Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome

Fotis Tsetsos; Apostolia Topaloudi; Pritesh Jain; Zhiyu Yang; Dongmei Yu; Petros Kolovos; Zeynep Tümer; Renata Rizzo; Andreas Hartmann; Christel Depienne; Yulia Worbe; Kirsten Müller‐Vahl; Daniëlle C. Cath; Dorret Irene Boomsma; Tomasz Wolańczyk; Cezary Żekanowski; Csaba Barta; Zsófia Nemoda; Zsanett Tárnok; Shanmukha Sampath Padmanabhuni; Joseph D. Buxbaum; Dorothy E. Grice; Jeffrey Colm Glennon; Hreinn Stefánsson; Bastian Hengerer; Evangelia Yannaki; John A. Stamatoyannopoulos; Noa Benaroya-Milshtein; Francesco Cardona; Tammy J. Hedderly

doi:10.1101/2021.12.11.21267560

Genetic & Genomic MedicinemedRxivDec 11, 2021

Preprint

Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome

Fotis Tsetsos iD, Apostolia Topaloudi iD, Pritesh Jain iD, Zhiyu Yang iD, Dongmei Yu iD, Petros Kolovos iD, Zeynep Tümer iD, Renata Rizzo iD, Andreas Hartmann iD, Christel Depienne iD, Yulia Worbe iD, Kirsten Müller‐Vahl iD, Daniëlle C. Cath iD, Dorret Irene Boomsma iD, Tomasz Wolańczyk iD, Cezary Żekanowski iD, Csaba Barta iD, Zsófia Nemoda iD, Zsanett Tárnok iD, Shanmukha Sampath Padmanabhuni iD, Joseph D. Buxbaum iD, Dorothy E. Grice iD, Jeffrey Colm Glennon iD, Hreinn Stefánsson iD, Bastian Hengerer iD, , Peristera Paschou iD

Abstract

Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture, characterized by multiple motor tics and at least one vocal tic persisting for more than one year. We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6,133 TS individuals and 13,565 ancestry-matched controls. We identified a genome-wide significant locus on chromosome 5q15 and one array-wide significant locus on chromosome 2q24.2. Integration of eQTL, Hi-C and GWAS data implicated the NR2F1 gene and associated lncRNAs within the 5q15 locus, and the RBMS1 gene within the 2q24.2 locus. Polygenic risk scoring using previous GWAS results demonstrated statistically significant ability to predict TS status in the novel cohort. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring on brain volume data identified statistically significant associations with right and left putamen volumes. Our work presents novel insights in the neurobiology of TS opening up new directions for future studies.

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