Review articleThe genetics of Tourette syndrome: A review☆
Introduction
In the original description of the syndrome that bears his name, Georges Gilles de la Tourette observed that the disorder was familial [1]. Subsequently, there has been considerable research devoted to systematically examining whether that original observation could be replicated and whether the observed familiality is due in part to genetic factors. These studies have included family studies, twin studies, genetic linkage studies, and genetic association (candidate gene) studies. This review is based on the comprehensive literature search of PubMed database with keywords such as Gilles de la Tourette, Tourette Syndrome, Tourette Disorder, GTS, ADHD, and OCD.
Section snippets
Family studies
Family studies have repeatedly demonstrated that Gilles de la Tourette syndrome (GTS) is highly familial. Establishing that there is familial aggregation does not “prove” that the disorder is influenced only by genetic factors, since family members also share common environmental factors. Nevertheless, results from these studies provide an important first step for determining whether genetic factors are important in the manifestation of the condition. Since first-degree relatives share on
Twin studies
Twin studies provide strong evidence for the genetic nature of GTS. The largest study included 30 monozygotic and 13 dizygotic pairs of twins [53]. These investigators utilized phone-based assessment and found that 77% of monozygotic twins were concordant for tic disorders (CT or GTS), but only 23% of dizygotic twins were concordant for these disorders [53]. Furthermore, the concordance rate of monozygotic twins reached 100% for GTS or CT when direct observational interviews were conducted [47]
Linkage analyses
Five genome wide linkage analyses have been performed to date [55], [56], [57], [58], [59]. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has conducted the largest of these genetic linkage studies. Their sample represents a joint analysis of most of the individuals contained in the four previous studies and consists of 238 nuclear families and 18 large multigenerational families totaling 2040 individuals [59]. Both parametric and nonparametric analyses were
Chromosomal translocations
Another valuable approach for identifying disease genes is the identification of chromosomal aberrations in patients. Translocations, duplications, or deletions of large chromosome segments can be visualized by karyotyping or fluorescence in situ hybridization. Newer methods for detection of duplications or deletions ranging from ∼1 kb to several megabases (Mb) in size, referred to as copy number variations (CNVs), have identified de novo and inherited CNVs associated with risk of many
Candidate gene studies
Candidate gene studies have focused mainly on genes involved in the dopaminergic pathway due to the fact that dopamine antagonists are the most effective medications for tic suppression. As shown in Table 1, similar to findings in other complex disorders [134], candidate gene association studies in GTS have not yielded any clearly replicated results that unequivocally identify a causative GTS susceptibility gene. It is likely that most of these candidate genes tested are not involved in the
Future directions
Recent advances in cataloging human genetic polymorphisms, in addition to the decreasing cost of high-throughput SNP genotyping and the development of statistical methodology to analyze large sample sets in a rigorous manner, have made genome-wide association studies (GWASs) a feasible method for genetic studies of complex disorders [134]. Based on the hypothesis that a proportion of the genetic susceptibility for common diseases may be caused by common genetic variants that arose early in
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Supported in part by grants from the National Institute of Neurological Disease and Stroke, NS16648 and NS40024.