t Worry, the Genetics of Obsessive-Compulsive Disorder Is Finally Catching Up
        Biological PsychiatryVol. 87Issue 12
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          The advent and application of high-throughput sequencing is revolutionizing our understanding of the molecular neurobiology of diverse psychiatric disorders. Whole-genome sequencing, which targets the coding regions of the genome, and whole-exome sequencing are being applied to study multiple psychiatric disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder, schizophrenia, and Tourette’s disorder, among others [(1–3); https://schema.broadinstitute.org ]. These studies have demonstrated a role for ultrarare, deleterious, frequently de novo variation in each disorder, and have identified high-confidence genes, including more than 100 high-confidence ASD genes (2).
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