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