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Original Investigation |

Lifetime Prevalence, Age of Risk, and Genetic Relationships of Comorbid Psychiatric Disorders in Tourette Syndrome FREE

Matthew E. Hirschtritt, MD, MPH1; Paul C. Lee, MD, MPH2; David L. Pauls, PhD2; Yves Dion, MD3; Marco A. Grados, MD4; Cornelia Illmann, PhD2; Robert A. King, MD5; Paul Sandor, MD6,7,8; William M. McMahon, MD9; Gholson J. Lyon, MD, PhD10; Danielle C. Cath, MD, PhD11,12; Roger Kurlan, MD13; Mary M. Robertson, MBChB, MD, DSc(Med), FRCP, FRCPCH, FRCPsych14,15,16; Lisa Osiecki, BA2; Jeremiah M. Scharf, MD, PhD2,17,18,19,20; Carol A. Mathews, MD1 ; for the Tourette Syndrome Association International Consortium for Genetics
[+] Author Affiliations
1Program for Genetics and Epidemiology of Neuropsychiatric Symptoms, Department of Psychiatry, University of California, San Francisco
2Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Harvard Medical School, Massachusetts General Hospital, Boston
3Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada
4Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
5Yale Child Study Center, Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
6Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
7University Health Network, Toronto Western Research Institute, Toronto, Ontario, Canada
8Youthdale Treatment Centers, Toronto, Ontario, Canada
9Department of Psychiatry, University of Utah, Salt Lake City
10Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, New York
11Department of Clinical and Health Psychology, Utrecht University, Utrecht, the Netherlands
12Altrecht Academic Anxiety Disorders Centre, Utrecht, the Netherlands
13Atlantic Neuroscience Institute, Overlook Hospital, Summit, New Jersey
14University College London, London, England
15St George’s Hospital and Medical School, London, England
16Department of Psychiatry, University of Cape Town, Cape Town, South Africa
17Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
18Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
19Department of Neurology, Massachusetts General Hospital, Boston
20Department of Psychiatry, Massachusetts General Hospital, Boston
JAMA Psychiatry. 2015;72(4):325-333. doi:10.1001/jamapsychiatry.2014.2650.
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Importance  Tourette syndrome (TS) is characterized by high rates of psychiatric comorbidity; however, few studies have fully characterized these comorbidities. Furthermore, most studies have included relatively few participants (<200), and none has examined the ages of highest risk for each TS-associated comorbidity or their etiologic relationship to TS.

Objective  To characterize the lifetime prevalence, clinical associations, ages of highest risk, and etiology of psychiatric comorbidity among individuals with TS.

Design, Setting, and Participants  Cross-sectional structured diagnostic interviews conducted between April 1, 1992, and December 31, 2008, of participants with TS (n = 1374) and TS-unaffected family members (n = 1142).

Main Outcomes and Measures  Lifetime prevalence of comorbid DSM-IV-TR disorders, their heritabilities, ages of maximal risk, and associations with symptom severity, age at onset, and parental psychiatric history.

Results  The lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% of the population had 2 or more psychiatric disorders. The mean (SD) number of lifetime comorbid diagnoses was 2.1 (1.6); the mean number was 0.9 (1.3) when obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) were excluded, and 72.1% of the individuals met the criteria for OCD or ADHD. Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30% of the participants. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years, with the exception of eating and substance use disorders, which began in adolescence (interquartile range, 15-19 years for both). Tourette syndrome was associated with increased risk of anxiety (odds ratio [OR], 1.4; 95% CI, 1.0-1.9; P = .04) and decreased risk of substance use disorders (OR, 0.6; 95% CI, 0.3-0.9; P = .02) independent from comorbid OCD and ADHD; however, high rates of mood disorders among participants with TS (29.8%) may be accounted for by comorbid OCD (OR, 3.7; 95% CI, 2.9-4.8; P < .001). Parental history of ADHD was associated with a higher burden of non-OCD, non-ADHD comorbid psychiatric disorders (OR, 1.86; 95% CI, 1.32-2.61; P < .001). Genetic correlations between TS and mood (RhoG, 0.47), anxiety (RhoG, 0.35), and disruptive behavior disorders (RhoG, 0.48), may be accounted for by ADHD and, for mood disorders, by OCD.

Conclusions and Relevance  This study is, to our knowledge, the most comprehensive of its kind. It confirms the belief that psychiatric comorbidities are common among individuals with TS, demonstrates that most comorbidities begin early in life, and indicates that certain comorbidities may be mediated by the presence of comorbid OCD or ADHD. In addition, genetic analyses suggest that some comorbidities may be more biologically related to OCD and/or ADHD rather than to TS.

Figures in this Article

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by multiple motor tics and 1 or more vocal tics that persist for at least 1 year.1,2 Multiple comorbid psychiatric disorders have been reported in TS-affected individuals; when present, these conditions typically cause more distress and impairment than do tics.37 High rates of comorbid attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) have been well documented and are thought to be core components of the TS phenotype.4,811 Although elevated rates for mood disorders, nonobsessional anxiety disorders, and disruptive behavior disorders (DBDs) have also been reported,4,1217 a significant gap in knowledge still exists regarding the range, prevalence, and clinical attributes of the non-OCD, non-ADHD comorbid disorders. The few available studies were limited by small sample sizes (<200 participants),3,7,1820 small number of diagnoses examined, or reliance on symptom checklists and severity scales rather than DSM-based, structured diagnostic psychiatric assessments.18,2124

Despite methodologic limitations, these studies12,13,15 suggest that a high proportion of individuals with TS (61%-96%) have at least 1 comorbid psychiatric disorder. Unfortunately, there is no consensus regarding expected rates of the noncore (ie, non-OCD, non-ADHD) psychiatric disorders in TS-affected individuals; in addition, there is limited knowledge regarding typical age at onset, ages of highest risk, and association with impairment for these disorders.

Although the shared genetic susceptibility to OCD and ADHD in TS-affected families has been established,2527 the etiologic relationships between TS and other psychiatric disorders have not been examined. Elevated rates of psychiatric comorbidity may arise from (1) shared genetic susceptibility with TS, (2) shared genetic susceptibility with comorbid OCD or ADHD, or (3) nongenetic factors (eg, shared environment). Together with quantifying the extent of concomitant occurrence, understanding the clinical and etiologic relationships between TS, OCD, ADHD, and other psychiatric comorbidities will help in understanding the sources of heterogeneity of this complex neuropsychiatric disorder. Therefore, the aims of the present study were to quantify psychiatric disorder burden, ages of highest risk, and underlying genetic relationship of psychiatric disorders in TS-affected individuals using the largest, most comprehensive data set available.

The study was described to all participants; adults provided written informed consent and children written assent before participating. Parents provided written consent for their children’s participation. Institutional review board approval was obtained from all participating sites. The participants did not receive financial compensation. The eAppendix in the Supplement includes the inclusion and exclusion criteria and informed consent details.

Participants

Phenotypic data were collected for genetic studies from TS-affected individuals aged 6 years or older and their parents and siblings, ascertained from 802 independent families between April 1, 1992, and December 31, 2008. Recruitment primarily occurred from tic disorder specialty clinics in the United States, Canada, Great Britain, and the Netherlands as well as from the Tourette Syndrome Association of the United States.

Phenotypic Assessments

A psychiatrist, neurologist, or psychologist trained in the use of clinical research assessments evaluated all participants (D.L.P., Y.D., M.A.G., C.I., R.A.K., P.S., W.M.M., D.C.C., R.K., M.M.R., and C.A.M.).28 Tics, OCD, and ADHD symptoms were assessed using a structured clinical interview specifically developed for TS genetic studies (eAppendix in the Supplement). The Structured Clinical Interview for DSM-IV Axis I Disorders–Non-Patient Edition, 2.029 (all sites except the University of Utah site) or the Schedule for Affective Disorders and Schizophrenia–Lifetime Version, Modified for the Study of Anxiety Disorders30 (University of Utah site) was used to gather data on DSM-IV-TR diagnoses for adults. The Schedule for Affective Disorders and Schizophrenia for School-Age Children, the Lifetime Version31 (all sites except Johns Hopkins University School of Medicine or University of Toronto) or the Epidemiologic Version32 (Johns Hopkins University School of Medicine and University of Toronto sites) was used to collect data on DSM-IV-TR diagnoses in children and adolescents. Final diagnoses were assigned using a best-estimate process, which requires diagnostic consensus by at least 2 raters.28,33 We grouped individual disorders into DSM-IV-TR–based categories (eg, anxiety disorders) to aid in clinical interpretation. The eAppendix in the Supplement includes details regarding diagnostic instruments, rater training and reliability, age-at-onset determination, and the best-estimate process.

Statistical Analysis

For lifetime prevalence estimates of comorbid disorders and ages at onset, we limited the sample to the 1374 participants with TS. We also examined the lifetime prevalence of disorders among probands compared with their TS-affected first-degree relatives (eAppendix in the Supplement). To examine the association among TS, OCD, and ADHD with other comorbid disorders and for heritability analyses, we included all individuals, including TS-unaffected family members. We compared the rates of comorbid disorders by sex and age at interview using χ2 and Fisher exact tests. We examined the relationship between psychiatric comorbidity and TS, OCD, and ADHD by comparing lifetime prevalence rates of comorbid disorders among participants with TS only, TS and OCD only (TS+OCD), TS and ADHD only (TS+ADHD), and TS with both OCD and ADHD (TS+OCD+ADHD) using χ2 tests. We used generalized estimating equations to examine the association of TS, ADHD, and OCD (individually and in combination) with other comorbid disorders, controlling for family relationships, age at interview, and sex.

For each disorder, we graphed the number of individuals with each age at onset using violin plots along with the median value and corresponding interquartile range. Age of highest risk was defined as the age at which the cumulative risk exceeded 10% (lower bound) through the upper bound of the interquartile range.

Using generalized estimating equation models clustering on family and controlling for age at interview and sex, we tested the association between the presence of 1 or more comorbid disorder (excluding OCD and ADHD) with OCD and tic severity; OCD and ADHD; parental history of OCD, ADHD, and TS; and TS, OCD, and ADHD ages at onset. To improve clinical interpretation, we transformed continuous severity measures into 3 categories (low, medium, and high) and ages at onset into early and late onset so that there were approximately equal numbers of participants in each group. Variables from each generalized estimating equation model with a significance level of P ≤ .20 were added simultaneously to a multivariate model.

We calculated the additive genetic and environmental correlations between TS and classes of comorbid disorders using the Sequential Oligogenic Linkage Analysis Routines (SOLAR, version 6.2.2)34 (eAppendix and eFigure in the Supplement). For these analyses, TS was combined with chronic motor or vocal tic disorders (CMVTDs). We did not examine the heritability of psychotic or eating disorders because of the low prevalence rates or of elimination disorders because of missing parental data.

Demographic Characteristics

The sample consisted of 1374 TS-affected individuals, including parents or siblings without a TS diagnosis who met the best estimate criteria for TS (583 [42.4%]), and 1142 TS-unaffected first-degree relatives. The subsample of TS-affected individuals showed a 3:1 male predominance (1006 [73.2%] male), and the mean (SD) age at assessment was 19.1 (13.5) years. Demographics and clinical characteristics of TS-affected and TS-unaffected participants are presented in eTable 1 in the Supplement.

Overall Burden of Psychiatric Comorbidity

Of the participants with TS, 85.7% met the criteria for 1 or more comorbid disorder (including OCD and ADHD) and 57.7% met the criteria for 2 or more comorbid disorders. Lifetime prevalence rates for classes of comorbid disorders are summarized in Table 1; rates of individual disorders by sex and age are presented in eTable 2 and eTable 3, respectively, in the Supplement. The mean (SD) number of lifetime disorders was 2.1 (1.6). When OCD and ADHD were excluded, 45.3% of the patients met the criteria for 1 or more comorbid disorder and 23.6% met the criteria for 2 or more comorbid disorders. The mean number of lifetime diagnoses, excluding OCD and ADHD, was 0.9 (1.3). There were no significant differences in the rates of comorbid diagnoses between probands and TS-affected relatives when controlling for age at assessment (eTable 4 in the Supplement); therefore, subsequent analyses combined these groups.

Table Graphic Jump LocationTable 1.  Lifetime Prevalence of Psychiatric Disorders by Sex
Prevalence of Specific Psychiatric Disorders
OCD and ADHD

The most common comorbid psychiatric disorders were OCD (50.0%) and ADHD (54.3%); 72.1% of the TS-affected participants met the criteria for either disorder. Females were more likely to have comorbid OCD (57.1% vs 47.5%; P < .01), and males were more likely to have comorbid ADHD (58.5% vs 42.3%; P < .01). Nearly one-third (29.5%) of the participants had TS+OCD+ADHD, 20.2% had TS+OCD, 22.4% had TS+ADHD, and 27.9% had TS only. There was a significant interaction of sex and age with diagnostic group (χ2 = 43.1, P < .001; and χ2 = 121.6, P < .001, respectively).

Other Conditions

After OCD and ADHD, mood disorders, anxiety disorders, and DBDs were the most prevalent classes of psychiatric comorbidity, each affecting approximately 30% of TS-affected participants; psychotic disorders were the least common (<1%). The prevalence of individual disorders ranged from 0.5% (bipolar II disorder) to 26.1% (major depressive disorder) (eTables 2-5 in the Supplement). Females were more likely to have major depressive disorder, most anxiety disorders, and eating disorders. Males were more likely to have ADHD and DBD (oppositional defiant disorder or conduct disorder) (Table 1 and eTable 2 in the Supplement). Adults and adolescents were most likely to have OCD as well as mood, anxiety, eating, and substance use disorders, whereas children were more likely to have ADHD (eTable 3 in the Supplement).

There was a clear relationship between OCD, ADHD, and the other psychiatric comorbidities in TS-affected participants. Mood, anxiety, and substance use disorders were more prevalent among participants with TS+OCD and TS+OCD+ADHD than among those with TS-only or TS+ADHD. Disruptive behavior disorders and psychotic disorders were more prevalent among participants with TS+OCD+ADHD than among the other 3 groups (Figure 1 and eTable 5 in the Supplement). When these analyses were repeated for males and females separately using the diagnostic groups shown in Figure 1, patterns of significance for χ2 analyses were comparable to those for all TS-affected participants combined, except for psychotic disorders, which is attributable to small sample sizes (eTable 5 in the Supplement).

Place holder to copy figure label and caption
Figure 1.
Lifetime Prevalence of Comorbid Disorders by the Presence of Obsessive-Compulsive Disorder (OCD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Among Individuals With Tourette Syndrome (TS)

Significance values reflect individual 4 × 2 χ2 tests (ie, TS, OCD, and ADHD grouped by the presence of the comorbid disorder).

Graphic Jump Location

To assess the relationships between TS, OCD, ADHD, and psychiatric comorbidity, we conducted a multivariate generalized estimating equation model in all individuals (eTable 6 in the Supplement). After controlling for OCD and ADHD, TS was independently associated with an increased risk of anxiety disorders (odds ratio [OR], 1.4; 95% CI, 1.0-1.9; P = .04) and a decreased risk of substance use disorder (OR, 0.6; 95% CI, 0.3-0.9; P = .02); there was no significant independent association between TS and mood disorder or DBD. Obsessive-compulsive disorder was independently associated with a 2-fold or greater risk of mood disorders (OR, 3.8; 95% CI, 2.9-4.9; P < .001), anxiety disorders (OR, 2.8; 95% CI, 2.2-3.6; P < .001), DBDs (OR, 2.0; 95% CI, 1.4-2.9; P < .001), and substance use disorders (OR, 3.9; 95% CI, 2.5-6.0; P < .001). Attention-deficit/hyperactivity disorder was independently associated with an increased risk of anxiety disorders (OR, 1.5; 95% CI, 1.2-2.0; P < .01) and DBDs (OR, 4.0; 95% CI, 2.6-6.2; P < .001) but not substance use or mood disorders. There were no significant associations between TS, OCD, ADHD, and elimination or eating disorders. The results of these models build on those summarized in Figure 1 because they control for the age and sex of the participants.

Age of Highest Risk

The median age at onset for TS was 6 years (interquartile range, 4-8 years) (Figure 2 and eTable 7 in the Supplement). Attention-deficit/hyperactivity disorder and DBD had the youngest median age at onset and earliest ages of highest risk (5 years: interquartile ranges, 3-6 and 3-8, respectively). The high-risk period began at age 4 years for anxiety disorders, 7 years for mood disorders, and 13 years for substance use and eating disorders. Compared with males, females tended to have later ages at onset of TS, DBDs, anxiety disorders, and mood disorders (eTable 7 in the Supplement).

Place holder to copy figure label and caption
Figure 2.
Ages at Onset for Comorbid Disorders Among Individuals With Tourette Syndrome (TS)

Data points and bars represent median ages at onset and interquartile ranges, respectively. The width of each plot is proportional to the number of individuals with the given age at TS onset. ADHD indicates attention-deficit/hyperactivity disorder; OCD, obsessive-compulsive disorder.

Graphic Jump Location
Clinical Correlates of Number of Psychiatric Disorders

High tic and moderate/high OCD symptom severity, lifetime prevalence of ADHD or OCD, and parental history of TS/CMVTD and ADHD were associated with having 1 or more noncore psychiatric comorbidity in univariate analyses (Table 2). In the multivariate model, only high tic severity (OR, 1.57; 95% CI, 1.11-2.21; P = .01), ADHD (OR, 1.51; 95% CI, 1.12-2.03; P < .01), OCD (OR, 1.77; 95% CI, 1.34-2.35; P < .001), and parental history of ADHD (OR, 1.55; 95% CI, 1.08-2.23; P = .02) remained significant. Obsessive-compulsive disorder severity was omitted from the multivariate model to avoid confounding with OCD diagnosis.

Table Graphic Jump LocationTable 2.  Clinical Predictors of Having 1 or More Comorbid Disordera
Genetic Relationships With TS

Consistent with previous findings,26,35 including those from a subset of the current sample, TS/CMVTD, OCD, and ADHD all demonstrated significant genetic correlations (eTable 8 in the Supplement). In addition, TS/CMVTD had significant genetic correlations with mood disorders (RhoG [SE], 0.47 [0.17]; P = .004), anxiety disorders (RhoG [SE], 0.35 [0.15]; P = .02), and DBDs (RhoG [SE], 0.40 [0.18]; P = .02); these correlations were not significant when controlling for OCD and ADHD (eTable 9 in the Supplement). Mood disorders, anxiety disorders, and DBDs were also genetically correlated with ADHD; these correlations remained significant after controlling for TS/CMVTD and OCD (Table 3). Furthermore, mood disorders were significantly genetically correlated with OCD, even when controlling for TS/CMVTD and ADHD (Table 3).

Table Graphic Jump LocationTable 3.  Bivariate Heritability of Comorbid Diagnoses With TS/CMVTD, OCD, and ADHDa

To our knowledge, this study represents the most comprehensive examination to date of the extent and burden of comorbid psychiatric disorders in TS and is the first to report the ages of highest risk and etiologic relationships with TS for a wide variety of psychiatric conditions. Our results have implications both clinically and for ongoing research into the causes and etiologic relationships between these psychiatric disorders.

Clinical Relevance

Consistent with previous studies,3,4,12,15,3639 we identified a very high burden of psychiatric disorders. Our results suggest that the vast majority of children with TS can be expected to develop 1 or more comorbid psychiatric disorder during their lifetime, and more than half will develop 2 disorders. In addition to high rates of OCD (50.0%) and ADHD (54.3%), we identified high rates of mood disorders (29.8%), anxiety disorders (36.1%), DBDs (29.7%), and elimination disorders (16.2%). We found relatively low rates of psychotic disorders and substance abuse disorders at the time of evaluation, although we do not have longitudinal data for the younger individuals as they age, when such disorders typically manifest.

To our knowledge, this study is the first to report the ages of highest risk for comorbid psychiatric disorders as well as the relationship of demographic and clinical characteristics with overall disorder burden in TS. For most disorders, the age of greatest risk began before 5 years, with high risk for anxiety and DBD continuing into adolescence and risk for depressive disorders continuing into young adulthood. Previous research has demonstrated that TS symptoms typically emerge between the ages of 5 and 7 years13,40; ADHD generally appears 2 to 3 years earlier41 and OCD 5 to 6 years later.42 In this study, DBD and ADHD began at or before age 5 years, prior to tic onset. In contrast to the findings of population-based epidemiologic studies,43,44 OCD and anxiety disorders also began early in the patients in our study, typically within 1 year of the onset of tics (with many cases beginning earlier); mood disorders had a more distributed age-at-onset pattern, beginning as early as age 5 years and becoming more frequent at approximately 7 to 8 years. These results, in combination with the high likelihood of developing a mood disorder, anxiety disorder, or DBD, suggest that psychiatric assessments of TS-affected children should begin early and continue throughout adolescence and adulthood.

Our results also suggest that TS-affected children who have concomitant OCD or a parent with ADHD should be carefully evaluated over time for the development of mood disorder, anxiety disorder, and DBD. In addition, adolescents, particularly those with OCD and/or ADHD, should be monitored for the development of a substance use disorder. In a similar manner, TS-affected children with ADHD should be evaluated for other DBD and anxiety disorders. The association between high tic severity and the number of non-ADHD/non-OCD comorbidities is consistent with a previous study12 demonstrating an association between tic severity and non-OCD anxiety disorders.

Etiologic Relevance

The heritability estimates we observed confirm previous research26,35 showing that TS, OCD, and ADHD are highly genetically related. However, for what we believe to be the first time, we also provide evidence of a strong genetic relationship between these TS-related phenotypes and mood disorders, anxiety disorders, and DBDs. Of particular interest, our analyses suggest that the observed genetic correlations between TS and these disorders are better accounted for by an underlying genetic relationship with ADHD and, in the case of mood disorders, by an underlying genetic relationship with both ADHD and OCD. In non-TS samples, there is considerable evidence45 to support shared genetic variance between ADHD and DBD and some data46 to support a shared genetic diathesis underlying ADHD and major depressive disorder. Genetic relationships between OCD and mood disorders have not previously been examined. Our findings are in line with those of a previous study that found no increased rates of ADHD47 or other non-OCD disorders, such as anxiety, affective, substance abuse, and psychotic disorders,48 among parents of probands with TS compared with controls, suggesting that these disorders segregate independently from TS. Our findings that parental history of ADHD predicts psychiatric disorder burden in TS-affected offspring, independent of parental history of TS and OCD, provides additional support for the observed genetic relationships between psychiatric disorders and ADHD.

Limitations

This study has several limitations. First, our data are cross-sectional; thus, we could not assess causation (eg, whether clinical characteristics predicted subsequent disorder onset). Second, the predominately clinic-based recruitment may have biased our sample to participants with more severe, comorbid, or familial TS, limiting generalizability. This concern is somewhat mitigated by the presence of parents and siblings with previously undiagnosed TS, who were typically less severely affected. Third, although consistent with previous studies, the total psychiatric burden identified in the present study is likely an underestimate given that some disorders were not assessed (eg, pervasive developmental disorders) and not everyone had passed the age of risk for all disorders. Specifically, parents were not routinely assessed for certain childhood disorders (eg, elimination disorders) and children were not assessed for schizophrenia, although they were evaluated for psychosis. In addition, the lifetime rates of schizophrenia, bipolar disorder, and substance use disorders could be attenuated by an ascertainment bias (ie, the children and adolescents in our sample may have developed these adult-onset disorders later in life). Fourth, ADHD severity was not uniformly assessed. Fifth, we did not have reliable data regarding the recruitment methods (ie, Tourette Syndrome Association vs specialty clinics), and the characteristics of participants may vary by recruitment method. Sixth, pervasive developmental disorders were not systematically assessed or uniformly excluded; future studies should examine patterns of comorbidity between TS and pervasive developmental disorders.49 Finally, because the parent genetic study focused on sibling pairs and parent-child trios, the heritabilities may be underestimates because the algorithm used by SOLAR is best suited to analysis of multigenerational families.

This study provides important new data regarding the prevalence, predictors, and ages of the highest risk for psychiatric illness among individuals affected with TS, as well as what we believe to be the first formal evaluation of the etiologic relationships between disorders other than OCD and ADHD. The key clinical findings, that mood disorders, anxiety disorders, and DBDs are very common among TS-affected individuals, tend to begin early in life, and are highly associated with comorbid OCD and ADHD, are of direct and immediate relevance for practitioners. The genetic analyses advance our understanding of the etiologic relationships between TS and other psychiatric disorders and provide a framework for future studies aimed at better understanding these complex, interrelated syndromes.

Submitted for Publication: May 16, 2014; final revision received August 20, 2014; accepted September 29, 2014.

Corresponding Author: Carol A. Mathews, MD, Program for Genetics and Epidemiology of Neuropsychiatric Symptoms, Department of Psychiatry, University of California, San Francisco, 401 Parnassus Ave, PO Box 0984, San Francisco, CA 94143 (carolm@lppi.ucsf.edu).

Published Online: February 11, 2015. doi:10.1001/jamapsychiatry.2014.2650.

Author Contributions: Drs Hirschtritt and Lee contributed equally to this study, as did Drs Scharf and Mathews. Drs Hirschtritt and Lee had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hirschtritt, Lee, Grados, King, Sandor, McMahon, Cath, Scharf, Mathews.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hirschtritt, Lee, Lyon, Cath, Scharf, Mathews.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Hirschtritt, Lee, Scharf, Mathews.

Obtained funding: Pauls, McMahon, Mathews.

Administrative, technical, or material support: Dion, Illmann, Sandor, Lyon, Osiecki, Scharf, Mathews.

Study supervision: McMahon, Cath, Scharf, Mathews.

Conflict of Interest Disclosures: Dr Scharf reports receiving research support, honoraria, and travel support from the Tourette Syndrome Association. Dr Sandor reports receiving research support for this study from the Tourette Syndrome Association, Tourette Syndrome Foundation of Canada, and the National Institutes of Health. Dr Robertson reports receiving grants from the Tourette’s Action–United Kingdom and Tourette Syndrome Association–USA, honoraria from Janssen-Cilag and Flynn Pharma, and book royalties from David Fulton/Granada/Taylor Francis, Jessica Kingsley Publishers, Oxford University Press, and Wiley-Blackwell; being a Patron of Tourette’s Action, and sitting on the medical advisory board of the Italian Tourette Syndrome Association and the Tourette Syndrome Foundation of Canada. Dr Robertson also reports being honorary lifetime president of the European Society for the Study of Tourette Syndrome. Dr Mathews reports receiving research support, honoraria, and travel support from the Tourette Syndrome Association. No other disclosures were reported.

Funding/Support: This study was supported in part by National Institutes of Health grant U01 NS40024 (Dr Scharf) from the National Institute of Neurological Disorders and Stroke, grants K23 MH085057 (Dr Scharf) and R01 MH096767 (Dr Mathews) from the National Institute of Mental Health, and by a Doris Duke Clinical Research Fellowship (Dr Hirschtritt).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Tourette Syndrome Association International Consortium for Genetics are Danielle Posthuma, PhD (Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam and Department of Clinical Genetics, Vrije Universiteit Amsterdam, De Boelelaan, Amsterdam, the Netherlands, and Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands); Marco A. Grados, MD, and Harvey S. Singer, MD (Departments of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland); Cornelia Illmann, PhD, Lisa Osiecki, BA, David L. Pauls, PhD, Jeremiah M. Scharf, MD, PhD, and Dongmei Yu, MS (Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston); Nancy J. Cox, PhD (Department of Human Genetics, University of Chicago, Chicago, Illinois); Mary M. Robertson, MBChB, MD, DSc(Med), FRCP, FRCPCH, FRCPsych (St George’s Hospital and Medical School, University College London, London, England); Nelson B. Freimer, MD (Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles); Cathy L. Budman, MD (Department of Psychiatry, North Shore–Long Island Jewish Health System, Manhasset, New York); Sylvain Chouinard, PhD, Yves Dion, MD, and G. A. Rouleau, PhD (University of Montreal, Montreal, Quebec, Canada); Robert A. King, MD (Department of Genetics and the Child Study Center, Yale University School of Medicine, New Haven, Connecticut); William M. McMahon, MD (Departments of Psychiatry and Human Genetics, University of Utah School of Medicine, Salt Lake City); Carol A. Mathews, MD (Department of Psychiatry, University of California, San Francisco); Roger Kurlan, MD (Atlantic Neuroscience Institute, Summit, New Jersey); Cathy L. Barr, PhD, and Paul Sandor, MD (Department of Psychiatry, University of Toronto and University Health Network, Toronto Western Research Institute and Youthdale Treatment Centers, Toronto, Ontario, Canada); Danielle C. Cath, MD, PhD (Department of Clinical and Health Psychology, Utrecht University, Utrecht, the Netherlands); and Gholson J. Lyon, MD, PhD (Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, New York).

Additional Contributions: We gratefully acknowledge the individuals with TS and their families who participated in this study.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
Swain  JE, Scahill  L, Lombroso  PJ, King  RA, Leckman  JF.  Tourette syndrome and tic disorders: a decade of progress. J Am Acad Child Adolesc Psychiatry. 2007;46(8):947-968.
PubMed   |  Link to Article
Coffey  BJ, Miguel  EC, Biederman  J,  et al.  Tourette’s disorder with and without obsessive-compulsive disorder in adults: are they different? J Nerv Ment Dis. 1998;186(4):201-206.
PubMed   |  Link to Article
Gorman  DA, Thompson  N, Plessen  KJ, Robertson  MM, Leckman  JF, Peterson  BS.  Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study. Br J Psychiatry. 2010;197(1):36-44.
PubMed   |  Link to Article
Sukhodolsky  DG, Scahill  L, Zhang  H,  et al.  Disruptive behavior in children with Tourette’s syndrome: association with ADHD comorbidity, tic severity, and functional impairment. J Am Acad Child Adolesc Psychiatry. 2003;42(1):98-105.
PubMed   |  Link to Article
Bernard  BA, Stebbins  GT, Siegel  S,  et al.  Determinants of quality of life in children with Gilles de la Tourette syndrome. Mov Disord. 2009;24(7):1070-1073.
PubMed   |  Link to Article
Bloch  MH, Peterson  BS, Scahill  L,  et al.  Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome. Arch Pediatr Adolesc Med. 2006;160(1):65-69.
PubMed   |  Link to Article
Peterson  BS, Pine  DS, Cohen  P, Brook  JS.  Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders in an epidemiological sample. J Am Acad Child Adolesc Psychiatry. 2001;40(6):685-695.
PubMed   |  Link to Article
Denckla  MB.  Attention deficit hyperactivity disorder: the childhood co-morbidity that most influences the disability burden in Tourette syndrome. Adv Neurol. 2006;99:17-21.
PubMed
Mathews  CA, Waller  J, Glidden  D,  et al.  Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control. J Neurol Neurosurg Psychiatry. 2004;75(8):1149-1155.
PubMed   |  Link to Article
Robertson  MM.  The Gilles de la Tourette syndrome: the current status. Arch Dis Child Educ Pract Ed. 2012;97(5):166-175.
PubMed   |  Link to Article
Coffey  BJ, Biederman  J, Smoller  JW,  et al.  Anxiety disorders and tic severity in juveniles with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(5):562-568.
PubMed   |  Link to Article
Freeman  RD, Fast  DK, Burd  L, Kerbeshian  J, Robertson  MM, Sandor  P.  An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol. 2000;42(7):436-447.
PubMed   |  Link to Article
Ghanizadeh  A, Mosallaei  S.  Psychiatric disorders and behavioral problems in children and adolescents with Tourette syndrome. Brain Dev. 2009;31(1):15-19.
PubMed   |  Link to Article
Mol Debes  NM, Hjalgrim  H, Skov  L.  Validation of the presence of comorbidities in a Danish clinical cohort of children with Tourette syndrome. J Child Neurol. 2008;23(9):1017-1027.
PubMed   |  Link to Article
Comings  BG, Comings  DE.  A controlled study of Tourette syndrome, V: depression and mania. Am J Hum Genet. 1987;41(5):804-821.
PubMed
Comings  DE, Comings  BG.  A controlled study of Tourette syndrome, II: conduct. Am J Hum Genet. 1987;41(5):742-760.
PubMed
Haddad  AD, Umoh  G, Bhatia  V, Robertson  MM.  Adults with Tourette’s syndrome with and without attention deficit hyperactivity disorder. Acta Psychiatr Scand. 2009;120(4):299-307.
PubMed   |  Link to Article
Berthier  ML, Kulisevsky  J, Campos  VM.  Bipolar disorder in adult patients with Tourette’s syndrome: a clinical study. Biol Psychiatry. 1998;43(5):364-370.
PubMed   |  Link to Article
Bloch  MH, Leckman  JF, Zhu  H, Peterson  BS.  Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology. 2005;65(8):1253-1258.
PubMed   |  Link to Article
Eapen  V, Fox-Hiley  P, Banerjee  S, Robertson  M.  Clinical features and associated psychopathology in a Tourette syndrome cohort. Acta Neurol Scand. 2004;109(4):255-260.
PubMed   |  Link to Article
Wand  RR, Matazow  GS, Shady  GA, Furer  P, Staley  D.  Tourette syndrome: associated symptoms and most disabling features. Neurosci Biobehav Rev. 1993;17(3):271-275.
PubMed   |  Link to Article
Rickards  H, Robertson  M.  A controlled study of psychopathology and associated symptoms in Tourette syndrome. World J Biol Psychiatry. 2003;4(2):64-68.
PubMed   |  Link to Article
Termine  C, Balottin  U, Rossi  G,  et al.  Psychopathology in children and adolescents with Tourette’s syndrome: a controlled study. Brain Dev. 2006;28(2):69-75.
PubMed   |  Link to Article
Grados  MA, Mathews  CA; Tourette Syndrome Association International Consortium for Genetics.  Latent class analysis of Gilles de la Tourette syndrome using comorbidities: clinical and genetic implications. Biol Psychiatry. 2008;64(3):219-225.
PubMed   |  Link to Article
Mathews  CA, Grados  MA.  Familiality of Tourette syndrome, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder: heritability analysis in a large sib-pair sample. J Am Acad Child Adolesc Psychiatry. 2011;50(1):46-54.
PubMed   |  Link to Article
Sheppard  DM, Bradshaw  JL, Purcell  R, Pantelis  C.  Tourette’s and comorbid syndromes: obsessive compulsive and attention deficit hyperactivity disorder: a common etiology? Clin Psychol Rev. 1999;19(5):531-552.
PubMed   |  Link to Article
Tourette Syndrome Association International Consortium for Genetics.  Genome scan for Tourette disorder in affected-sibling-pair and multigenerational families. Am J Hum Genet. 2007;80(2):265-272.
PubMed   |  Link to Article
First  MB, Spitzer  RL, Gibbon  M, Williams  JBW. Structured Clinical Interview for DSM-IV Axis I Disorders–Non-Patient Edition (SCID-I/NP, version 2.0). New York: Biometrics Research Dept, New York State Psychiatric Institute; 1995.
Fyer  A, Endicott  J, Mannuzza  S, Klein  DF. Schedule for Affective Disorders and Schizophrenia–Lifetime Version, Modified for the Study of Anxiety Disorders (SADS-LA). New York: Anxiety Disorders Clinic, New York State Psychiatric Institute; 1985.
Kaufman  J, Birmaher  B, Brent  D,  et al.  Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36(7):980-988.
PubMed   |  Link to Article
Orvaschel  H, Puig-Antich  J, Chambers  W, Tabrizi  MA, Johnson  R.  Retrospective assessment of prepubertal major depression with the Kiddie-SADS-e. J Am Acad Child Psychiatry. 1982;21(4):392-397.
PubMed   |  Link to Article
Leckman  JF, Sholomskas  D, Thompson  WD, Belanger  A, Weissman  MM.  Best estimate of lifetime psychiatric diagnosis: a methodological study. Arch Gen Psychiatry. 1982;39(8):879-883.
PubMed   |  Link to Article
Almasy  L, Blangero  J.  Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62(5):1198-1211.
PubMed   |  Link to Article
Grados  MA, Mathews  CA.  Clinical phenomenology and phenotype variability in Tourette syndrome. J Psychosom Res. 2009;67(6):491-496.
PubMed   |  Link to Article
Chee  KY, Sachdev  P.  The clinical features of Tourette’s disorder: an Australian study using a structured interview schedule. Aust N Z J Psychiatry. 1994;28(2):313-318.
PubMed   |  Link to Article
Kurlan  R, Como  PG, Miller  B,  et al.  The behavioral spectrum of tic disorders: a community-based study. Neurology. 2002;59(3):414-420.
PubMed   |  Link to Article
Khalifa  N, von Knorring  AL.  Psychopathology in a Swedish population of school children with tic disorders. J Am Acad Child Adolesc Psychiatry. 2006;45(11):1346-1353.
PubMed   |  Link to Article
Specht  MW, Woods  DW, Piacentini  J,  et al.  Clinical characteristics of children and adolescents with a primary tic disorder. J Dev Phys Disabil. 2011;23(1):15-31.
PubMed   |  Link to Article
Leckman  JF, Zhang  H, Vitale  A,  et al.  Course of tic severity in Tourette syndrome: the first two decades. Pediatrics. 1998;102(1, pt 1):14-19.
PubMed   |  Link to Article
Robertson  MM.  Attention deficit hyperactivity disorder, tics and Tourette’s syndrome: the relationship and treatment implications: a commentary. Eur Child Adolesc Psychiatry. 2006;15(1):1-11.
PubMed   |  Link to Article
Delorme  R, Golmard  JL, Chabane  N,  et al.  Admixture analysis of age at onset in obsessive-compulsive disorder. Psychol Med. 2005;35(2):237-243.
PubMed   |  Link to Article
Kessler  RC, Berglund  P, Demler  O, Jin  R, Merikangas  KR, Walters  EE.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.
PubMed   |  Link to Article
Kessler  RC, Angermeyer  M, Anthony  JC,  et al.  Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’s World Mental Health Survey Initiative. World Psychiatry. 2007;6(3):168-176.
PubMed
Nadder  TS, Rutter  M, Silberg  JL, Maes  HH, Eaves  LJ.  Genetic effects on the variation and covariation of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder/conduct disorder (ODD/CD) symptomatologies across informant and occasion of measurement. Psychol Med. 2002;32(1):39-53.
PubMed   |  Link to Article
Lee  SH, Ripke  S, Neale  BM,  et al; Cross-Disorder Group of the Psychiatric Genomics Consortium; International Inflammatory Bowel Disease Genetics Consortium (IIBDGC).  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45(9):984-994.
PubMed   |  Link to Article
Pauls  DL, Hurst  CR, Kruger  SD, Leckman  JF, Kidd  KK, Cohen  DJ.  Gilles de la Tourette’s syndrome and attention deficit disorder with hyperactivity: evidence against a genetic relationship. Arch Gen Psychiatry. 1986;43(12):1177-1179.
PubMed   |  Link to Article
Pauls  DL, Leckman  JF, Cohen  DJ.  Evidence against a genetic relationship between Tourette’s syndrome and anxiety, depression, panic and phobic disorders. Br J Psychiatry. 1994;164(2):215-221.
PubMed   |  Link to Article
Clarke  RA, Lee  S, Eapen  V.  Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including autism. Transl Psychiatry. 2012;2:e158.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Lifetime Prevalence of Comorbid Disorders by the Presence of Obsessive-Compulsive Disorder (OCD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Among Individuals With Tourette Syndrome (TS)

Significance values reflect individual 4 × 2 χ2 tests (ie, TS, OCD, and ADHD grouped by the presence of the comorbid disorder).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Ages at Onset for Comorbid Disorders Among Individuals With Tourette Syndrome (TS)

Data points and bars represent median ages at onset and interquartile ranges, respectively. The width of each plot is proportional to the number of individuals with the given age at TS onset. ADHD indicates attention-deficit/hyperactivity disorder; OCD, obsessive-compulsive disorder.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Lifetime Prevalence of Psychiatric Disorders by Sex
Table Graphic Jump LocationTable 2.  Clinical Predictors of Having 1 or More Comorbid Disordera
Table Graphic Jump LocationTable 3.  Bivariate Heritability of Comorbid Diagnoses With TS/CMVTD, OCD, and ADHDa

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
Swain  JE, Scahill  L, Lombroso  PJ, King  RA, Leckman  JF.  Tourette syndrome and tic disorders: a decade of progress. J Am Acad Child Adolesc Psychiatry. 2007;46(8):947-968.
PubMed   |  Link to Article
Coffey  BJ, Miguel  EC, Biederman  J,  et al.  Tourette’s disorder with and without obsessive-compulsive disorder in adults: are they different? J Nerv Ment Dis. 1998;186(4):201-206.
PubMed   |  Link to Article
Gorman  DA, Thompson  N, Plessen  KJ, Robertson  MM, Leckman  JF, Peterson  BS.  Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study. Br J Psychiatry. 2010;197(1):36-44.
PubMed   |  Link to Article
Sukhodolsky  DG, Scahill  L, Zhang  H,  et al.  Disruptive behavior in children with Tourette’s syndrome: association with ADHD comorbidity, tic severity, and functional impairment. J Am Acad Child Adolesc Psychiatry. 2003;42(1):98-105.
PubMed   |  Link to Article
Bernard  BA, Stebbins  GT, Siegel  S,  et al.  Determinants of quality of life in children with Gilles de la Tourette syndrome. Mov Disord. 2009;24(7):1070-1073.
PubMed   |  Link to Article
Bloch  MH, Peterson  BS, Scahill  L,  et al.  Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome. Arch Pediatr Adolesc Med. 2006;160(1):65-69.
PubMed   |  Link to Article
Peterson  BS, Pine  DS, Cohen  P, Brook  JS.  Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders in an epidemiological sample. J Am Acad Child Adolesc Psychiatry. 2001;40(6):685-695.
PubMed   |  Link to Article
Denckla  MB.  Attention deficit hyperactivity disorder: the childhood co-morbidity that most influences the disability burden in Tourette syndrome. Adv Neurol. 2006;99:17-21.
PubMed
Mathews  CA, Waller  J, Glidden  D,  et al.  Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control. J Neurol Neurosurg Psychiatry. 2004;75(8):1149-1155.
PubMed   |  Link to Article
Robertson  MM.  The Gilles de la Tourette syndrome: the current status. Arch Dis Child Educ Pract Ed. 2012;97(5):166-175.
PubMed   |  Link to Article
Coffey  BJ, Biederman  J, Smoller  JW,  et al.  Anxiety disorders and tic severity in juveniles with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(5):562-568.
PubMed   |  Link to Article
Freeman  RD, Fast  DK, Burd  L, Kerbeshian  J, Robertson  MM, Sandor  P.  An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol. 2000;42(7):436-447.
PubMed   |  Link to Article
Ghanizadeh  A, Mosallaei  S.  Psychiatric disorders and behavioral problems in children and adolescents with Tourette syndrome. Brain Dev. 2009;31(1):15-19.
PubMed   |  Link to Article
Mol Debes  NM, Hjalgrim  H, Skov  L.  Validation of the presence of comorbidities in a Danish clinical cohort of children with Tourette syndrome. J Child Neurol. 2008;23(9):1017-1027.
PubMed   |  Link to Article
Comings  BG, Comings  DE.  A controlled study of Tourette syndrome, V: depression and mania. Am J Hum Genet. 1987;41(5):804-821.
PubMed
Comings  DE, Comings  BG.  A controlled study of Tourette syndrome, II: conduct. Am J Hum Genet. 1987;41(5):742-760.
PubMed
Haddad  AD, Umoh  G, Bhatia  V, Robertson  MM.  Adults with Tourette’s syndrome with and without attention deficit hyperactivity disorder. Acta Psychiatr Scand. 2009;120(4):299-307.
PubMed   |  Link to Article
Berthier  ML, Kulisevsky  J, Campos  VM.  Bipolar disorder in adult patients with Tourette’s syndrome: a clinical study. Biol Psychiatry. 1998;43(5):364-370.
PubMed   |  Link to Article
Bloch  MH, Leckman  JF, Zhu  H, Peterson  BS.  Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology. 2005;65(8):1253-1258.
PubMed   |  Link to Article
Eapen  V, Fox-Hiley  P, Banerjee  S, Robertson  M.  Clinical features and associated psychopathology in a Tourette syndrome cohort. Acta Neurol Scand. 2004;109(4):255-260.
PubMed   |  Link to Article
Wand  RR, Matazow  GS, Shady  GA, Furer  P, Staley  D.  Tourette syndrome: associated symptoms and most disabling features. Neurosci Biobehav Rev. 1993;17(3):271-275.
PubMed   |  Link to Article
Rickards  H, Robertson  M.  A controlled study of psychopathology and associated symptoms in Tourette syndrome. World J Biol Psychiatry. 2003;4(2):64-68.
PubMed   |  Link to Article
Termine  C, Balottin  U, Rossi  G,  et al.  Psychopathology in children and adolescents with Tourette’s syndrome: a controlled study. Brain Dev. 2006;28(2):69-75.
PubMed   |  Link to Article
Grados  MA, Mathews  CA; Tourette Syndrome Association International Consortium for Genetics.  Latent class analysis of Gilles de la Tourette syndrome using comorbidities: clinical and genetic implications. Biol Psychiatry. 2008;64(3):219-225.
PubMed   |  Link to Article
Mathews  CA, Grados  MA.  Familiality of Tourette syndrome, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder: heritability analysis in a large sib-pair sample. J Am Acad Child Adolesc Psychiatry. 2011;50(1):46-54.
PubMed   |  Link to Article
Sheppard  DM, Bradshaw  JL, Purcell  R, Pantelis  C.  Tourette’s and comorbid syndromes: obsessive compulsive and attention deficit hyperactivity disorder: a common etiology? Clin Psychol Rev. 1999;19(5):531-552.
PubMed   |  Link to Article
Tourette Syndrome Association International Consortium for Genetics.  Genome scan for Tourette disorder in affected-sibling-pair and multigenerational families. Am J Hum Genet. 2007;80(2):265-272.
PubMed   |  Link to Article
First  MB, Spitzer  RL, Gibbon  M, Williams  JBW. Structured Clinical Interview for DSM-IV Axis I Disorders–Non-Patient Edition (SCID-I/NP, version 2.0). New York: Biometrics Research Dept, New York State Psychiatric Institute; 1995.
Fyer  A, Endicott  J, Mannuzza  S, Klein  DF. Schedule for Affective Disorders and Schizophrenia–Lifetime Version, Modified for the Study of Anxiety Disorders (SADS-LA). New York: Anxiety Disorders Clinic, New York State Psychiatric Institute; 1985.
Kaufman  J, Birmaher  B, Brent  D,  et al.  Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36(7):980-988.
PubMed   |  Link to Article
Orvaschel  H, Puig-Antich  J, Chambers  W, Tabrizi  MA, Johnson  R.  Retrospective assessment of prepubertal major depression with the Kiddie-SADS-e. J Am Acad Child Psychiatry. 1982;21(4):392-397.
PubMed   |  Link to Article
Leckman  JF, Sholomskas  D, Thompson  WD, Belanger  A, Weissman  MM.  Best estimate of lifetime psychiatric diagnosis: a methodological study. Arch Gen Psychiatry. 1982;39(8):879-883.
PubMed   |  Link to Article
Almasy  L, Blangero  J.  Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62(5):1198-1211.
PubMed   |  Link to Article
Grados  MA, Mathews  CA.  Clinical phenomenology and phenotype variability in Tourette syndrome. J Psychosom Res. 2009;67(6):491-496.
PubMed   |  Link to Article
Chee  KY, Sachdev  P.  The clinical features of Tourette’s disorder: an Australian study using a structured interview schedule. Aust N Z J Psychiatry. 1994;28(2):313-318.
PubMed   |  Link to Article
Kurlan  R, Como  PG, Miller  B,  et al.  The behavioral spectrum of tic disorders: a community-based study. Neurology. 2002;59(3):414-420.
PubMed   |  Link to Article
Khalifa  N, von Knorring  AL.  Psychopathology in a Swedish population of school children with tic disorders. J Am Acad Child Adolesc Psychiatry. 2006;45(11):1346-1353.
PubMed   |  Link to Article
Specht  MW, Woods  DW, Piacentini  J,  et al.  Clinical characteristics of children and adolescents with a primary tic disorder. J Dev Phys Disabil. 2011;23(1):15-31.
PubMed   |  Link to Article
Leckman  JF, Zhang  H, Vitale  A,  et al.  Course of tic severity in Tourette syndrome: the first two decades. Pediatrics. 1998;102(1, pt 1):14-19.
PubMed   |  Link to Article
Robertson  MM.  Attention deficit hyperactivity disorder, tics and Tourette’s syndrome: the relationship and treatment implications: a commentary. Eur Child Adolesc Psychiatry. 2006;15(1):1-11.
PubMed   |  Link to Article
Delorme  R, Golmard  JL, Chabane  N,  et al.  Admixture analysis of age at onset in obsessive-compulsive disorder. Psychol Med. 2005;35(2):237-243.
PubMed   |  Link to Article
Kessler  RC, Berglund  P, Demler  O, Jin  R, Merikangas  KR, Walters  EE.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.
PubMed   |  Link to Article
Kessler  RC, Angermeyer  M, Anthony  JC,  et al.  Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’s World Mental Health Survey Initiative. World Psychiatry. 2007;6(3):168-176.
PubMed
Nadder  TS, Rutter  M, Silberg  JL, Maes  HH, Eaves  LJ.  Genetic effects on the variation and covariation of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder/conduct disorder (ODD/CD) symptomatologies across informant and occasion of measurement. Psychol Med. 2002;32(1):39-53.
PubMed   |  Link to Article
Lee  SH, Ripke  S, Neale  BM,  et al; Cross-Disorder Group of the Psychiatric Genomics Consortium; International Inflammatory Bowel Disease Genetics Consortium (IIBDGC).  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45(9):984-994.
PubMed   |  Link to Article
Pauls  DL, Hurst  CR, Kruger  SD, Leckman  JF, Kidd  KK, Cohen  DJ.  Gilles de la Tourette’s syndrome and attention deficit disorder with hyperactivity: evidence against a genetic relationship. Arch Gen Psychiatry. 1986;43(12):1177-1179.
PubMed   |  Link to Article
Pauls  DL, Leckman  JF, Cohen  DJ.  Evidence against a genetic relationship between Tourette’s syndrome and anxiety, depression, panic and phobic disorders. Br J Psychiatry. 1994;164(2):215-221.
PubMed   |  Link to Article
Clarke  RA, Lee  S, Eapen  V.  Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including autism. Transl Psychiatry. 2012;2:e158.
PubMed   |  Link to Article

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Multimedia

Supplement.

eAppendix. Methods

eTable 1. Demographic and Clinical Characteristics of the Sample

eTable 2. Lifetime Prevalence of Psychiatric Disorders by Sex in Individuals With Tourette Syndrome

eTable 3. Lifetime Prevalence of Psychiatric Disorders by Age in Individuals With Tourette Syndrome

eTable 4. Lifetime Prevalence of Psychiatric Disorders by Proband Status in Individuals With Tourette Syndrome

eTable 5. Lifetime Prevalence of Psychiatric Disorders by Presence of OCD and ADHD in Individuals With Tourette Syndrome

eTable 6. Associations Among TS, OCD, ADHD, and Other Comorbid Disorders

eTable 7. Ages of Onset for TS and Comorbid Disorders

eTable 8. Bivariate Heritability Estimates Among TS/CMVTD, OCD, and ADHD

eTable 9. Bivariate Heritability of Comorbid Diagnoses With TS/CMVTD

eFigure. Algorithm for Heritability Testing

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