The Association Between De Novo Sequence/copy Number Variants And Tourette Disorder

Tourette Disorder(TD)is an early onset neurodevelopmental disorder characterized by persistent chronic motor and vocal tics.The worldwide prevalence of TD is estimated to be between 0.3%and 0.9%.There is also a pronounced sex bias,with males much more likely to be affected(male-to-female ratio is approximately 2-4:1).Family and twin studies have long indicated that genetic factors contribute to TD pathology.Additionally,our group and others have implicated rare and/or de novo variants with TD risk.However,the genetic architecture of TD is still largely uncharacterized.In this study,whole-exome sequencing(WES)data from 802 TD trios were analyzed to investigate the contribution of genetic factors in TD risk.Comparing with unaffected controls,de novo damaging variants are significantly enriched in TD simplex trios(child with TD but the parents have no history of Tic phenotypes)but not in multiplex trios(child with TD and one or more parents have history of Tic phenotypes).The results suggest that female TD probands from simplex families tend to have more de novo damaging variants than male probands,supporting the idea of the female protective effect.Within the WES data,this study also identified,for the first time,a statistically significant enrichment of de novo copy number variants(CNVs)in TD.This observation was further confirmed with microarray genotyping data from 399 TD trios.These observations clarify the genetic architecture of TD and are consistent with other early-onset neurodevelopmental disorders,such as Autism Spectrum Disorders(ASD).A combined analysis of de novo sequence variants and de novo CNVs indicated that 9.7%of TD patients from simplex families carry at least one de novo sequence variant and 1.5%carry a de novo CNV mediating risk.As a result,around 10%TD patients from simplex families carry at least a de novo event contributing to TD risk.Taking use of de novo damaging variants,it is estimated that around 483 genes contribute risk to TD.Moreover,this study identified a new high-confidence TD risk gene,CELSR3(Cadherin EGF LAG Seven-Pass G-Type Receptor 3),and two new probable TD risk genes,OPA1(OPA1,Mitochondrial Dynamin Like GTPase)and FBN2(Fibrillin 2).Additionally,genes involved in cell polarity are more often disrupted by a de novo sequence variant than expected by chance,suggesting this pathway may be relevant to TD.Compared to those from other psychiatric disorders,the results demonstrated that de novo sequence variants from TD and Obsessive-compulsive Disorder(OCD)tend to overlap,and that de novo CNVs from TD and ASD tend to overlap,suggesting common genetic risk factors in different disorders.In summary,these results demonstrate that both de novo sequence variants and de novo copy number variants are involved in TD pathogenesis,and provide evidence to support the hypothesis that cell polarity is involved in TD pathogenesis.The results in this study not only informs sample collection and genetic studies in the future,but also provide the theoretical basis for following study of genetic mechanisms of TD.