Dataset Information

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

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.

SUBMITTER: Darrow SM

PROVIDER: S-EPMC5378637 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

Darrow Sabrina M SM Hirschtritt Matthew E ME Davis Lea K LK Illmann Cornelia C Osiecki Lisa L Grados Marco M Sandor Paul P Dion Yves Y King Robert R Pauls David D Budman Cathy L CL Cath Danielle C DC Greenberg Erica E Lyon Gholson J GJ Yu Dongmei D McGrath Lauren M LM McMahon William M WM Lee Paul C PC Delucchi Kevin L KL Scharf Jeremiah M JM Mathews Carol A CA

The American journal of psychiatry 20161104 4

<h4>Objective</h4>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.<h4>Method</h4>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 ...[more]

PMID: 27809572

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Project description:ImportanceThere are limited data concerning the risk of metabolic and cardiovascular disorders among individuals with Tourette syndrome (TS) or chronic tic disorder (CTD).ObjectiveTo investigate the risk of metabolic and cardiovascular disorders among individuals with TS or CTD over a period of 40 years.Design, settings, and participantsThis longitudinal population-based cohort study included all individuals living in Sweden between January 1, 1973, and December 31, 2013. Families with clusters of full siblings discordant for TS or CTD were further identified. Data analyses were conducted from August 1, 2017, to October 11, 2018.ExposuresPreviously validated International Classification of Diseases diagnoses of TS or CTD in the Swedish National Patient Register.Main outcomes and measuresRegistered diagnoses of obesity, dyslipidemia, hypertension, type 2 diabetes, and cardiovascular diseases (including ischemic heart diseases, arrhythmia, cerebrovascular diseases and transient ischemic attack, and arteriosclerosis).ResultsOf the 14 045 026 individuals in the cohort, 7804 individuals (5964 males [76.4%]; median age at first diagnosis, 13.3 years [interquartile range, 9.9-21.3 years]) had a registered diagnosis of TS or CTD in specialist care. Of 2 675 482 families with at least 2 singleton full siblings, 5141 families included siblings who were discordant for these disorders. Individuals with TS or CTD had a higher risk of any metabolic or cardiovascular disorders compared with the general population (hazard ratio adjusted by sex and birth year [aHR], 1.99; 95% CI, 1.90-2.09) and sibling controls (aHR for any disorder, 1.37; 95% CI, 1.24-1.51). Specifically, individuals with TS or CTD had higher risks for obesity (aHR, 2.76; 95% CI, 2.47-3.09), type 2 diabetes (aHR, 1.67; 95% CI, 1.42-1.96), and circulatory system diseases (aHR, 1.76; 95% CI, 1.67-1.86). The risk of any cardiometabolic disorder was significantly greater in males than in females (aHR, 2.13; 95% CI, 2.01-2.26 vs aHR, 1.79; 95% CI, 1.64-1.96), as was the risk of obesity (aHR, 3.24; 95% CI, 2.83-3.70 vs aHR, 1.97; 95% CI, 1.59-2.44). The risks were already evident from childhood (the groups were significantly different by age 8 years) and were significantly reduced with the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder (aHR, 1.52; 95% CI, 1.42-1.62), while excluding other comorbidities did not significantly affect the results. Compared with patients with TS or CTD who were not taking antipsychotics, patients with a longer duration of antipsychotic treatment (>1 year) had significantly lower risks of metabolic and cardiovascular disorders.Conclusions and relevanceThe findings of this study suggest that TS and CTD are associated with a substantial risk of metabolic and cardiovascular disorders. The results highlight the importance of carefully monitoring cardiometabolic health in patients with TS or CTD across the lifespan, particularly in those with comorbid attention-deficit/hyperactivity disorder.

Dataset Information

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

Publications

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

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