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. 2017 Apr 1;174(4):387-396.
doi: 10.1176/appi.ajp.2016.16020240. Epub 2016 Nov 4.

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome

Sabrina M Darrow  1 , Matthew E Hirschtritt  1 , Lea K Davis  1 , Cornelia Illmann  1 , Lisa Osiecki  1 , Marco Grados  1 , Paul Sandor  1 , Yves Dion  1 , Robert King  1 , David Pauls  1 , Cathy L Budman  1 , Danielle C Cath  1 , Erica Greenberg  1 , Gholson J Lyon  1 , Dongmei Yu  1 , Lauren M McGrath  1 , William M McMahon  1 , Paul C Lee  1 , Kevin L Delucchi  1 , Jeremiah M Scharf  1 , Carol A Mathews  1 ; Tourette Syndrome Association International Consortium for Genetics  1
Affiliations

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome

Sabrina M Darrow et al. Am J Psychiatry. .

Abstract

Objective: Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts.

Method: Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated.

Results: The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not.

Conclusions: The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

Keywords: Attention Deficit Hyperactivity Disorder; Genetics; Latent Variable Modeling; Obsessive-Compulsive Disorder; Tourette’s Disorder.

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Conflict of interest statement

Conflict of interest

Drs. Darrow, Hirschtritt, Illmann, Greenberg, McGrath, and Delucchi, and Ms. Osiecki reported no biomedical financial interests or potential conflicts of interest. Drs. Grados, Sandor, McMahon, Pauls, Dion, King, Budman, Freimer, Cox, Cath, Lyon and Lee received research support from the Tourette Association of America (TAA). Dr. Cath has received speakers’ honoraria from Pfizer BV. Dr. Budman reported funding for clinical research studies from Psyadon Pharmaceuticals and Otsuka Pharmaceuticals. Dr. Sandor reported Unrestricted Educational Grants from Purdue and Shire, a speaker fee from Purdue and support for clinical research from Otsuka Pharmaceuticals. Dr. Sandor was a member of the data safety monitoring committee for Psyadon Pharmaceuticals. Dr. Scharf has received consulting fees from Nuvelation Pharma, Inc. Drs. Scharf and Mathews have received research support, honoraria and travel support from the TAA and are members of the TAA Scientific Advisory Board. None of the funding agencies for this project (NINDS, NIMH, the Tourette Syndrome Association) had any influence or played any role in a) the design or conduct of the study; b) management, analysis or interpretation of the data; c) preparation, review or approval of the manuscript. The views expressed in this publication are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

Figures

Figure 1
Figure 1
Probabilities of endorsing symptoms in original latent class analyses with probands & family members
Figure 2
Figure 2
Rates of parents (a) and comorbidity (b) for classes of probands & family members. Note: Letters above bars indicate pairwise comparisons that are not significantly different P< 0.05. Significant differences were found for all diagnoses: OCD (χ2=1709.34, df=4, p≤.001), ADHD (χ2=2796.01, df=4, p≤.001), and mood (χ2=71.17, df=4, p≤.001), anxiety (χ2=62.42, df=4, p≤.001), and disruptive behavior (χ2=60.31, df=4, p≤.001) disorders.
See this image and copyright information in PMC

References

    1. Pauls DL, Fernandez TV, Mathews CA, State MW, Scharf JM. The Inheritance of Tourette Disorder: A review. Journal of obsessive-compulsive and related disorders. 2014;3(4):380–5. - PMC - PubMed
    1. Coffey BJ, Biederman J, Smoller JW, Geller DA, Sarin P, Schwartz S, et al. Anxiety disorders and tic severity in juveniles with Tourette’s disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2000;39(5):562–8. - PubMed
    1. 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. British Journal of Psychiatry. 2010;197(1):36–44. - PMC - PubMed
    1. Hirschtritt ME, Lee PC, Pauls DL, Dion Y, Grados MA, Illmann C, et al. Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in tourette syndrome. JAMA Psychiatry. 2015;72(4):325–33. - PMC - PubMed
    1. Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bilguvar K, O’Roak BJ, Mason CE, et al. L-histidine decarboxylase and Tourette’s syndrome. The New England journal of medicine. 2010;362(20):1901–8. - PMC - PubMed

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