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• W4387476746 abstract "Tourette syndrome (TS) is an early-onset neurodevelopmental disorder (NDD) characterized by vocal and motor tics. TS is highly heritable (60-80%) and has a complex genetic architecture with both rare and common variants contributing to the genetic etiology. However, the contribution of de novo variants has not been widely studied due to the lack of large-scale high-quality family-structured sequencing datasets and insufficient statistical power. In this study, we generated whole-exome sequencing (WES) data for over 1,300 TS trio families and jointly called the data with a selected subset of over 6,600 families from SSC and SPARK datasets containing at least one Autism Spectrum Disorder (ASD) proband. This produced a high-quality unified dataset with 30,803 individuals and 4,425,974 variants. Our principal component analysis showed a diverse ancestry background with all major population groups present in the ASD cohorts, while only Europeans and Admixture Americans were present in the TS cohort. Analyzing samples from all three cohorts demonstrated a trend of increased burden of de novo pathogenic singletons (FC_{TS/Control}=1.23; n.s.), defined as protein-truncating variants (PTVs), in TS probands compared to healthy controls, while confirming a significant enrichment of de novo mutations in ASD probands compared to healthy controls (FC_{ASD/Control}=1.05; P_{ASD,Control}=4.70*10^-2). Considering the phenotypic heterogeneity previously reported for the SPARK cohort, we further investigated a subset with only TS and SSC cohorts (N_{Proband+Control}=3,655) and revealed a significant stepwise enrichment of de novo pathogenic variants across healthy controls, TS probands, and ASD probands (FC_{TS/Control}=1.04; P_{Control,TS}=2.59*10^-2; FC_{ASD/TS}=1.11; P_{TS,ASD}=4.62*10^-7), recapitulating the phenotypic spectrum of NDD. In brief, our study includes one of the largest TS-ASD WES family datasets that will facilitate future genetic and clinical studies on TS and comorbidities with improved power. Moreover, our work provides evidence of the contribution of de novo mutations to TS etiology, as well as the shared genetic architecture between TS and ASD. Further studies will focus on locating TS-specific and TS-ASD shared risks through gene-specific and gene-set analysis, bridging rare variant effects to polygenic scores to boost modeling accuracy, and dissecting the heterogeneity in the SPARK cohort for improved statistical power." @default.
• W4387476746 created "2023-10-11" @default.
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• W4387476746 date "2023-10-01" @default.
• W4387476746 modified "2023-10-16" @default.
• W4387476746 title "T50. ANALYZING LARGE-SCALE TOURETTE SYNDROME WHOLE-EXOME SEQUENCING DATA REVEALS A SIGNIFICANT CONTRIBUTION OF DE NOVO MUTATIONS" @default.
• W4387476746 doi "https://doi.org/10.1016/j.euroneuro.2023.08.335" @default.
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