1. Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.
- Author
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Darrow, Sabrina M, Hirschtritt, Matthew E, Davis, Lea K, Illmann, Cornelia, Osiecki, Lisa, Grados, Marco, Sandor, Paul, Dion, Yves, King, Robert, Pauls, David, Budman, Cathy L, Cath, Danielle C, Greenberg, Erica, Lyon, Gholson J, Yu, Dongmei, McGrath, Lauren M, McMahon, William M, Lee, Paul C, Delucchi, Kevin L, Scharf, Jeremiah M, Mathews, Carol A, and Tourette Syndrome Association International Consortium for Genetics
- Subjects
Tourette Syndrome Association International Consortium for Genetics ,Humans ,Tourette Syndrome ,Genetic Predisposition to Disease ,Risk Assessment ,Mothers ,Obsessive-Compulsive Disorder ,Attention Deficit Disorder with Hyperactivity ,Comorbidity ,Multifactorial Inheritance ,Phenotype ,Adolescent ,Adult ,Middle Aged ,Child ,Child ,Preschool ,Child of Impaired Parents ,Female ,Male ,Genome-Wide Association Study ,Young Adult ,Endophenotypes ,Attention Deficit Hyperactivity Disorder ,Genetics ,Latent Variable Modeling ,Tourette’s Disorder ,Genetic Testing ,Pediatric ,Brain Disorders ,Serious Mental Illness ,Mental Health ,Clinical Research ,Anxiety Disorders ,Human Genome ,Attention Deficit Hyperactivity Disorder (ADHD) ,Neurodegenerative ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
ObjectivePhenotypic 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.MethodAssessments 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.ResultsThe 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.ConclusionsThe 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.
- Published
- 2017