Dataset Information

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

ABSTRACT: OBJECTIVE:Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS:GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS:GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS:Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

SUBMITTER: Yu D

PROVIDER: S-EPMC6677250 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

Yu Dongmei D Sul Jae Hoon JH Tsetsos Fotis F Nawaz Muhammad S MS Huang Alden Y AY Zelaya Ivette I Illmann Cornelia C Osiecki Lisa L Darrow Sabrina M SM Hirschtritt Matthew E ME Greenberg Erica E Muller-Vahl Kirsten R KR Stuhrmann Manfred M Dion Yves Y Rouleau Guy G Aschauer Harald H Stamenkovic Mara M Schlögelhofer Monika M Sandor Paul P Barr Cathy L CL Grados Marco M Singer Harvey S HS Nöthen Markus M MM Hebebrand Johannes J Hinney Anke A King Robert A RA Fernandez Thomas V TV Barta Csaba C Tarnok Zsanett Z Nagy Peter P Depienne Christel C Worbe Yulia Y Hartmann Andreas A Budman Cathy L CL Rizzo Renata R Lyon Gholson J GJ McMahon William M WM Batterson James R JR Cath Danielle C DC Malaty Irene A IA Okun Michael S MS Berlin Cheston C Woods Douglas W DW Lee Paul C PC Jankovic Joseph J Robertson Mary M MM Gilbert Donald L DL Brown Lawrence W LW Coffey Barbara J BJ Dietrich Andrea A Hoekstra Pieter J PJ Kuperman Samuel S Zinner Samuel H SH Luðvigsson Pétur P Sæmundsen Evald E Thorarensen Ólafur Ó Atzmon Gil G Barzilai Nir N Wagner Michael M Moessner Rainald R Ophoff Roel R Pato Carlos N CN Pato Michele T MT Knowles James A JA Roffman Joshua L JL Smoller Jordan W JW Buckner Randy L RL Willsey A Jeremy AJ Tischfield Jay A JA Heiman Gary A GA Stefansson Hreinn H Stefansson Kári K Posthuma Danielle D Cox Nancy J NJ Pauls David L DL Freimer Nelson B NB Neale Benjamin M BM Davis Lea K LK Paschou Peristera P Coppola Giovanni G Mathews Carol A CA Scharf Jeremiah M JM

The American journal of psychiatry 20190301 3

<h4>Objective</h4>Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with wors ...[more]

PMID: 30818990

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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.

Project description:ImportanceSevere forms of Tourette syndrome or chronic tic disorder (TS/CTD) may involve repeated head jerking. Isolated case reports have described a spectrum of severe neck disorders in individuals with TS/CTD. However, the nature and prevalence of cervical spine disorders in TS/CTD are unknown.ObjectiveTo establish if TS/CTD are associated with an increased risk of cervical spine disorders and related neurological complications compared with individuals from the general population.Design, setting, and participantsAll individuals born from 1973 to 2013 and living in Sweden between 1997 and 2013 were identified. Individuals with a record of TS/CTD diagnosed in specialist settings were matched on age, sex, and county of birth with 10 unexposed individuals randomly selected from the general population. Cox proportional hazards regression models were used to estimate the risk of vascular and nonvascular cervical spine disorders among exposed individuals, compared with unexposed individuals. Models were adjusted for other known causes of cervical spine injury. Data were analyzed from March 19 to May 16, 2021.ExposuresInternational Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of TS/CTD in the Swedish National Patient Register.Main outcomes and measuresRecords of cervical vascular disorders (ie, aneurysm, cerebral infarction, transitory cerebral ischemia) and cervical nonvascular disorders (ie, spondylosis, cervical disc disorders, fractures of the cervical spine, cervicalgia) and cervical surgeries. Covariates included rheumatic disorders, traffic injuries, fall- or sport-related injuries, and attention-deficit/hyperactivity disorder comorbidity.ResultsA total of 6791 individuals with TS/CTD were identified (5238 [77.1%] were male; median [interquartile] age at first diagnosis, 15.6 [11.4-23.7] years) and matched to 67 910 unexposed individuals. Exposed individuals had a 39% increased risk of any cervical spine disorder (adjusted hazard ratio, 1.39; 95% CI, 1.22-1.59). Adjusted hazard ratios for cervical vascular and nonvascular disorders were 1.57 (95% CI, 1.16-2.13) and 1.38 (95% CI, 1.19-1.60), respectively. Risks were similar among men and women.Conclusions and relevanceIndividuals with severe TS/CTD are at increased risk of cervical spine disorders. These outcomes are relatively rare but may lead to persistent disability in some individuals and thus require close monitoring to facilitate early interventions.

Dataset Information

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

Publications

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

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