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

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

doi:10.1016/j.biopsych.2023.01.023

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

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

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
Journal	Biological Psychiatry
Early online date	2023
DOIs	https://doi.org/10.1016/j.biopsych.2023.01.023
Publication status	E-pub ahead of print - 2023

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10.1016/j.biopsych.2023.01.023

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@article{956d5a749f4a486c96e4d591c018ede0,

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 = "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 {The TSAICG} and Batterson, {James R.} and Cheston Berlin and Budman, {Cathy L.} and Giovanni Coppola and Cox, {Nancy J.} and Sabrina Darrow and Yves Dion and Freimer, {Nelson B.} and Grados, {Marco A.} and Erica Greenberg and Hirschtritt, {Matthew E.} and Huang, {Alden Y.} and Cornelia Illmann and King, {Robert A.} and Roger Kurlan and Leckman, {James F.} and Lyon, {Gholson J.} and {The TIC Genetics Collaborative Group} and Malaty, {Irene A.} and McMahon, {William M.} and Neale, {Benjamin M.} and Okun, {Michael S.} and Lisa Osiecki and Robertson, {Mary M.} and Rouleau, {Guy A.} and Paul Sandor and Singer, {Harvey S.} and Smit, {Jan H.} and Sul, {Jae Hoon} and Christos Androutsos and {The TSGeneSEE Initiative} and Entela Basha and Luca Farkas and Jakub Fichna and Piotr Janik and Mira Kapisyzi and Iordanis Karagiannidis and Anastasia Koumoula and Peter Nagy and {The EMTICS Collaborative Group} and Joanna Puchala and Natalia Szejko and Urszula Szymanska and Vaia Tsironi and Alan Apter and Juliane Ball and Benjamin Bodmer and Emese Bognar and Judith Buse and Vela, {Marta Correa} and Carolin Fremer and Blanca Garcia-Delgar and Mariangela Gulisano and Annelieke Hagen and Julie Hagstr{\o}m and Marcos Madruga-Garrido and Alessandra Pellico and Daphna Ruhrman and Jaana Schnell and Silvestri, {Paola Rosaria} and Liselotte Skov and Tamar Steinberg and Gloor, {Friederike Tagwerker} and Turner, {Victoria L.} and Elif Weidinger and John Alexander and {The TS-EUROTRAIN Network} and Tamas Aranyi and Buisman, {Wim R.} and Buitelaar, {Jan K.} and Nicole Driessen and Petros Drineas and Siyan Fan and Forde, {Natalie J.} and Sarah Gerasch and {van den Heuvel}, {Odile A.} and Cathrine Jespersgaard and Kanaan, {Ahmad S.} and M{\"o}ller, {Harald E.} and Nawaz, {Muhammad S.} and Ester Nespoli and Luca Pagliaroli and Geert Poelmans and Pouwels, {Petra J. W.} and Francesca Rizzo and Veltman, {Dick J.} and {van der Werf}, {Ysbrand D.} and Joanna Widomska and Zilh{\"a}o, {Nuno R.} and Brown, {Lawrence W.} and Keun-Ah Cheon and Coffey, {Barbara J.} and Fernandez, {Thomas V.} and Gilbert, {Donald L.} and Hong, {Hyun Ju} and Laura Ibanez-Gomez and Eun-Joo Kim and Kim, {Young Key} and Young-Shin Kim and Yun-Joo Koh and Sodahm Kook and Samuel Kuperman and Leventhal, {Bennett L.} and Athanasios Maras and Murphy, {Tara L.} and Eun-Young Shin and Dong-Ho Song and Jungeun Song and State, {Matthew W.} and Frank Visscher and Sheng Wang and Zinner, {Samuel H.} and Tischfield, {Jay A.} and Heiman, {Gary A.} and Willsey, {A. Jeremy} and Andrea Dietrich and Davis, {Lea K.} and Crowley, {James J.} and Mathews, {Carol A.} and Scharf, {Jeremiah M.} and {The PGC TS Working Group} and Marianthi Georgitsi and Hoekstra, {Pieter J.} and Peristera Paschou",

note = "Funding Information: 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. Funding Information: 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. R01MH12621 3 [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. Publisher Copyright: {\textcopyright} 2023 Society of Biological Psychiatry",

year = "2023",

doi = "10.1016/j.biopsych.2023.01.023",

language = "English",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

}

TY - JOUR

T1 - Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

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.

AU - Cath, Danielle C.

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.

AU - Grice, Dorothy

AU - Glennon, Jeffrey

AU - Stefansson, Hreinn

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 - The TSAICG

AU - Batterson, James R.

AU - Berlin, Cheston

AU - Budman, Cathy L.

AU - Coppola, Giovanni

AU - Cox, Nancy J.

AU - Darrow, Sabrina

AU - Dion, Yves

AU - Freimer, Nelson B.

AU - Grados, Marco A.

AU - Greenberg, Erica

AU - Hirschtritt, Matthew E.

AU - Huang, Alden Y.

AU - Illmann, Cornelia

AU - King, Robert A.

AU - Kurlan, Roger

AU - Leckman, James F.

AU - Lyon, Gholson J.

AU - The TIC Genetics Collaborative Group

AU - Malaty, Irene A.

AU - McMahon, William M.

AU - Neale, Benjamin M.

AU - Okun, Michael S.

AU - Osiecki, Lisa

AU - Robertson, Mary M.

AU - Rouleau, Guy A.

AU - Sandor, Paul

AU - Singer, Harvey S.

AU - Smit, Jan H.

AU - Sul, Jae Hoon

AU - Androutsos, Christos

AU - The TSGeneSEE Initiative

AU - Basha, Entela

AU - Farkas, Luca

AU - Fichna, Jakub

AU - Janik, Piotr

AU - Kapisyzi, Mira

AU - Karagiannidis, Iordanis

AU - Koumoula, Anastasia

AU - Nagy, Peter

AU - The EMTICS Collaborative Group

AU - Puchala, Joanna

AU - Szejko, Natalia

AU - Szymanska, Urszula

AU - Tsironi, Vaia

AU - Apter, Alan

AU - Ball, Juliane

AU - Bodmer, Benjamin

AU - Bognar, Emese

AU - Buse, Judith

AU - Vela, Marta Correa

AU - Fremer, Carolin

AU - Garcia-Delgar, Blanca

AU - Gulisano, Mariangela

AU - Hagen, Annelieke

AU - Hagstrøm, Julie

AU - Madruga-Garrido, Marcos

AU - Pellico, Alessandra

AU - Ruhrman, Daphna

AU - Schnell, Jaana

AU - Silvestri, Paola Rosaria

AU - Skov, Liselotte

AU - Steinberg, Tamar

AU - Gloor, Friederike Tagwerker

AU - Turner, Victoria L.

AU - Weidinger, Elif

AU - Alexander, John

AU - The TS-EUROTRAIN Network

AU - Aranyi, Tamas

AU - Buisman, Wim R.

AU - Buitelaar, Jan K.

AU - Driessen, Nicole

AU - Drineas, Petros

AU - Fan, Siyan

AU - Forde, Natalie J.

AU - Gerasch, Sarah

AU - van den Heuvel, Odile A.

AU - Jespersgaard, Cathrine

AU - Kanaan, Ahmad S.

AU - Möller, Harald E.

AU - Nawaz, Muhammad S.

AU - Nespoli, Ester

AU - Pagliaroli, Luca

AU - Poelmans, Geert

AU - Pouwels, Petra J. W.

AU - Rizzo, Francesca

AU - Veltman, Dick J.

AU - van der Werf, Ysbrand D.

AU - Widomska, Joanna

AU - Zilhäo, Nuno R.

AU - Brown, Lawrence W.

AU - Cheon, Keun-Ah

AU - Coffey, Barbara J.

AU - Fernandez, Thomas V.

AU - Gilbert, Donald L.

AU - Hong, Hyun Ju

AU - Ibanez-Gomez, Laura

AU - Kim, Eun-Joo

AU - Kim, Young Key

AU - Kim, Young-Shin

AU - Koh, Yun-Joo

AU - Kook, Sodahm

AU - Kuperman, Samuel

AU - Leventhal, Bennett L.

AU - Maras, Athanasios

AU - Murphy, Tara L.

AU - Shin, Eun-Young

AU - Song, Dong-Ho

AU - Song, Jungeun

AU - State, Matthew W.

AU - Visscher, Frank

AU - Wang, Sheng

AU - Zinner, Samuel H.

AU - Tischfield, Jay A.

AU - Heiman, Gary A.

AU - Willsey, A. Jeremy

AU - Dietrich, Andrea

AU - Davis, Lea K.

AU - Crowley, James J.

AU - Mathews, Carol A.

AU - Scharf, Jeremiah M.

AU - The PGC TS Working Group

AU - Georgitsi, Marianthi

AU - Hoekstra, Pieter J.

AU - Paschou, Peristera

N1 - Funding Information: 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. Funding Information: 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. R01MH12621 3 [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. Publisher Copyright: © 2023 Society of Biological Psychiatry

PY - 2023

Y1 - 2023

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.

AB - 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.

KW - GWAS

KW - Meta-analysis

KW - NR2F1

KW - Tourette syndrome

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85151260500&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/36738982

U2 - 10.1016/j.biopsych.2023.01.023

DO - 10.1016/j.biopsych.2023.01.023

M3 - Article

C2 - 36738982

SN - 0006-3223

JO - Biological Psychiatry

JF - Biological Psychiatry

ER -

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

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