Darrow, S. M., Hirschtritt, M. E., Davis, L. K., Illmann, C., Osiecki, L., Grados, M., Sandor, P., Dion, Y., King, R., Pauls, D., Budman, C. L., Cath, D. C., Greenberg, E., Lyon, G. J., Yu, D., McGrath, L. M., McMahon, W. M., Lee, P. C., Delucchi, K. L., Scharf, J. M., Mathews, C. A. (April 2017) Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome. Am J Psychiatry, 174 (4). pp. 387-396. ISSN 1535-7228 (Electronic)0002-953X (Linking)
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Attention Deficit Hyperactivity Disorder Genetics Latent Variable Modeling Obsessive-Compulsive Disorder Tourette's Disorder |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function diseases & disorders > mental disorders > Tourette Syndrome |
| CSHL Authors: | |
| Communities: | CSHL labs > Lyon lab |
| Depositing User: | Matt Covey |
| Date: | 1 April 2017 |
| Date Deposited: | 15 Nov 2016 15:52 |
| Last Modified: | 20 Apr 2017 20:19 |
| PMCID: | PMC5378637 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33888 |
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