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

Fotis TsetsosDongmei YuJae Hoon SulAlden Y HuangCornelia IllmannLisa OsieckiSabrina M DarrowMatthew E HirschtrittErica GreenbergKirsten R Muller-VahlManfred StuhrmannYves DionGuy A RouleauHarald AschauerMara StamenkovicMonika SchlögelhoferPaul SandorCathy L BarrMarco A GradosHarvey S SingerMarkus M NöthenJohannes HebebrandAnke HinneyRobert A KingThomas V FernandezCsaba BartaZsanett TarnokPeter NagyChristel DepienneYulia WorbeAndreas HartmannCathy L BudmanRenata RizzoGholson J LyonWilliam M McMahonJames R BattersonDanielle C CathIrene A MalatyMichael S OkunCheston BerlinDouglas W WoodsPaul C LeeJoseph JankovicMary M RobertsonDonald L GilbertLawrence W BrownBarbara J CoffeyAndrea DietrichPieter J HoekstraSamuel KupermanSamuel H ZinnerMichael WagnerJames A KnowlesA Jeremy WillseyJay A TischfieldGary A HeimanNancy J CoxNelson A FreimerBenjamin M NealeLea K DavisGiovanni CoppolaCarol A MathewsJeremiah M ScharfPeristera Paschounull nullCathy L BarrJames R BattersonCheston BerlinCathy L BudmanDanielle C CathGiovanni CoppolaNancy J CoxSabrina DarrowLea K DavisYves DionNelson B FreimerMarco A GradosErica GreenbergMatthew E HirschtrittAlden Y HuangCornelia IllmannRobert A KingRoger KurlanJames F LeckmanGholson J LyonIrene A MalatyCarol A MathewsWilliam M McMahonBenjamin M NealeMichael S OkunLisa OsieckiMary M RobertsonGuy A RouleauPaul SandorJeremiah M ScharfHarvey S SingerJan H SmitJae Hoon SulDongmei Yunull nullHarald Aschauer Harald AschauerCsaba BartaCathy L BudmanDanielle C CathChristel DepienneAndreas HartmannJohannes HebebrandAnastasios KonstantinidisCarol A MathewsKirsten Müller-VahlPeter NagyMarkus M NöthenPeristera PaschouRenata RizzoGuy A RouleauPaul SandorJeremiah M ScharfMonika SchlögelhoferMara StamenkovicManfred StuhrmannFotis TsetsosZsanett TarnokTomasz WolanczykYulia Worbenull nullLawrence BrownKeun-Ah CheonBarbara J CoffeyAndrea DietrichThomas V FernandezBlanca Garcia-DelgarDonald GilbertDorothy E GriceJulie HagstrømTammy HedderlyGary A HeimanIsobel HeymanPieter J HoekstraChaim HuyserYoung Key KimYoung-Shin KimRobert A KingYun-Joo KohSodahm KookSamuel KupermanBennett L LeventhalMarcos Madruga-GarridoPablo MirAstrid MorerAlexander MünchauKerstin J PlessenVeit RoessnerEun-Young ShinDong-Ho SongJungeun SongJay A TischfieldA Jeremy WillseySamuel Zinnernull nullHarald AschauerCathy L BarrCsaba BartaJames R BattersonCheston BerlinLawrence BrownCathy L BudmanDanielle C CathBarbara J CoffeyGiovanni CoppolaNancy J CoxSabrina DarrowLea K DavisChristel DepienneAndrea DietrichYves DionThomas FernandezNelson B FreimerDonald GilbertMarco A GradosErica GreenbergAndreas HartmannJohannes HebebrandGary HeimanMatthew E HirschtrittPieter HoekstraAlden Y HuangCornelia IllmannJoseph JankovicRobert A KingSamuel KupermanPaul C LeeGholson J LyonIrene A MalatyCarol A MathewsWilliam M McMahonKirsten Müller-VahlPeter NagyBenjamin M NealeMarkus M NöthenMichael S OkunLisa OsieckiPeristera PaschouRenata RizzoMary M RobertsonGuy A RouleauPaul SandorJeremiah M ScharfMonika SchlögelhoferHarvey S SingerMara StamenkovicManfred StuhrmannJae Hoon SulZsanett TarnokJay TischfieldFotis TsetsosA Jeremy WillseyDouglas WoodsYulia WorbeDongmei YuSamuel Zinner
Published in: Translational psychiatry (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.
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