Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

The PGC TS Working Group; The TSAICG; The TSGeneSEE Initiative; The EMTICS Collaborative Group; The TS-EUROTRAIN Network; The TIC Genetics Collaborative Group

doi:10.1016/j.biopsych.2023.01.023

Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

The PGC TS Working Group, The TSAICG, The TSGeneSEE Initiative, The EMTICS Collaborative Group, The TS-EUROTRAIN Network, The TIC Genetics Collaborative Group

Chair Engelhard

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Original language	English
Pages (from-to)	114-124
Number of pages	11
Journal	Biological Psychiatry
Volume	96
Issue number	2
Early online date	2 Feb 2023
DOIs	https://doi.org/10.1016/j.biopsych.2023.01.023
Publication status	Published - 15 Jul 2024

Bibliographical note

Publisher Copyright:
© 2023 Society of Biological Psychiatry

Funding

This work was supported by EMTICS (FP7-HEALTH, Grant agreement ID No. 278367 [to PP and PJH]), TS-EUROTRAIN (FP7-PEOPLE, Grant agreement ID No. 316978 [to PP]), the National Institute of Neurological Disorders and Stroke (Grant No. R01NS105746), U.S. National Science Foundation (Grant Nos. 2006929 and 1715202 [to PP]), and the National Institute of Mental Health (Grant No. R01MH126213 [to PP]). AJW also received funding from the National Institute of Neurological Disorders and Stroke Grant No. R01NS105746, the Tourette Association of America, and the Weill Institute for Neurosciences. AM received funding from the Deutsche Forschungsgemeinschaft (Grant No. FOR 2698). AS received support from the NIHR UCL/H Biomedical Research Centre. BH is an employee of Boehringer Ingelheim Pharma. CJ received funding from Lundbeck Fonden (Grant No. R100-2011-9332). CB received funding from the Merit-prize fellowship of Semmelweis University, the Bolyai Janos research fellowship of the Hungarian Academy of Sciences (Grant No.BO/00987/16/5), the UNKP-18-4 of the new National Excellence Program of the Ministry of Human Capacities, and the Baron Munchausen Program of the Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University. DCC received funding from the TSAA, the Stichting VC-GGZ, and TS-EUROTRAIN. DM has received research support from Ipsen Corporate and funding grants from Dystonia Medical Research Foundation Canada, Parkinson Canada, The Owerko Foundation, and the Michael P. Smith Family. LKD was supported by grants from the National Institutes of Health (Grant Nos. R01NS102371 and R01NS105746). PM has received grants from the Spanish Ministry of Science and Innovation (Grant No. RTC2019-007150-1), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (Grant Nos. PI16/01575, PI19/01576), the Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia (Grant Nos. CVI-02526, CTS-7685), and the Consejeria de Salud y Bienestar Social de la Junta de Andalucia, (Grant No. PE-0210-2018). PJ and CZ were funded by the National Science Center, Poland (Grant No. UMO-2016/23/B/NZ2/03030). ZT was funded by Lundbeck Fonden (Grant No. R100-2011-9332). TIC Genetics (Tourette International Collaborative Genetics) was supported by the National Institutes of Health (Grant Nos. MH115958, MH115960, MH115962, MH115961, MH115993, MH115963, and MH115959) and the New Jersey Center for Tourette Syndrome and Associated Disorder. Summary statistics data are available upon request to the corresponding authors. The authors report no biomedical financial interests or potential conflicts of interest. This study was supported by the EMTICS (FP7-HEALTH, Grant agreement ID: 278367), TSEUROTRAIN (FP7-PEOPLE, Grant agreement ID: 316978), NINDS (R01NS105746), NIMH (R01MH126213) grants to PP. AJW was funded by R01NS105746, the Tourette Association of America, and the Weill Institute for Neurosciences. AM was funded by the Deutsche Forschungsgemeinschaft (DFG; FOR 2698). AS received support from the NIHR UCL/H Biomedical Research Centre. BH is an employee of Boehringer Ingelheim Pharma. CJ was funded by Lundbeck Fonden, grant number R100-2011-9332. CB was supported by funding from the Merit-prize fellowship of Semmelweis University, the Bolyai Janos research fellowship of the Hungarian Academy of Sciences BO/00987/16/5, the UNKP-18-4 of the new National Excellence Program of the Ministry of Human Capacities and the Baron Munchausen Program of the Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University. DCC was funded by the TSAA, by the Stichting VC-GGZ, and by TS-EUROTRAIN. DM has received research support from Ipsen Corporate and funding grants from Dystonia Medical Research Foundation Canada, Parkinson Canada, The Owerko Foundation, and the Michael P Smith Family. LKD was supported by grants from the National Institutes of Health including R01NS102371 and R01NS105746. PM has received grants from the Spanish Ministry of Science and Innovation [RTC2019-007150-1], the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER), PI16/01575, PI19/01576], the Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia [CVI-02526, CTS-7685], the Consejeria de Salud y Bienestar Social de la Junta de Andalucia, PE-0210-2018]. PJ and CZ were funded by the National Science Center, Poland: UMO-2016/23/B/NZ2/03030. ZT funded by Lundbeck Fonden, grant number R100-2011-9332. TIC Genetics was supported by grants from NIH (MH115958, MH115960, MH115962, MH115961, MH115993, MH115963, MH115959) and the New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS).

Funders	Funder number
Tourette Association of America
Parkinson Canada
Stichting VC-GGZ
Ipsen Corporate
Weill Institute for Neurosciences, University of California, San Francisco
Emberi Eroforrások Minisztériuma
Boehringer Ingelheim
Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional
TSAA
Dystonia Medical Research Foundation Canada
Semmelweis Egyetem
New Jersey Center for Tourette Syndrome and Associated Disorders
TS-EUROTRAIN
Michael P. Smith Family
National Science Center, Poland
NIHR UCL
Owerko Foundation
Manchester Biomedical Research Centre
Michael P Smith Family
New Jersey Center for Tourette Syndrome and Associated Disorder
ISCIII-FEDER	PI16/01575, PI19/01576
Consejería de Salud y Bienestar Social, Junta de Andalucía	PE-0210-2018
EMTICS	278367, FP7-HEALTH
National Institutes of Health	MH115958, MH115959, MH115963, R01NS102371, MH115993, MH115960, MH115961, MH115962
Magyar Tudományos Akadémia	UNKP-18-4, BO/00987/16/5, /00987/16/5
National Science Foundation	2006929, 1715202
Ministerio de Ciencia e Innovación	RTC2019-007150-1
Narodowe Centrum Nauki	UMO-2016/23/B/NZ2/03030
National Institute of Mental Health	R01MH126213
TSEUROTRAIN	316978, FP7-PEOPLE
Junta de Andalucía	CTS-7685, CVI-02526
Deutsche Forschungsgemeinschaft	FOR 2698
Lundbeck Fonden	R100-2011-9332
National Institute of Neurological Disorders and Stroke	R01NS105746

Keywords

GWAS
Meta-analysis
NR2F1
Tourette syndrome

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10.1016/j.biopsych.2023.01.023

1-s2.0-S0006322323000513-mainFinal published version, 660 KBLicence: Taverne

Cite this

@article{92e638e135554406989f1cda91c27720,

title = "Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome",

abstract = "Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.",

keywords = "GWAS, Meta-analysis, NR2F1, Tourette syndrome",

author = "{The PGC TS Working Group} and {The TSAICG} and {The TSGeneSEE Initiative} and {The EMTICS Collaborative Group} and {The TS-EUROTRAIN Network} and {The TIC Genetics Collaborative Group} and Fotis Tsetsos and Apostolia Topaloudi and Pritesh Jain and Zhiyu Yang and Dongmei Yu and Petros Kolovos and Zeynep Tumer and Renata Rizzo and Andreas Hartmann and Christel Depienne and Yulia Worbe and M{\"u}ller-Vahl, {Kirsten R.} and Cath, {Danielle C.} and Boomsma, {Dorret I.} and Tomasz Wolanczyk and Cezary Zekanowski and Csaba Barta and Zsofia Nemoda and Zsanett Tarnok and Padmanabhuni, {Shanmukha S.} and Buxbaum, {Joseph D.} and Dorothy Grice and Jeffrey Glennon and Hreinn Stefansson and Bastian Hengerer and Evangelia Yannaki and Stamatoyannopoulos, {John A.} and Noa Benaroya-Milshtein and Francesco Cardona and Tammy Hedderly and Isobel Heyman and Chaim Huyser and Pablo Mir and Astrid Morer and Norbert Mueller and Alexander Munchau and Plessen, {Kerstin J.} and Cesare Porcelli and Veit Roessner and Susanne Walitza and Anette Schrag and Davide Martino and Barr, {Cathy L.} and Batterson, {James R.} and Cheston Berlin and Budman, {Cathy L.} and Giovanni Coppola and Cox, {Nancy J.} and Sabrina Darrow and Yves Dion",

note = "Publisher Copyright: {\textcopyright} 2023 Society of Biological Psychiatry",

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AU - The TS-EUROTRAIN Network

AU - The TIC Genetics Collaborative Group

AU - Tsetsos, Fotis

AU - Topaloudi, Apostolia

AU - Jain, Pritesh

AU - Yang, Zhiyu

AU - Yu, Dongmei

AU - Kolovos, Petros

AU - Tumer, Zeynep

AU - Rizzo, Renata

AU - Hartmann, Andreas

AU - Depienne, Christel

AU - Worbe, Yulia

AU - Müller-Vahl, Kirsten R.

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AU - Boomsma, Dorret I.

AU - Wolanczyk, Tomasz

AU - Zekanowski, Cezary

AU - Barta, Csaba

AU - Nemoda, Zsofia

AU - Tarnok, Zsanett

AU - Padmanabhuni, Shanmukha S.

AU - Buxbaum, Joseph D.

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AU - Hengerer, Bastian

AU - Yannaki, Evangelia

AU - Stamatoyannopoulos, John A.

AU - Benaroya-Milshtein, Noa

AU - Cardona, Francesco

AU - Hedderly, Tammy

AU - Heyman, Isobel

AU - Huyser, Chaim

AU - Mir, Pablo

AU - Morer, Astrid

AU - Mueller, Norbert

AU - Munchau, Alexander

AU - Plessen, Kerstin J.

AU - Porcelli, Cesare

AU - Roessner, Veit

AU - Walitza, Susanne

AU - Schrag, Anette

AU - Martino, Davide

AU - Barr, Cathy L.

AU - Batterson, James R.

AU - Berlin, Cheston

AU - Budman, Cathy L.

AU - Coppola, Giovanni

AU - Cox, Nancy J.

AU - Darrow, Sabrina

AU - Dion, Yves

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N2 - Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

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Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Abstract

Bibliographical note

Funding

Keywords

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