This study represents the first latent class analysis of GTS and its most common comorbidities, OCD and ADHD. We identified three GTS “affected” classes, corresponding to GTS + OCS/OCB (class III; n = 107), GTS + OCD (class IV; n = 300) and GTS + OCD + ADHD (class V; n = 229). Two additional classes were also identified in the larger family sample, minimal disorder (class I; n = 281) and chronic tics (class II; n = 35). We are confident that the LCA classes derived from these analyses are reliable, as the two random sib samples and the omnibus sample replicated the same three affected classes. However, the functional meaning of the classes is somewhat less clear. One potential use of the LCA is to examine the question of whether GTS is predominantly a disorder of motor disinhibition, or should be considered in the larger context of disinhibition across functional realms (e.g., the cognitive disinhibition of OCD and the behavioral disinhibition of ADHD) for genetic and other etiological studies. Etiologically, GTS, OCD and ADHD have common putative abnormalities in the fronto-striatal systems (27
), and common biological markers have been sought (30
Besides the truly unaffected Class I, a ‘minor’ version of GTS appears as a separate class once the parents and other sibs are included in the analysis (i.e., Class II: chronic tics + OCD). In addition to chronic tics, 100% of individuals in Class II have OCD, making it plausible that in familial samples the presence of OCD is ubiquitous and may respond to common genes influencing the expression of both tics and OCD.
Class III, characterized by GTS + OCS/OCB, corresponds to the “GTS only” group previously reported in the literature, and is generally considered to be spared of major disability in relation to motor control and executive function (32
). Denckla et al. (2006) reported that up to 40% of children with TS are “free of ADHD”, noting that they are also free of the motor control and executive control deficits of children with ADHD alone or GTS + ADHD. However, it was also noted that this clinical group had oculomotor control deficits in the initiation of prosaccades, regardless of their ADHD status (33
). More recently, Rizzo et al. (2007) confirm that the addition of ADHD to GTS confers greater maladaptive behavior and worse cognitive functioning compared to GTS alone (34
). It is important to point out that 100% of members of the “GTS only” class have OCS/OCB. While the relationship of OCS/OCB to OCD remains an area of investigation (35
), OCS/OCB associated with GTS have been repeatedly observed to correspond to a specific group of OCD symptoms (36
), and as discussed below, may represent a different phenomenological entity than OCD rather than a “forme fruste” of OCD.
Class IV is characterized by GTS + OCD and was the most numerous class in our sample, concurrent with other studies (39
). GTS + OCD (Class IV) may constitute a more severe form of GTS + OCS/OCB (class III) or be a qualitatively different clinical entity. Coffey et al. (1998) set out to explore the differences between GTS, OCD and GTS + OCD. GTS + OCD was found to have higher rates of bipolar disorder, social phobia, body dysmorphic disorder and ADHD than the GTS only and OCD only groups. Since most of the increased comorbidities relate to GTS and not OCD, the authors conclude that GTS + OCD is more related to GTS and qualitatively “more severe” than either of each alone (40
). The fact that OCD and OCS/OCB consistently separate into different latent classes in this sample suggests hitherto unidentified but important differences between subclinical and clinical OCD in relation to GTS. Multiple studies note OC phenomenological differences when OCD is comorbid with GTS, such as a younger age at onset of OCD, a male predominance, sensory phenomena, sexual obsessions and hoarding, repeating, and counting compulsions compared to OCD alone (41
); these, however, are not the symptoms usually identified in OCS/OCB accompanying GTS (38
). The heritability results, which are relatively low but positive for Class IV, and the high frequency of the GTS + OCD class in our sample continue to support a possible common genetic background for GTS and OCD as previously reported (6
Class V, GTS + OCD + ADHD, comprises about one-third of GTS individuals in the affected classes and has many “core” GTS characteristics such as a preponderance of males, and an earlier age at onset of motor tics compared to classes III and IV. GTS + OCD + ADHD is also highly heritable in this sample (h = 0.18 ± 0.05; p = 7 × 10−5
), with the caveat that the value is not overly high even in complex genetics. These data support the notion that a comorbid syndrome may be heritable in these families. Previous studies provide additional evidence for the hypothesis that GTS, OCD, and ADHD may all be part of a common disinhibition syndrome. Principal component factor analyses in four samples from three studies show that subjects with GTS can be divided into those with a “pure” or simple form consistent with class III (GTS + OCS/OCB), and those with a more complex form, consistent with classes IV (GTS + OCD) and V (GTS + OCD + ADHD) (43
). In these studies, the “pure” form was essentially comprised of simple tics while more complex forms of tics comprised the additional forms of GTS. In the first study, the “complex” symptoms included such disinhibition syndromes as temper fits, argumentativeness, self-injurious behaviors, copralalia, and imitation, which grouped into one of four identified clusters (termed aggressive disinhibition), that was associated with comorbid ADHD in the sample (43
). A related complex compulsive factor comprised of touching, picking, echolalia, and palilalia was also identified in this study, and was also found to be associated with comorbid ADHD, but not OCD. In the second study, which examined two independent samples, the “complex” cluster included symptoms related to disinhibition, reckless and impulsive behaviors, self-injury, injury to others, and coprolalia (44
). Membership in the complex cluster was associated with increased tic severity, increased global impairment, need for medication treatment, family history of tics, higher rates of OCD and ADHD, and an earlier age of onset. Finally, a third study also found a “pure tics” factor with two additional more complex factors characterizing some forms of GTS: an “ADHD-aggressive” factor and a “negative affective-OCD” factor (45
). A family study of GTS and ADHD has underscored the complex relationship between these two disorders. Relatives of ADHD only probands have more tics than expected, but only when they co-occurs with ADHD; vice versa, relatives of GTS only probands have more ADHD than expected, but only if concurrent with tics. OCD was more common in both groups of relatives compared to control relatives, and the presence of OCD predicted the presence of ADHD and GTS in both groups (10
). Future studies that employ symptom-level factor analyses of GTS, OCD, and ADHD in combination may help to further elucidate the relationships between these disorders.
Of interest, there were only 60 subjects or about 10% of GTS subjects who had the combination GTS + ADHD, without OCD, as shown in . These subjects did not comprise a large enough group to constitute a separate class analytically. The presence of this subgroup suggests that OCD plays a role mediating the relationship between GTS and ADHD that needs further elucidation (i.e., when GTS and ADHD are comorbid, in most instances OCD is also present).
In summary, the present study is an attempt to go beyond DSM-IV diagnoses to identify person-centered subgroups of GTS in a refinement of the phenotype for etiological studies, including genetic studies. From a clinical perspective, it will be important to recognize that each of these classes may respond to a different treatment strategies, given possible different underlying biological determinants. From a genetic perspective, our results, while exploratory, suggest that individuals with GTS can be effectively grouped into comorbid subtypes for etiological studies. That is, at least in families with multiple affected individuals, GTS is more likely to occur in the context of OCD and/or ADHD than on its own. While the classes derived from our sample were not in themselves surprising, the heritability estimates were somewhat unexpected. Previous research has suggested that GTS + OCD may represent a heritable subgroup of GTS subjects that may be useful for understanding the genetic contributions to a GTS + OCD syndrome. Concordant with recent reports (46
), our results suggest that there may be a more complex subtype, the multiply comorbid, or GTS + OCD +ADHD subtype (class V), that may also be heritable, and may be caused by different or additional susceptibility loci than GTS + OCS/OCB (class III) or GTS + OCD (class IV). Whether these classes represent a continuum of clinical complexity and severity or truly discrete entities is not tested in the current manuscript; future analyses using alternate latent class mixture models or multilevel (severity) latent class models could elucidate this question. By inference, future gene discovery studies may need to consider GTS complex phenotypes in order to more reliably locate susceptibility genes, especially in linkage studies. If this assumption is true, the full expression of the disorder would consist of a multiply affected phenotype, while moderating factors, including environmental factors and partial penetrance of susceptibility genes, may lead to more simple phenotypes
The primary limitation of this study relates to the sample composition. Because the sample consists of nuclear families ascertained for having at least two siblings with GTS, there is little phenotypic variability in the offspring generation with regard to tic diagnoses. This decrease in variability for the GTS phenotype may falsely decreaseheritability estimates for class III (GTS + subclinical OCD). Additionally, the relative lack of GTS-unaffected siblings, as well as the lack of additional generations within families, makes segregation analyses and other approaches aimed at identifying transmission patterns impractical. Additional limitations arise with regard to the heritability estimates. Although we are confident that classes IV and V are heritable as a result of our analyses, we are less confident of the precise heritability estimates. Limitations are imposed by the data structure and software, which is unable to correct for the non-independence of class probabilities (i.e., class probabilities have to add up to one). In addition, we do not have data on putative environmental contributors to GTS, OCD, and ADHD, which are ostensibly accounting for variance not explained by the genetic variance (h2). Despite these limitations, the large sample size and the completeness of the clinical data make it possible to maximize the information available from such a sample in useful and previously unexplored ways. Thus, the current analyses cannot distinguish whether the heritability findings for Class V are due to common genetic factors underlying GTS, OCD, and ADHD, or whether there are other mechanisms at play, such as common environmental factors or assortative mating between individuals with the different disorders.
Finally, the familial nature of the sample, ascertained through having two affected sibs, limits the generalizability of the GTS subtypes and may have implications for gene discovery. For example, the Class V phenotype, a more severe, complex form of the disorder may be caused by a rare high-penetrance genetic variant that is more readily found in multiplex families and would be useful for gene discovery through linkage methods. This same complex phenotype, if responsive to a highly penetrant rare genetic variant, might not be as useful in a large-scale genetic association studies that seek to locate more common susceptibility genes of minor effect.