Abstract
Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
Original language | English (US) |
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Pages (from-to) | 217-227 |
Number of pages | 11 |
Journal | American Journal of Psychiatry |
Volume | 176 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2019 |
ASJC Scopus subject areas
- Psychiatry and Mental health
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Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies. / Tourette Association of America International Consortium for Genetics; Gilles de la Tourette GWAS Replication Initiative; Tourette International Collaborative Genetics Study et al.
In: American Journal of Psychiatry, Vol. 176, No. 3, 01.03.2019, p. 217-227.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies
AU - Tourette Association of America International Consortium for Genetics
AU - Gilles de la Tourette GWAS Replication Initiative
AU - Tourette International Collaborative Genetics Study
AU - Psychiatric Genomics Consortium Tourette Syndrome Working Group
AU - Yu, Dongmei
AU - Sul, Jae Hoon
AU - Tsetsos, Fotis
AU - Nawaz, Muhammad S.
AU - Huang, Alden Y.
AU - Zelaya, Ivette
AU - Illmann, Cornelia
AU - Osiecki, Lisa
AU - Darrow, Sabrina M.
AU - Hirschtritt, Matthew E.
AU - Greenberg, Erica
AU - Muller-Vahl, Kirsten R.
AU - Stuhrmann, Manfred
AU - Dion, Yves
AU - Rouleau, Guy
AU - Aschauer, Harald
AU - Stamenkovic, Mara
AU - Schlögelhofer, Monika
AU - Sandor, Paul
AU - Barr, Cathy L.
AU - Grados, Marco
AU - Singer, Harvey S.
AU - Nöthen, Markus M.
AU - Hebebrand, Johannes
AU - Hinney, Anke
AU - King, Robert A.
AU - Fernandez, Thomas V.
AU - Barta, Csaba
AU - Tarnok, Zsanett
AU - Nagy, Peter
AU - Depienne, Christel
AU - Worbe, Yulia
AU - Hartmann, Andreas
AU - Budman, Cathy L.
AU - Rizzo, Renata
AU - Lyon, Gholson J.
AU - McMahon, William M.
AU - Batterson, James R.
AU - Cath, Danielle C.
AU - Malaty, Irene A.
AU - Okun, Michael S.
AU - Berlin, Cheston
AU - Woods, Douglas W.
AU - Lee, Paul C.
AU - Jankovic, Joseph
AU - Robertson, Mary M.
AU - Gilbert, Donald L.
AU - Brown, Lawrence W.
AU - Coffey, Barbara J.
AU - Barzilai, Nir
N1 - Funding Information: Prothena Biosciences, Parexel, Revance Therapeutics, Retrophin, and Teva; he has received royalties from Cambridge, Elsevier, Future Science Group,HodderArnold,Medlink:Neurology,LippincottWilliams&Wilkins, and Wiley-Blackwell; and he serves on the editorial boards of Expert Review of Neurotherapeutics, Medlink, Neurology in Clinical Practice, the Botulinum Journal, PeerJ, Therapeutic Advances in Neurological Disorders, Neurotherapeutics, Tremor and Other Hyperkinetic Movements, and the Journal of Parkinson’s Disease. Dr. Coffey is on the scientific advisory boards of Abide Therapeutics and Genco Sciences; she receives honoraria from the American Academy of Child and Adolescent Psychiatry; she receives research support from Catalyst Pharmaceuticals, Neurocrine Biosciences, NIMH/UCSF, Otsuka, and Shire; she is on the scientific advisory boards of and receives research support from Auspex, Teva, and Nuvelution; and she is a co-chair and on the medical advisory board of the TAA, TAA-CDC Partnership. Dr. Kuperman is involved with Neurocrine for the purpose of recruiting a small number of individuals with Tourette syndrome for enrollment in a drug trial for a new medication to treat severe Tourette’s syndrome. Dr. Wagner has received a nonprofit grant from the German Research Foundation. Dr. Smoller is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. Dr. Buckner has served as a consultant for Roche. Dr. Willsey has served as a consultant for Daiichi Sankyo. Dr. Heiman has received funding from the New Jersey Center for Tourette Syndrome and Associated Disorders. Dr.NealeisamemberofthescientificadvisoryboardforDeepGenomics and serves as a consultant for Avanir, Camp4 Therapeutics, and Merck. Dr. Mathews has received research support, honoraria, and travel support from the TAA and is a co-chair of the TAA scientific advisory board. Dr. Scharf has received consulting fees from Nuvelution Pharma and Abide Pharmaceuticals; he has received travel and grant support from the TAA and the TLC Foundation for Body-Focused Repetitive Behaviors; and he is a member of the scientific advisory boards for the TAA and the TLC Foundation for Body-Focused Repetitive Behaviors. The other authors report no financial relationships with commercial interests. Funding Information: Supported by NIH grants U01 NS040024 to Drs. Pauls, Mathews, and Scharf and the Tourette Association of America International Consortium for Genetics, NIH grants K23 MH085057 and K02 NS085048 and ARRA grant NS040024-09S1 to Dr. Scharf, NIH grant NS016648 and ARRA grant NS040024-07S1 to Dr. Pauls, grant MH096767 to Dr. Mathews, National Institute of Neurological Disorders and Stroke (NINDS) Informatics Center for Neurogenetics and Neurogenomics grant P30 NS062691 to Drs. Coppola and Freimer, and grants from the Tourette Association of America to Drs. Paschou, Pauls, Mathews, and Scharf. This study was also funded in part by NIH grants R01MH092290 to Dr. Brown, R01MH092291 to Dr. Kuperman, R01MH092292 to Dr. Coffey, R01MH092293 to Dr. Heiman, R01MH092513 to Dr. Zinner, R01MH092516 to Dr. Grice, R01MH092520 to Dr. Gilbert, R01MH092289 to Dr. State, P01AG021654 and the Nathan Shock Center of Excellence for the Biology of Aging P30AG038072 to Dr. Barzilai, and R01AG042188 to Dr. Atzmon, as well as a grant from the German Research Society to Dr. Hebebrand. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment, and Health Initiative [GEI] (U01 HG004422); SAGE is one of the genomewide association studies funded as part of the Gene Environment Association Studies (GENEVA) under the NIH GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (P01 CA089392), and the Family Study of Cocaine Dependence (R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, NIDA, and the NIH contract “High Throughput Genotyping for Studying the Genetic Contributions to Human Disease” (HHSN268200782096C). The data sets used for the analyses described here were obtained from dbGaP (http://www.ncbi.nlm. nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000092.v1.p1) through dbGaP accession number phs000092.v1.p. Funding Information: Supported by NIH grants U01 NS040024 to Drs. Pauls, Mathews, and Scharf and the Tourette Association of America International Consortium for Genetics, NIH grants K23 MH085057 and K02 NS085048 and ARRA grant NS040024-09S1 to Dr. Scharf, NIH grant NS016648 and ARRA grant NS040024-07S1 to Dr. Pauls, grant MH096767 to Dr. Mathews, National Institute of Neurological Disorders and Stroke (NINDS) Informatics Center for Neurogenetics and Neurogenomics grant P30 NS062691 to Drs. Coppola and Freimer, and grants from the Tourette Association of America to Drs. Paschou, Pauls, Mathews, and Scharf. This study was also funded in part by NIH grants R01MH092290 to Dr. Brown, R01MH092291 to Dr. Kuperman, R01MH092292 to Dr. Coffey, R01MH092293 to Dr. Heiman, R01MH092513 to Dr. Zinner, R01MH092516 to Dr. Grice, R01MH092520 to Dr. Gilbert, R01MH092289 to Dr. State, P01AG021654 and the Nathan Shock Center of Excellence for the Biology of Aging P30AG038072 to Dr. Barzilai, and R01AG042188 to Dr. Atzmon, as well as a grant from the German Research Society to Dr. Hebebrand. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment, and Health Initiative [GEI] (U01 HG004422); SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under the NIH GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (P01 CA089392), and the Family Study of Cocaine Dependence (R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, NIDA, and the NIH contract “High Throughput Genotyping for Studying the Genetic Contributions to Human Disease” (HHSN268200782096C). The data sets used for the analyses described here were obtained from dbGaP (http://www.ncbi.nlm. Funding Information: The views expressed here are those of the authors and do not necessarily reflect the official policy or position of the U.S. Department of the Army, the U.S. Department of Defense, or the U.S. government. Drs. Budman, Cath, Dion, Gilbert, Grados, Lee, Lyon, King, McMahon, Malaty, Mathews, Pauls, Sandor, Scharf, and Singer have received research support from the Tourette Association of America (TAA). Drs. Nawaz, H. Stefansson, and K. Stefansson are employees of deCODE Genetics/ Amgen. Dr. Muller-Vahl has received research support from the German Research Society (GZ MU 1527/3-1), the German Ministry of Education and Research (01KG1421), the Else-Kroner-Fresenius-Stiftung, Almirall, Abide Therapeutics, GW, NIMH, Therapix Biosciences, and the Tourette Gesellschaft Deutschland e.V.; he has received consulting honoraria from Abide Therapeutics, Fundacion Canna, and Therapix Biosciences, speaking honoraria from Tilray, and royalties from Medizinisch Wissen-schaftliche Verlagsgesellschaft Berlin; he is a member of the advisory board of Therapix Biosciences; and he is a consultant for Zynerba Pharmaceuticals. Dr. Sandor owns shares in Alnylam Pharmaceuticals, Extendicare, Illumina, and Neurozone MSH and was a member of the data safety monitoring committee for Psyadon Pharmaceuticals. Dr. Singer receives book royalties from Elsevier and is a consultant for Teva Pharmaceuticals. Dr. Nöthen has been a member of the scientific advisory boards for the Lundbeck Foundation and Robert-Bosch-Stiftung, is a member of the Medical-Scientific Editorial Office of Deutsches Ärzteblatt, has received travel support from Shire Deutschland GmbH, and receives a salary from and holds shares in Life and Brain GmbH. Dr. Fernandez has received research funding from NIH, the Simons Foundation, and Shire and is a consultant for Cogstate and Guidepoint. Dr. McMahon has received royalties from LineaGen and has served as a consultant for Pathways to Careers. Dr. Batterson receives stipend funding from the American Psychiatric Association (APA) and is the Speaker of the APA Assembly. Dr. Malaty has received travel and grant support from the TAA and the National Parkinson Foundation and has participated in research funded by the Parkinson Foundation, TAA, the Dystonia Coalition, and the Huntington Study Group as well as AbbVie, Auspex, Biogen, Biotie, Boston Scientific, Eli Lilly, Intrepid, Lundbeck, Merz, Neurocrine, Nuvelution, Pfizer, Revance, and Teva. Dr. Okun has served as a consultant for the National Parkinson Foundation; he has received research grants from the Bachmann-Strauss Foundation, the National Parkinson Foundation, NIH, the Michael J. Fox Foundation, the Parkinson Alliance, the Smallwood Foundation, TAA, and the UF Foundation; he has received royalties from Amazon, Books4Patients, Cambridge, Demos, Manson, and Smashwords; he is an associate editor for Journal Watch Neurology; he has participated in CME and educational activities sponsored by Henry Stewart, Medicus, MedNet, PeerView, Prime, QuantiaMD, WebMD, and Vanderbilt University; and he has received grants from Medtronic, AbbVie, Allergan, and Advanced Neuromodulation Systems/St. Jude. Dr. Woods receives royalties from Oxford University Press and Guilford Press and speaking fees from the TAA-CDC partnership. Dr. Gilbert has received honoraria and/or travel support from the TAA-CDC, the American Academy of Pediatrics, and the Child Neurology Society; he has received compensation for expert testimony for the U.S. National Vaccine Injury Compensation Program, through the Department of Health and Human Services; he has received research support from NIH (NIMH, NINDS), funding from Ecopipam Pharmaceuticals and EryDel, and book royalties from Elsevier and Wolters Kluwer. Dr. Jankovic has received research and/or training grants from Adamas Pharmaceuticals, Allergan, CHDI Foundation, Civitas/ Acorda Therapeutics, the Dystonia Coalition, the Dystonia Medical Research Foundation, Hoffmann–La Roche, the Huntington Study Group, Medtronic Neuromodulation, Merz, the Michael J. Fox Foundation for Parkinson Research, NIH, Neurocrine Biosciences, the Parkinson’s Foundation, Nuvelution, the Parkinson Study Group, Pfizer, Prothena Biosciences, Psyadon Pharmaceuticals, Revance Therapeutics, Teva, and U.S. WorldMeds; he has served on advisory or data monitoring committees or as a consultant for Adamas Pharmaceuticals, Allergan, Merz, Publisher Copyright: © 2019 American Psychiatric Association. All rights reserved.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
AB - Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
UR - http://www.scopus.com/inward/record.url?scp=85063063105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063063105&partnerID=8YFLogxK
U2 - 10.1176/appi.ajp.2018.18070857
DO - 10.1176/appi.ajp.2018.18070857
M3 - Article
C2 - 30818990
AN - SCOPUS:85063063105
VL - 176
SP - 217
EP - 227
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
SN - 0002-953X
IS - 3
ER -