Genetic architecture of Tourette syndrome: our current understanding

Abstract

Tourette syndrome (TS) is a severe neuropsychiatric disorder characterized by recurrent, involuntary physical and verbal tics. With a prevalence as high as 1% in children, a deeper understanding of the etiology of the disorder and contributions to risk is critical. Here, we cover the current body of knowledge in scientific literature regarding the genetics of TS. We first review the history and diagnostic criteria for TS cases. We then cover the prevalence, and begin to address the etiology of the disorder. We highlight long-standing evidence for a genetic contribution to TS risk from epidemiology studies focused on twins, families, and population-scale data. Finally, we summarize current large-scale genetic studies of TS along specific classes of genetic variation, including common variation, rare copy number variation, and de novo variation that impact protein-coding sequence. Although these variants do not account for the entirety of TS genetic risk, current evidence is clear that each class of variation is a factor in the overall risk architecture across TS cases.

Keywords: TS; Tourette; genetic variants; genetics; genomics; review.

Figure 1:. Key genetic studies and findings in TS.

Adapted from (Mary M. Robertson et al., 2017). Twin studies in yellow; non-twin studies in green; linkage studies in salmon; genome-wide association studies (GWAS) in blue; rare copy number variant (CNVs) in white; whole exome sequencing (WES) in grey. TS: Tourette Syndrome; OCD: obsessive-compulsive disorder; ADHD: attention deficit hyperactivity disorder; CTD: chronic tic disorder; rMZ: monozygotic twin correlation (for diagnosis); rDZ: dizygotic twin correlation (for diagnosis); SNP: single nucleotide polymorphism; LD: linkage disequilibrium; eQTL: expression quantitative trait locus; mQTL: methylation quantitative trait locus; h2-snp; SNP-based heritability estimate; RR: relative risk; HDC: Histidine Decarboxylase; NRXN1: Neurexin 1.

Figure 2:. Genetic correlations between TS and other neuropsychiatric disorders from available GWAS summary statistics.

Publicly available GWAS statistics for TS (4,819 cases, 9,488 controls) and for 6 separate neuropsychiatric disorders (ADHD, (Demontis et al., 2019); AN, (Duncan et al., 2017); ASD, (Grove et al., 2019); BD, (Stahl et al., 2019); OCD, (International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS), 2018); SCZ, (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014)) were obtained for genetic correlation calculations using LDSC v1.0.1 (Bulik-Sullivan et al., 2015). Sample sizes have been included for each disorder on the X axis. Significant genetic correlations are defined as those with a p-value reported by LDSC less than the Bonferroni threshold, here defined as 0.05 / 6 tests = 8x10⁻³. Only ADHD and OCD have genetic correlations with TS that pass this threshold. These disorders have been noted as among the highest comorbid diagnoses in TS cases.