This study attempts to further elucidate the familial relationships between TS, OCD, and ADHD in a large sample of TS-affected sib pair families. Our results demonstrate not only the independent familiality and heritability patterns of the two main TS-associated disorders, OCD and ADHD, but also further elucidate the genetic and environmental relationships between these disorders and TS.
We found high rates of complex phenotypes (i.e., TS+OCD or TS+OCD+ADHD), in both parents and offspring, and unexpectedly high rates of TS (with or without comorbidities) among mothers. The reasons for this are unclear. While we originally hypothesized that we would find evidence of bilineal mating in our sample, at least for ADHD, and that this might account for the high rates of ADHD in offspring, we did not find evidence for this. One possible explanation for the high rates of maternal TS and also perhaps for the high rates of complex phenotypes is that mothers with TS may be more likely to transmit TS and related phenotypes to their offspring than are TS-affected fathers. Examination of this hypothesis is outside the scope of the current analysis, requiring the inclusion of additional families, including bilineal families and those with offspring who are unaffected with TS.
We found that, consistent with previous studies, and as expected, TS and OCD were heritable in our TS families11, 50, 51
. TS had a somewhat lower heritability estimate than either OCD or ADHD; this is most likely an artifact caused by the decreased variation in the sample (i.e., the vast majority of sibs were TS-affected). TS and OCD had an extremely strong genetic correlation of over 90%, and no significant environmental correlation, suggesting that, in multiply-affected families at least, TS and OCD are likely to be due to the same underlying genetic factors. One possibility is that TS+OCD in offspring may represent a more severe expression of the TS phenotype, perhaps resulting from a greater genetic loading. Another is that OCD represents an alternative phenotypic expression of TS-susceptibility genes, a hypothesis that has been put forward in previous family studies52
. Unfortunately we are unable in the current study to distinguish between these hypotheses, which could be best tested in multi-generational families.
These results have potential relevance both for genetic studies of TS and related disorders and for clinicians. The high RhoG between TS and OCD suggests that OCD could either be considered as a potentially relevant phenotype in genetic studies of TS, for example including OCD (particularly OCD-affected individuals who also have tics) together with TS in genome-wide association studies, or alternatively, as a constraint on TS genetic studies, limiting such studies to the potentially more genetically homogenous subgroup of individuals with TS+OCD. Another possibility would be to use individuals with one disorder as a replication sample for the other, for example, examining genetic variants associated with TS in a sample of OCD-affected individuals. For clinicians, our findings suggest that TS-affected families may need to be counseled that TS and OCD share genetic susceptibility factors, and thus that offspring of TS families may be at increased risk for either TS or OCD or for the combination of the two.
We also found that ADHD was highly heritable in our TS families, although, in contrast to OCD, there was no significant genetic correlation between TS and ADHD. In our parent-offspring analyses, the primary predictor of ADHD among TS-affected offspring was a parental diagnosis of ADHD rather than parental diagnoses of TS or OCD. Together with the heritability analyses, these results suggest that TS and ADHD are most likely genetically separate disorders, with the high rates of ADHD among TS-affected individuals resulting partly from increased but separate parental transmission of TS and ADHD susceptibility. These findings also have implications for genetic studies, suggesting that the presence or absence of ADHD is not of direct relevance for genetic studies of TS and should not be considered either as an inclusion or exclusion factor for such studies. Note that this does not necessarily extend to the more complex phenotype of TS+OCD+ADHD, which is highly heritable, and may in fact be an appropriate alternate phenotype for genetic studies. On the clinical side, the association between maternal ADHD and offspring ADHD and/or OCD is of particular interest, particularly when counseling TS-affected families about potential risks to offspring. However, these results are preliminary, and the complex relationship between these disorders requires further investigation to have clear clinical relevance.
We initially hypothesized that the increased rates of ADHD found in TS families would be due to bilineal mating between individuals with ADHD and individuals with TS or OCD. However, we did not find evidence of non-random mating for ADHD, or for ADHD with either TS or OCD. Thus, we cannot easily explain the strong environmental correlation and lack of genetic correlation between TS and ADHD. It is possible that the observed association is related to specific environmental exposures (such as prenatal maternal smoking) that predispose an individual to both TS and ADHD, either alone or in combination with additional environmental or genetic environmental influences53, 54
It is also possible that the observed relationship between TS and ADHD is partly mediated through OCD, as has been previously suggested26, 30, 31
. For example, Geller and colleagues have suggested that, based on their studies of ADHD families and pediatric OCD families, ADHD+OCD exists as a distinct familial subtype rather than being alternative expressions of the same underlying genetic susceptibility30, 31
. We found some evidence to support this hypothesis in our TS families as well. First, although a TS+ADHD phenotype (without comorbid OCD) does exist in our families, it is not a large proportion, comprising only 11.8% of the sample, whereas the proportion of individuals with TS+OCD+ADHD is much higher (34%)35
. Second, we found strong genetic correlations between OCD and ADHD, and between TS and OCD+ADHD, although not between TS and ADHD. Third, we found that maternal ADHD was associated with offspring OCD, with an odds ratio of 1.8 (CI 1.1–3.1), in addition to being associated with offspring ADHD.
The hypothesis that the observed association between TS and ADHD is mediated through the genetic relationships between ADHD and OCD and OCD and TS could in future be tested through formal mediation analyses. Such analyses, which are outside of the scope of this paper, are of particular interest in genetic epidemiological studies of complex traits such as TS, where the relationships between commonly co-occurring phenotypes are difficult to define.
Finally, and somewhat surprisingly, and in contrast to previous family studies, we did not find evidence for increased heritability of the less severe phenotypes of CMVT and OCB in combination with the more severe phenotypes of TS and OCD. This may be due to the fact that the sample consists of nuclear families rather than multigenerational pedigrees, where the co-segregation of these phenotypes has been more clearly established11, 24
. However, it does suggest that the inclusion of CMVT and/or OCB would not provide a significant advantage, and may in fact be a disadvantage, at least in genetic studies of nuclear families or other samples (such as case-control studies) where there is not clearly a strong genetic loading.
There are some limitations to our study, most of which relate to the sample composition. Because the sample consists of nuclear families ascertained for having at least two siblings with TS, generally excluding families who were bilineal for tics or OCD, there is little phenotypic variability with regard to tic diagnoses (only 14 sibs were unaffected for TS), and there are only a small number of families where both parents have either a tic disorder or OCD. Additionally, although some information is provided by the few half-siblings, the vast majority of families in this study were biological full siblings. Because we do not have diagnostic information on second and third degree family members, the heritability estimates are just that, estimates, as the VA component is not able to distinguish some genetic effects from environmental effects present within the family structure, potentially resulting in an over-estimate of the heritability if the shared environmental effects are substantial. Conversely, the decrease in variability for the TS phenotype may falsely decrease heritability estimates for TS and perhaps also for CMVT. Similarly, the fact our sample was specifically ascertained for genetic studies rather than being a population-based sample may also affect the heritability estimates, in this case, leading to a potential under-estimate of the heritabilities. In addition, we do not have data on putative environmental contributors to TS, 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.
In summary, while comorbidities are often seen clinically and are the most common management currency for clinicians, they have not been consistently considered in phenomenology and etiology studies. Taken together, our results extend the previously reported heritability analyses based on latent classes in TS families, now examining parent-offspring concordance for OCD and ADHD and genetic and environmental correlations between individual diagnoses35
. While further research is clearly needed into the complex relationships, both genetic and environmental, between TS, OCD, and ADHD, for the present, our studies suggest that in genetic studies of TS, OCD could also be appropriately considered as a relevant phenotype, (either as an alternate phenotype or as a more genetically homogenous subgroup within the TS phenotype) while ADHD should not. Similarly, clinicians should be aware that TS and OCD share genetic susceptibility factors, and thus that offspring of TS families may be at increased risk for either TS or OCD or for the combination.