Genetic Susceptibility in Tourette Syndrome

Abstract

Abstract Early twin and family studies point to a significant genetic contribution to Tourette syndrome (TS). Informed by early segregation analyses in TS families pointing to a single-gene autosomal dominant inheritance pattern with partial penetrance, initial efforts at gene discovery in TS utilized parametric linkage analysis in large multigenerational families but failed to identify a single specific genetic locus. Later segregation analyses supported the current characterization of TS as a complex, genetically heterogeneous disorder. Nonparametric linkage analyses have yet to identify common TS risk alleles. Candidate gene association studies in TS have not yielded significant reproducible findings. Genome-wide association studies (GWAS) have proven valuable for identifying and replicating loci for common complex traits and disorders across the medical field. A GWAS meta-analysis of almost 5,000 cases identified a significant locus in FLT3. Polygenic risk scores, calculated from the most recent TS GWAS summary statistics, have shown correlation with tic severity and affected status in independent samples. There has been an increasing effort to evaluate the contribution of rare allele variants toward TS. Recent studies have found a greater burden of rare copy number variants in TS cases; the largest study to date identified NRXN1 and CNTN6 as TS risk genes. Identifying rare de novo single nucleotide variants and indels in more than 800 parent–child trios has so far identified six likely TS risk genes (WWC1, CELSR3, OPA1, NIPBL, FN1, and FBN2), which present an enriched function for cell polarity.