Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study

Abstract

Objective Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable, neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. Method The primary analyses utilized a cross-disorder design for 2,699 patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Results Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p=.09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 patient deletions: 0 control deletions, p=0.08 in current study, p=0.025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support to the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in autism or schizophrenia (2–4%). Conclusion Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

“…Our group and others have reported on copy number variations (CNVs) in TD (Fernandez et al, 2012; McGrath et al, 2014; Nag et al, 2013; Sundaram et al, 2010), confirming a role for rare structural variants and showing a trend toward enrichment of de novo events. These findings also provide additional support for the involvement of histaminergic neurotransmission, as well as dopaminergic neurotransmission, in the pathogenesis of TD (Ercan-Sencicek et al, 2010; Fernandez et al, 2012) and suggest a potential overlap with CNVs contributing to other neurodevelopmental syndromes (Malhotra and Sebat, 2012).…”

Hoarding in children and adolescents with obsessive–compulsive disorder

“…Moreover, although collecting rituals are developmentally normative, with peak age of occurrence about 2 years of age (Evans et al, 1997), children with high levels of fear, shyness, and need for order and predictability may maintain and extend these rituals beyond the age when they are adaptive (Zohar & Felz, 2001). Alternatively, hoarding and autism may be neurodevelopmental consequences of deletions of the same, specific chromosomal regions, as suggested by recent findings (Lionel et al, 2014; McGrath et al, 2014). …”

Gilles de la Tourette syndrome

“…Yu and colleagues used polygenic risk scores to identify distinct differences between polygenic risk burden of OCD with and without co-occurring GTS/Chronic Tic Disorder 73 . Also noteworthy is the significant overlap of rare GTS CNVs in loci previously shown to harbour recurrent deletions/duplications in other developmental neuropsychiatric disorders, including autism, ASD, schizophrenia, and epilepsy including 1q21, NRXN1, and 16p13.11 deletions, as well as 22q11 duplications 67,74 . The first reported epigenome-wide association study for GTS, although limited in size, also found significant enrichment among the top hits in genes related to neuropsychiatric and neurological disorders 75 .…”