Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome
Authors: Jain Pritesh , Miller-Fleming Tyne , Topaloudi Apostolia , Yu Dongmei , Drineas Petros , Georgitsi Marianthi , Yang Zhiyu , Rizzo Renata , Müller-Vahl Kirsten R. , Tumer Zeynep , Mol Debes Nanette , Hartmann Andreas , Depienne Christel , Worbe Yulia , Mir Pablo , Cath Danielle C. , Boomsma Dorret I. , Roessner Veit , Wolanczyk Tomasz , Janik Piotr , Szejko Natalia , Zekanowski Cezary , Barta Csaba , Nemoda Zsofia , Tarnok Zsanett , Buxbaum Joseph D. , Grice Dorothy , Glennon Jeffrey , Stefansson Hreinn , Hengerer Bastian , Benaroya-Milshtein Noa , Cardona Francesco , Hedderly Tammy , Heyman Isobel , Huyser Chaim , Morer Astrid , Mueller Norbert , Munchau Alexander , Plessen Kerstin J. , Porcelli Cesare , Walitza Susanne , Schrag Anette , Martino Davide ,   The Psychiatric Genomics Consortium Tourette Syndrome Working Group (PGC-TS), Als Thomas D. , Aschauer Harald , Atzmon Gil , Bækvad-Hansen Matie , Barta Csaba , Barr Cathy L. , Barzilai Nir , Batterson James R. , Batterson Robert , Benarroch Fortu , Berlin Cheston , Boberg Julia , Bodmer Benjamin , Bohnenpoll Julia , Børglum Anders D. , Brown Lawrence W. , Bruun Ruth , Budman Cathy L. , Buckner Randy L. , Buxbaum Joseph D. , Bybjerg-Grauholm Jonas , Cath Danielle C. , Cheon Keun-Ah , Chouinard Sylvain , Coffey Barbara J. , Coppola Giovanni , Crowley James J. , Dahl Niklas , Davis Lea K. , Darrow Sabrina M. , Daly Mark J. , Depienne Christel , De Rubeis Silvia , Dietrich Andrea , Dion Yves , Djurfeldt Diana R. , Domenech-Salgado Laura , Eapen Valsamma , Elzerman Lonneke , Fernandez Thomas V. , Freimer Carolin Fremer Nelson B. , Garcia-Delgar Blanca , Garrido Marcos , Gilbert Donald L. , Giusti-Rodriguez Paola , Grados Marco , Greenberg Erica , Grove Jakob , Grice Dorothy E. , Hagstrom Julie , Halvorsen Matt , Hartmann Andreas , Hansen Bjarne , Haavik Jan , Hebebrand Johannes , Heiman Gary A. , Herrera Luis , Heyman Isobel , Hinney Anke , Hirschtritt Matthew E. , Hoekstra Pieter J. , Sul Jae Hoon , Hong Hyun Ju , Hougaard David M. , Huang Alden Y. , Ibanez-Gomez Laura , Ivankovic Franjo , Jankovic Joseph , Karlsson Elinor K. , Kaprio Jakko A. , Kim Young Key , Kim Young-Shin , King Robert A. , Knowles James A. , Koh Yun-Joo , Kook Sodham , Khalifa Najah , Konstantinidis Anastasios , Kuperman Samuel , Kurlan Roger , Kvale Gerd , Leckman James , Lee Paul C. , Leventhal Bennett , Lichtenstein Paul , Lindbald-Toh Kerstin , Lowe Thomas , Ludolph Andrea , da Silva Claudia Luhrs , Luðvigsson Pétur , Luykx Jurjen , Lyon Gholson J. , Mahjani Behrang , Maras Athanasios , Mataix-Cols David , Mattheisen Manuel , Mathews Carol A. , Malaty Irene A. , McMahon William M. , McQuillin Andrew , Meier Sandra M. , Miller-Fleming Tyne , Mir Pablo , Moessner Rainald , Morer Astrid , Mortensen Preben B. , Mors Ole , Mudgal Poorva , Muller-Vahl Kirsten R. , Munchau Alexander , Nagy Peter , Naarden Allan , Neale Benjamin M. , Nawaz Muhammad S. , Nissen Judith Becker , Nöthen Merete Nordentoft Markus M. , Nordsletten Ashley E. , Okun Michael S. , Ophoff Roel , Osiecki Lisa , Palotie Aarno , Palviainen Teemu P. , Paschou Peristera , Pato Michele T. Pato Carlos N. , Pittenger Christopher , Plessen Kerstin J. , Pollak Yehuda , Posthuma Danielle , Ramos Eliana , Reichert Jennifer , Rizzo Renata , Robertson Mary M. , Roessner Veit , Roffman Joshua L. , Rouleau Guy , Rück Christian , Sæmundsen Evald , Samuels Jack , Sandin Sven , Sandor Paul , Schlögelhofer Monika , Scharf Jeremiah M. , Shin Eun-Young , Singer Harvey S. , Smit Jan , Smoller Jordan W. , State Matthew , Solem Stian , Song Dong-Ho , Song Jungeun , Stamenkovic Mara , Stefansson Hreinn , Stefansson Kári , Strom Nora , Stuhrmann Manfred , Szatkiewicz Jin , Szymanska Urszula , Tarnok Zsanett , Tischfield Jay A. , Tsetsos Fotis , Thorarensen Ólafur , Tubing Jennifer , Visscher Frank , Wagner Michael , Wanderer Sina , Wang Sheng , Werge Thomas , Willsey Jeremy A. , Wolancyk Tomasz , Woods Douglas W. , Woods Martin , Worbe Yulia , Dion Yves , Yu Dongmei , Zelaya Ivette , Zinner Samuel H. ,   The EMTICS collaborative group, Apter Alan , Ball Juliane , Bodmer Benjamin , Bognar Emese , Buse Judith , Vela Marta Correa , Fremer Carolin , Garcia-Delgar Blanca , Gulisano Mariangela , Hagen Annelieke , Hagstrøm Julie , Madruga-Garrido Marcos , Nagy Peter , Pellico Alessandra , Ruhrman Daphna , Schnell Jaana , Silvestri Paola Rosaria , Skov Liselotte , Steinberg Tamar , Gloor Friederike Tagwerker , Turner Victoria L. , Weidinger Elif , Benaroya-Milshtein Noa , Cardona Francesco , Dietrich Andrea , Georgitsi Marianthi , Hedderly Tammy , Heyman Isobel , Hoekstra Pieter J. , Huyser Chaim , Martino Davide , Mir Pablo , Morer Astrid , Muller-Vahl Kirsten R. , Paschou Peristera , Plessen Kerstin J. , Porcelli Cesare , Rizzo Renata , Roessner Veit , Schrag Anette , Tarnok Zsanett , Dietrich Andrea ,   The TS-EUROTRAIN Network, Alexander John , Aranyi Tamas , Buisman Wim R. , Buitelaar Jan K. , Driessen Nicole , Drineas Petros , Fan Siyan , Forde Natalie J. , Gerasch Sarah , van den Heuvel Odile A. , Jespersgaard Cathrine , Kanaan Ahmad S. , Möller Harald E. , Nawaz Muhammad S. , Nespoli Ester , Pagliaroli Luca , Poelmans Geert , Pouwels Petra J. W. , Rizzo Francesca , Veltman Dick J. , van der Werf Ysbrand D. , Widomska Joanna , Zilhäo Nuno R. , Barta Csaba , Boomsma Dorret I. , Cath Danielle C. , Georgitsi Marianthi , Glennon Jeffrey , Hengerer Bastian , Hoekstra Pieter J. , Muller-Vahl Kirsten R. , Paschou Peristera , Stefansson Hreinn , Tumer Zeynep , Mathews Carol A. , Scharf Jeremiah M. , Hoekstra Pieter J. , Davis Lea K. , Paschou Peristera 
Published: February 2023

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.