The genetics of Tourette syndrome: a review

Abstract

Objectives: This article summarizes and evaluates recent advances in the genetics of Gilles de la Tourette syndrome (GTS).

Methods: This is a review of recent literature focusing on (1) the genetic etiology of GTS; (2) common genetic components of GTS, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD); (3) recent linkage studies of GTS; (4) chromosomal translocations in GTS; and (5) candidate gene studies.

Results: Family, twin, and segregation studies provide strong evidence for the genetic nature of GTS. GTS is a heterogeneous disorder with complex inheritance patterns and phenotypic manifestations. Family studies of GTS and OCD indicate that an early-onset form of OCD is likely to share common genetic factors with GTS. While there apparently is an etiological relationship between GTS and ADHD, it appears that the common form of ADHD does not share genetic factors with GTS. The largest genome wide linkage study to date observed evidence for linkage on chromosome 2p23.2 (P=3.8x10(-5)). No causative candidate genes have been identified, and recent studies suggest that the newly identified candidate gene SLITRK1 is not a significant risk gene for the majority of individuals with GTS.

Conclusion: The genetics of GTS are complex and not well understood. The Genome Wide Association Study (GWAS) design can hopefully overcome the limitations of linkage and candidate gene studies. However, large-scale collaborations are needed to provide enough power to utilize the GWAS design for discovery of causative mutations. Knowledge of susceptibility mutations and biological pathways involved should eventually lead to new treatment paradigms for GTS.

Figure 1

Heat map of chromosome 2 linkage analysis from 15 large multigenerational pedigrees [59]. X = −log(P) if Z>0 and X = log(1−P) if Z<0 Positive Z scores indicate an increased likelihood of linkage, while negative Z scores indicate a decreased likelihood of linkage. No single locus shows moderate or significant linkage across all pedigrees, suggesting that there is genetic heterogeneity of GTS, although low positive Z scores can also indicate the lack of power in a particular family to reach a significant threshold for linkage. The most significant overall linkage at D2S319 (Z score >3.719) resulted from one pedigree with a high Z score (3.09~3.719), and 8 pedigrees with moderate Z scores (2.326~3.09). The adjacent marker D2S2211 has only a moderately significant overall Z score because fewer pedigrees with moderate Z scores (2.326~3.09) contribute. Furthermore the map shows three different pedigrees with strong evidence for linkage (Z score >3.719) at adjacent loci on chromosome 2: Family 11 at D2S2216, Family 14 at D2S352 and D2S2368, and Family 15 at D2S2259. However, the summed Z scores for these markers across all 15 pedigrees are only moderately positive, indicating that in the majority of tested pedigrees these loci either do not have enough power to detect linkage or do not contribute to the susceptibility to GTS.

Figure 2

The number of cases and controls required in an association study to achieve 80% power across a range of minor allele frequencies (MAF) and genotype relative risks (GRR) for a multiplicative model. GTS prevalence was set at 2% (1% GTS genes + 1% OCD genes) and linkage disequilibrium between marker and causative allele was set to 1. Power calculations were performed for Type I error rate (alpha) of p< 5 × 10⁻⁸ as required to reach a Bonferroni corrected p<0.05 significance level for ~ 1million independent tests performed in a GWAS [162]. Calculations were performed with the Genetic Power Calculator [163].