W50. LARGE-SCALE TOURETTE SYNDROME WHOLE-EXOME SEQUENCING ANALYSIS REVEALS A SIGNIFICANT CONTRIBUTION OF DE NOVO MUTATIONS DIFFERENT FROM AUTISM SPECTRUM DISORDER

• Published in: European neuropsychopharmacology Vol. 87; pp. 127 - 128
• Main Authors: Zhan, Lingyu, Yu, Dongmei, Domenech, Laura, Ivankovic, Franjo, Giusti-Rodriguez, Paola, Niarchou, Maria, Davis, Lea K., Mathews, Carol, Scharf, Jeremiah, Ophoff, Roel
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2024
• ISSN: 0924-977X
• DOI: 10.1016/j.euroneuro.2024.08.259

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 mutations (DNMs) 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 and an unaffected sibling. 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 European and Admixed American ancestries were present in the TS cohort. Analyzing samples from all three cohorts demonstrated a significant exome-wide enrichment of DNMs, in the category of protein-truncating variants (PTVs) and damaging missense variants (Dmis), in TS probands compared to healthy controls, while confirming a significant enrichment of DNMs in ASD probands compared to healthy controls. The enrichment was further increased when we focused on genes with high pLI scores, indicating an impact of DNMs on the core body functionalities. To compare the genetic architecture of TS and ASD, we obtained genesets known to be associated with ASD and DD and confirmed a significant enrichment of DNMs in ASD probands compared to healthy controls, while TS probands only demonstrated a trend of enrichment in DD genes. Interestingly, when we looked at non-ASD genes, both TS probands and ASD probands from the SPARK cohort demonstrated significant enrichments of DNMs, suggesting a different genetic architecture between TS and ASD, while also recapitulating the potential phenotypic heterogeneity within the SPARK cohort. Lastly, to identify TS risk genes, we performed transmitted-and-de-novo-analysis (TADA) and identified three significant genes with FDR<0.05.
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, shows a different genetic architecture between TS and ASD, and pinpointed three TS risk genes. Further studies will focus on bridging rare variant effects to polygenic scores to boost modeling accuracy and dissect the heterogeneity in the SPARK cohort for improved statistical power.