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Am J Psychiatry. 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.

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From the Department of Psychiatry, University of California, San Francisco; the Department of Medicine, Vanderbilt University Medical Center, Nashville; the Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry and University Health Network, University of Toronto, Toronto; the Youthdale Treatment Centres, Toronto; the Department of Psychiatry, University of Montreal, Montreal; the Yale Child Study Center and the Department of Genetics, Yale University School of Medicine, New Haven, Conn.; the Feinstein Institute for Medical Research, North Shore/Long Island Jewish Health System, Manhasset, N.Y.; the Faculty of Social and Behavioral Sciences, Utrecht University, Utrecht, The Netherlands; the Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.; the Department of Psychology, University of Denver, Denver; the Department of Psychiatry, University of Utah, Salt Lake City; the Department of Behavioral Health, Tripler Army Medical Center, Honolulu; the Departments of Neurology, Brigham and Women's Hospital and Massachusetts General Hospital, Boston; and the Department of Psychiatry, University of Florida, Gainesville.



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.


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.


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.


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.


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

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