Polygenic Risk Score-based Phenome-wide Association Study Identifies Novel Associations for Tourette Syndrome

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

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References

Mataix-Cols D, Isomura K, Perez-Vigil A, Chang Z, Ruck C, Larsson K . Familial Risks of Tourette Syndrome and Chronic Tic Disorders. A Population-Based Cohort Study. JAMA Psychiatry. 2015; 72(8):787-93. DOI: 10.1001/jamapsychiatry.2015.0627. View

Millard L, Davies N, Gaunt T, Davey Smith G, Tilling K . Software Application Profile: PHESANT: a tool for performing automated phenome scans in UK Biobank. Int J Epidemiol. 2017; 47(1):29-35. PMC: 5837456. DOI: 10.1093/ije/dyx204. View

Darrow S, Muller-Vahl K, Hinney A, Woods D, Gilbert D, Brown L . Synaptic processes and immune-related pathways implicated in Tourette syndrome. Transl Psychiatry. 2021; 11(1):56. PMC: 7814139. DOI: 10.1038/s41398-020-01082-z. View

Perez-Vigil A, Fernandez de la Cruz L, Brander G, Isomura K, Jangmo A, Kuja-Halkola R . Association of Tourette Syndrome and Chronic Tic Disorders With Objective Indicators of Educational Attainment: A Population-Based Sibling Comparison Study. JAMA Neurol. 2018; 75(9):1098-1105. PMC: 6143116. DOI: 10.1001/jamaneurol.2018.1194. View

Paschou P, Yu D, Gerber G, Evans P, Tsetsos F, Davis L . Genetic association signal near NTN4 in Tourette syndrome. Ann Neurol. 2014; 76(2):310-5. PMC: 4140987. DOI: 10.1002/ana.24215. View

Davis L, Yu D, Keenan C, Gamazon E, Konkashbaev A, Derks E . Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet. 2013; 9(10):e1003864. PMC: 3812053. DOI: 10.1371/journal.pgen.1003864. View

Robertson M . The prevalence and epidemiology of Gilles de la Tourette syndrome. Part 1: the epidemiological and prevalence studies. J Psychosom Res. 2008; 65(5):461-72. DOI: 10.1016/j.jpsychores.2008.03.006. View

Piedad J, Cavanna A . Depression in Tourette syndrome: A controlled and comparison study. J Neurol Sci. 2016; 364:128-32. DOI: 10.1016/j.jns.2016.03.030. View

Flory K, Molina B, Pelham Jr W, Gnagy E, Smith B . Childhood ADHD predicts risky sexual behavior in young adulthood. J Clin Child Adolesc Psychol. 2006; 35(4):571-7. DOI: 10.1207/s15374424jccp3504_8. View

10.

Ge T, Chen C, Ni Y, Feng Y, Smoller J . Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat Commun. 2019; 10(1):1776. PMC: 6467998. DOI: 10.1038/s41467-019-09718-5. View

11.

Purcell S, Wray N, Stone J, Visscher P, ODonovan M, Sullivan P . Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009; 460(7256):748-52. PMC: 3912837. DOI: 10.1038/nature08185. View

12.

Brander G, Isomura K, Chang Z, Kuja-Halkola R, Almqvist C, Larsson H . Association of Tourette Syndrome and Chronic Tic Disorder With Metabolic and Cardiovascular Disorders. JAMA Neurol. 2019; 76(4):454-461. PMC: 6459125. DOI: 10.1001/jamaneurol.2018.4279. View

13.

Fritsche L, Gruber S, Wu Z, Schmidt E, Zawistowski M, Moser S . Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative. Am J Hum Genet. 2018; 102(6):1048-1061. PMC: 5992124. DOI: 10.1016/j.ajhg.2018.04.001. View

14.

Levy A, Paschou P, Tumer Z . Candidate Genes and Pathways Associated with Gilles de la Tourette Syndrome-Where Are We?. Genes (Basel). 2021; 12(9). PMC: 8468358. DOI: 10.3390/genes12091321. View

15.

Anttila V, Bulik-Sullivan B, Finucane H, Walters R, Bras J, Duncan L . Analysis of shared heritability in common disorders of the brain. Science. 2018; 360(6395). PMC: 6097237. DOI: 10.1126/science.aap8757. View

16.

Yang Z, Wu H, Lee P, Tsetsos F, Davis L, Yu D . Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum. Biol Psychiatry. 2021; 90(5):317-327. PMC: 9152955. DOI: 10.1016/j.biopsych.2020.12.028. View

17.

Garcia-Delgar B, Servera M, Coffey B, Lazaro L, Openneer T, Benaroya-Milshtein N . Tic disorders in children and adolescents: does the clinical presentation differ in males and females? A report by the EMTICS group. Eur Child Adolesc Psychiatry. 2021; 31(10):1539-1548. DOI: 10.1007/s00787-021-01751-4. View

18.

Grove J, Ripke S, Als T, Mattheisen M, Walters R, Won H . Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019; 51(3):431-444. PMC: 6454898. DOI: 10.1038/s41588-019-0344-8. View

19.

Bose A, Kalantzis V, Kontopoulou E, Elkady M, Paschou P, Drineas P . TeraPCA: a fast and scalable software package to study genetic variation in tera-scale genotypes. Bioinformatics. 2019; 35(19):3679-3683. DOI: 10.1093/bioinformatics/btz157. View

20.

. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell. 2019; 179(7):1469-1482.e11. PMC: 7077032. DOI: 10.1016/j.cell.2019.11.020. View