Synaptic processes and immune-related pathways implicated in Tourette syndrome
Authors: Tsetsos Fotis , Yu Dongmei , Sul Jae Hoon , Huang Alden Y. , Illmann Cornelia , Osiecki Lisa , Darrow Sabrina M. , Hirschtritt Matthew E. , Greenberg Erica , Muller-Vahl Kirsten R. , Stuhrmann Manfred , Dion Yves , Rouleau Guy A. , Aschauer Harald , Stamenkovic Mara , Schlögelhofer Monika , Sandor Paul , Barr Cathy L. , Grados Marco A. , Singer Harvey S. , Nöthen Markus M. , Hebebrand Johannes , Hinney Anke , King Robert A. , Fernandez Thomas V. , Barta Csaba , Tarnok Zsanett , Nagy Peter , Depienne Christel , Worbe Yulia , Hartmann Andreas , Budman Cathy L. , Rizzo Renata , Lyon Gholson J. , McMahon William M. , Batterson James R. , Cath Danielle C. , Malaty Irene A. , Okun Michael S. , Berlin Cheston , Woods Douglas W. , Lee Paul C. , Jankovic Joseph , Robertson Mary M. , Gilbert Donald L. , Brown Lawrence W. , Coffey Barbara J. , Dietrich Andrea , Hoekstra Pieter J. , Kuperman Samuel , Zinner Samuel H. , Wagner Michael , Knowles James A. , Jeremy Willsey A. , Tischfield Jay A. , Heiman Gary A. , Cox Nancy J. , Freimer Nelson B. , Neale Benjamin M. , Davis Lea K. , Coppola Giovanni , Mathews Carol A. , Scharf Jeremiah M. , Paschou Peristera ,   on behalf of the Tourette Association of America International Consortium for Genetics, Barr Cathy L. , Batterson James R. , Berlin Cheston , Budman Cathy L. , Cath Danielle C. , Coppola Giovanni , Cox Nancy J. , Darrow Sabrina , Davis Lea K. , Dion Yves , Freimer Nelson B. , Grados Marco A. , Greenberg Erica , Hirschtritt Matthew E. , Huang Alden Y. , Illmann Cornelia , King Robert A. , Kurlan Roger , Leckman James F. , Lyon Gholson J. , Malaty Irene A. , Mathews Carol A. , McMahon William M. , Neale Benjamin M. , Okun Michael S. , Osiecki Lisa , Robertson Mary M. , Rouleau Guy A. , Sandor Paul , Scharf Jeremiah M. , Singer Harvey S. , Smit Jan H. , Sul Jae Hoon , Yu Dongmei ,   the Gilles de la Tourette GWAS Replication Initiative, Aschauer Harald Aschauer Harald , Barta Csaba , Budman Cathy L. , Cath Danielle C. , Depienne Christel , Hartmann Andreas , Hebebrand Johannes , Konstantinidis Anastasios , Mathews Carol A. , Müller-Vahl Kirsten , Nagy Peter , Nöthen Markus M. , Paschou Peristera , Rizzo Renata , Rouleau Guy A. , Sandor Paul , Scharf Jeremiah M. , Schlögelhofer Monika , Stamenkovic Mara , Stuhrmann Manfred , Tsetsos Fotis , Tarnok Zsanett , Wolanczyk Tomasz , Worbe Yulia ,   the Tourette International Collaborative Genetics Study, Brown Lawrence , Cheon Keun-Ah , Coffey Barbara J. , Dietrich Andrea , Fernandez Thomas V. , Garcia-Delgar Blanca , Gilbert Donald , Grice Dorothy E. , Hagstrøm Julie , Hedderly Tammy , Heiman Gary A. , Heyman Isobel , Hoekstra Pieter J. , Huyser Chaim , Kim Young Key , Kim Young-Shin , King Robert A. , Koh Yun-Joo , Kook Sodahm , Kuperman Samuel , Leventhal Bennett L. , Madruga-Garrido Marcos , Mir Pablo , Morer Astrid , Münchau Alexander , Plessen Kerstin J. , Roessner Veit , Shin Eun-Young , Song Dong-Ho , Song Jungeun , Tischfield Jay A. , Willsey A. Jeremy , Zinner Samuel ,   and the Psychiatric Genomics Consortium Tourette Syndrome Working Group, Aschauer Harald , Barr Cathy L. , Barta Csaba , Batterson James R. , Berlin Cheston , Brown Lawrence , Budman Cathy L. , Cath Danielle C. , Coffey Barbara J. , Coppola Giovanni , Cox Nancy J. , Darrow Sabrina , Davis Lea K. , Depienne Christel , Dietrich Andrea , Dion Yves , Fernandez Thomas , Freimer Nelson B. , Gilbert Donald , Grados Marco A. , Greenberg Erica , Hartmann Andreas , Hebebrand Johannes , Heiman Gary , Hirschtritt Matthew E. , Hoekstra Pieter , Huang Alden Y. , Illmann Cornelia , Jankovic Joseph , King Robert A. , Kuperman Samuel , Lee Paul C. , Lyon Gholson J. , Malaty Irene A. , Mathews Carol A. , McMahon William M. , Müller-Vahl Kirsten , Nagy Peter , Neale Benjamin M. , Nöthen Markus M. , Okun Michael S. , Osiecki Lisa , Paschou Peristera , Rizzo Renata , Robertson Mary M. , Rouleau Guy A. , Sandor Paul , Scharf Jeremiah M. , Schlögelhofer Monika , Singer Harvey S. , Stamenkovic Mara , Stuhrmann Manfred , Sul Jae Hoon , Tarnok Zsanett , Tischfield Jay , Tsetsos Fotis , Willsey A. Jeremy , Woods Douglas , Worbe Yulia , Yu Dongmei , Zinner Samuel 
Published: January 2021

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.