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Synaptic processes and immune-related pathways implicated in Tourette syndrome.

  • Author(s): 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;
  • 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;
  • 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;
  • 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;
  • 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
  • et al.
Abstract

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.

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