The familial association of Gilles de la Tourette Syndrome and Attention Deficit Hyperactivity Disorder: The impact of Obsessive Compulsive Disorder.

摘要

Gilles de la Tourette Syndrome (GTS) is a common childhood onset psychiatric disorder characterized by the presence of motor and vocal tics that last for of at least one year. GTS is a familial disorder, with the first degree relatives of affected individuals having a 10 to 100 times greater risk of developing the disorder compared to the general population. The underlying genetic mechanisms of GTS are complex and currently unknown.;Individuals affected with GTS are about 10 times more likely to also be affected with comorbid Obsessive Compulsive Disorder (OCD) or comorbid Attention Deficit Hyperactivity Disorder (ADHD) compared to the general population. Results from family studies of GTS and OCD have demonstrated that some forms of OCD share some common genetic etiology with GTS. This thesis utilized the family study design to investigate the genetic relationship between GTS and ADHD. The family study design is based on the assumption that first degree relatives share on average 50% of their genetic material. Thus, if disorders share some genetic etiology, the patterns of transmission within families should reflect that.;This study included information from 931 individuals (239 probands and 692 biological first degree relatives). Four different types of families were investigated: (1) 205 relatives of 75 probands with GTS and ADHD (GTS+ADHD); (2) 219 relatives of 74 probands with GTS and no ADHD (GTS-ADHD); (3) 114 relatives of 41 probands with ADHD and no GTS (ADHD-GTS); and (4) 154 relatives of 49 control individuals who did not have GTS, ADHD or OCD. Each participant was interviewed in person and the diagnoses were independently assigned by two PhD level psychiatrists who had to agree on the final diagnoses. Frequency analysis, loglinear regression and multivariate logistic regression techniques were utilized.;This study supports the existence of an etiological relationship between GTS and ADHD but only when they occur within the same individual. Furthermore, it appears that the common form of ADHD does not share genetic factors with GTS. Furthermore, results from this study suggest that the comorbid GTS + ADHD type does not represent a distinct subtype of GTS, but is likely to be etiologically related to the OCD symptoms: relatives of probands with OCD or subclinical OCD were 7.8 times more likely to develop comorbid GTS+ADHD. Based on this work and a critical literature review, we theorize that GTS+ADHD represents a more severe form of GTS.;The genetics of GTS are complex and not well understood. The newly available Genome Wide Association Study (GWAS) design can hopefully overcome the limitations of previous genetic studies and also facilitate the identification of genes that may contribute to both GTS and ADHD in the same individuals. Recent GWAS studies have identified a large number of genetic polymorphisms which are shown to slightly but significantly increase the risk to develop complex disorders. Thus, it is likely that many different polymorphisms in different genes might be important in the development of GTS. Future work on the genetics of GTS and ADHD will focus on discovering the biological functions of these polymorphisms. To select the most viable genes for further examination, a bioinformatics approach is proposed which has been demonstrated to be valid by successfully identifying candidate genes for Reading Disability. This approach is based on scoring genes in several categories such as gene expression, genomic location in relation to previous genetic studies, participation in the disease specific pathways and others. This method should help in selecting the most viable genes identified in genome-wide studies for further analysis to improve our knowledge of the biology of GTS. This knowledge of susceptibility mutations and biological pathways involved should eventually lead to new treatment paradigms for GTS and its comorbid conditions.