Genome-wide association study of Tourette's syndrome

J. M. Scharf; D. Yu; C. A. Mathews; B. M. Neale; S. E. Stewart; J. A. Fagerness; P. Evans; E. Gamazon; C. K. Edlund; S. K. Service; A. Tikhomirov; L. Osiecki; C. Illmann; A. Pluzhnikov; A. Konkashbaev; L. K. Davis; B. Han; J. Crane; P. Moorjani; A. T. Crenshaw; M. A. Parkin; V. I. Reus; T. L. Lowe; M. Rangel-Lugo; S. Chouinard; Y. Dion; S. Girard; D. C. Cath; J. H. Smit; R. A. King; T. V. Fernandez; J. F. Leckman; K. K. Kidd; J. R. Kidd; A. J. Pakstis; M. W. State; L. D. Herrera; R. Romero; E. Fournier; P. Sandor; C. L. Barr; N. Phan; V. Gross-Tsur; F. Benarroch; Y. Pollak; C. L. Budman; R. D. Bruun; G. Erenberg; A. L. Naarden; P. C. Lee; N. Weiss; B. Kremeyer; G. B. Berrío; D. D. Campbell; J. C. Cardona Silgado; W. C. Ochoa; S. C. Mesa Restrepo; H. Muller; A. V. Valencia Duarte; G. J. Lyon; M. Leppert; J. Morgan; R. Weiss; M. A. Grados; K. Anderson; S. Davarya; H. Singer; J. Walkup; J. Jankovic; J. A. Tischfield; G. A. Heiman; D. L. Gilbert; P. J. Hoekstra; M. M. Robertson; R. Kurlan; C. Liu; J. R. Gibbs; A. Singleton; J. Hardy; E. Strengman; R. A. Ophoff; M. Wagner; R. Moessner; D. B. Mirel; D. Posthuma; C. Sabatti; E. Eskin; D. V. Conti; J. A. Knowles; A. Ruiz-Linares; G. A. Rouleau; S. Purcell; P. Heutink; B. A. Oostra; W. M. McMahon; N. B. Freimer; N. J. Cox; D. L. Pauls

doi:10.1038/mp.2012.69

Genome-wide association study of Tourette's syndrome

J. M. Scharf, D. Yu, C. A. Mathews, B. M. Neale, S. E. Stewart, J. A. Fagerness, P. Evans, E. Gamazon, C. K. Edlund, S. K. Service, A. Tikhomirov, L. Osiecki, C. Illmann, A. Pluzhnikov, A. Konkashbaev, L. K. Davis, B. Han, J. Crane, P. Moorjani, A. T. CrenshawM. A. Parkin, V. I. Reus, T. L. Lowe, M. Rangel-Lugo, S. Chouinard, Y. Dion, S. Girard, D. C. Cath, J. H. Smit, R. A. King, T. V. Fernandez, J. F. Leckman, K. K. Kidd, J. R. Kidd, A. J. Pakstis, M. W. State, L. D. Herrera, R. Romero, E. Fournier, P. Sandor, C. L. Barr, N. Phan, V. Gross-Tsur, F. Benarroch, Y. Pollak, C. L. Budman, R. D. Bruun, G. Erenberg, A. L. Naarden, P. C. Lee, N. Weiss, B. Kremeyer, G. B. Berrío, D. D. Campbell, J. C. Cardona Silgado, W. C. Ochoa, S. C. Mesa Restrepo, H. Muller, A. V. Valencia Duarte, G. J. Lyon, M. Leppert, J. Morgan, R. Weiss, M. A. Grados, K. Anderson, S. Davarya, H. Singer, J. Walkup, J. Jankovic, J. A. Tischfield, G. A. Heiman, D. L. Gilbert, P. J. Hoekstra, M. M. Robertson, R. Kurlan, C. Liu, J. R. Gibbs, A. Singleton, J. Hardy, E. Strengman, R. A. Ophoff, M. Wagner, R. Moessner, D. B. Mirel, D. Posthuma, C. Sabatti, E. Eskin, D. V. Conti, J. A. Knowles, A. Ruiz-Linares, G. A. Rouleau, S. Purcell, P. Heutink, B. A. Oostra, W. M. McMahon, N. B. Freimer, N. J. Cox, D. L. Pauls

School of Medicine

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

Abstract

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10 -8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10 -6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10 -7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Original language	English (US)
Pages (from-to)	721-728
Number of pages	8
Journal	Molecular psychiatry
Volume	18
Issue number	6
DOIs	https://doi.org/10.1038/mp.2012.69
State	Published - Jun 2013

Keywords

GWAS
Tourette's syndrome
genetics
neurodevelopmental disorder
tics

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

Access to Document

10.1038/mp.2012.69

Cite this

Scharf, J. M., Yu, D., Mathews, C. A., Neale, B. M., Stewart, S. E., Fagerness, J. A., Evans, P., Gamazon, E., Edlund, C. K., Service, S. K., Tikhomirov, A., Osiecki, L., Illmann, C., Pluzhnikov, A., Konkashbaev, A., Davis, L. K., Han, B., Crane, J., Moorjani, P., ... Pauls, D. L. (2013). Genome-wide association study of Tourette's syndrome. Molecular psychiatry, 18(6), 721-728. https://doi.org/10.1038/mp.2012.69

Genome-wide association study of Tourette's syndrome. / Scharf, J. M.; Yu, D.; Mathews, C. A.; Neale, B. M.; Stewart, S. E.; Fagerness, J. A.; Evans, P.; Gamazon, E.; Edlund, C. K.; Service, S. K.; Tikhomirov, A.; Osiecki, L.; Illmann, C.; Pluzhnikov, A.; Konkashbaev, A.; Davis, L. K.; Han, B.; Crane, J.; Moorjani, P.; Crenshaw, A. T.; Parkin, M. A.; Reus, V. I.; Lowe, T. L.; Rangel-Lugo, M.; Chouinard, S.; Dion, Y.; Girard, S.; Cath, D. C.; Smit, J. H.; King, R. A.; Fernandez, T. V.; Leckman, J. F.; Kidd, K. K.; Kidd, J. R.; Pakstis, A. J.; State, M. W.; Herrera, L. D.; Romero, R.; Fournier, E.; Sandor, P.; Barr, C. L.; Phan, N.; Gross-Tsur, V.; Benarroch, F.; Pollak, Y.; Budman, C. L.; Bruun, R. D.; Erenberg, G.; Naarden, A. L.; Lee, P. C.; Weiss, N.; Kremeyer, B.; Berrío, G. B.; Campbell, D. D.; Cardona Silgado, J. C.; Ochoa, W. C.; Mesa Restrepo, S. C.; Muller, H.; Valencia Duarte, A. V.; Lyon, G. J.; Leppert, M.; Morgan, J.; Weiss, R.; Grados, M. A.; Anderson, K.; Davarya, S.; Singer, H.; Walkup, J.; Jankovic, J.; Tischfield, J. A.; Heiman, G. A.; Gilbert, D. L.; Hoekstra, P. J.; Robertson, M. M.; Kurlan, R.; Liu, C.; Gibbs, J. R.; Singleton, A.; Hardy, J.; Strengman, E.; Ophoff, R. A.; Wagner, M.; Moessner, R.; Mirel, D. B.; Posthuma, D.; Sabatti, C.; Eskin, E.; Conti, D. V.; Knowles, J. A.; Ruiz-Linares, A.; Rouleau, G. A.; Purcell, S.; Heutink, P.; Oostra, B. A.; McMahon, W. M.; Freimer, N. B.; Cox, N. J.; Pauls, D. L.

In: Molecular psychiatry, Vol. 18, No. 6, 06.2013, p. 721-728.

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

Scharf, JM, Yu, D, Mathews, CA, Neale, BM, Stewart, SE, Fagerness, JA, Evans, P, Gamazon, E, Edlund, CK, Service, SK, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, LK, Han, B, Crane, J, Moorjani, P, Crenshaw, AT, Parkin, MA, Reus, VI, Lowe, TL, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, DC, Smit, JH, King, RA, Fernandez, TV, Leckman, JF, Kidd, KK, Kidd, JR, Pakstis, AJ, State, MW, Herrera, LD, Romero, R, Fournier, E, Sandor, P, Barr, CL, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, CL, Bruun, RD, Erenberg, G, Naarden, AL, Lee, PC, Weiss, N, Kremeyer, B, Berrío, GB, Campbell, DD, Cardona Silgado, JC, Ochoa, WC, Mesa Restrepo, SC, Muller, H, Valencia Duarte, AV, Lyon, GJ, Leppert, M, Morgan, J, Weiss, R, Grados, MA, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, JA, Heiman, GA, Gilbert, DL, Hoekstra, PJ, Robertson, MM, Kurlan, R, Liu, C, Gibbs, JR, Singleton, A, Hardy, J, Strengman, E, Ophoff, RA, Wagner, M, Moessner, R, Mirel, DB, Posthuma, D, Sabatti, C, Eskin, E, Conti, DV, Knowles, JA, Ruiz-Linares, A, Rouleau, GA, Purcell, S, Heutink, P, Oostra, BA, McMahon, WM, Freimer, NB, Cox, NJ & Pauls, DL 2013, 'Genome-wide association study of Tourette's syndrome', Molecular psychiatry, vol. 18, no. 6, pp. 721-728. https://doi.org/10.1038/mp.2012.69

Scharf, J. M. ; Yu, D. ; Mathews, C. A. ; Neale, B. M. ; Stewart, S. E. ; Fagerness, J. A. ; Evans, P. ; Gamazon, E. ; Edlund, C. K. ; Service, S. K. ; Tikhomirov, A. ; Osiecki, L. ; Illmann, C. ; Pluzhnikov, A. ; Konkashbaev, A. ; Davis, L. K. ; Han, B. ; Crane, J. ; Moorjani, P. ; Crenshaw, A. T. ; Parkin, M. A. ; Reus, V. I. ; Lowe, T. L. ; Rangel-Lugo, M. ; Chouinard, S. ; Dion, Y. ; Girard, S. ; Cath, D. C. ; Smit, J. H. ; King, R. A. ; Fernandez, T. V. ; Leckman, J. F. ; Kidd, K. K. ; Kidd, J. R. ; Pakstis, A. J. ; State, M. W. ; Herrera, L. D. ; Romero, R. ; Fournier, E. ; Sandor, P. ; Barr, C. L. ; Phan, N. ; Gross-Tsur, V. ; Benarroch, F. ; Pollak, Y. ; Budman, C. L. ; Bruun, R. D. ; Erenberg, G. ; Naarden, A. L. ; Lee, P. C. ; Weiss, N. ; Kremeyer, B. ; Berrío, G. B. ; Campbell, D. D. ; Cardona Silgado, J. C. ; Ochoa, W. C. ; Mesa Restrepo, S. C. ; Muller, H. ; Valencia Duarte, A. V. ; Lyon, G. J. ; Leppert, M. ; Morgan, J. ; Weiss, R. ; Grados, M. A. ; Anderson, K. ; Davarya, S. ; Singer, H. ; Walkup, J. ; Jankovic, J. ; Tischfield, J. A. ; Heiman, G. A. ; Gilbert, D. L. ; Hoekstra, P. J. ; Robertson, M. M. ; Kurlan, R. ; Liu, C. ; Gibbs, J. R. ; Singleton, A. ; Hardy, J. ; Strengman, E. ; Ophoff, R. A. ; Wagner, M. ; Moessner, R. ; Mirel, D. B. ; Posthuma, D. ; Sabatti, C. ; Eskin, E. ; Conti, D. V. ; Knowles, J. A. ; Ruiz-Linares, A. ; Rouleau, G. A. ; Purcell, S. ; Heutink, P. ; Oostra, B. A. ; McMahon, W. M. ; Freimer, N. B. ; Cox, N. J. ; Pauls, D. L. / Genome-wide association study of Tourette's syndrome. In: Molecular psychiatry. 2013 ; Vol. 18, No. 6. pp. 721-728.

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title = "Genome-wide association study of Tourette's syndrome",

abstract = "Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10 -8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10 -6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10 -7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.",

keywords = "GWAS, Tourette's syndrome, genetics, neurodevelopmental disorder, tics",

author = "Scharf, {J. M.} and D. Yu and Mathews, {C. A.} and Neale, {B. M.} and Stewart, {S. E.} and Fagerness, {J. A.} and P. Evans and E. Gamazon and Edlund, {C. K.} and Service, {S. K.} and A. Tikhomirov and L. Osiecki and C. Illmann and A. Pluzhnikov and A. Konkashbaev and Davis, {L. K.} and B. Han and J. Crane and P. Moorjani and Crenshaw, {A. T.} and Parkin, {M. A.} and Reus, {V. I.} and Lowe, {T. L.} and M. Rangel-Lugo and S. Chouinard and Y. Dion and S. Girard and Cath, {D. C.} and Smit, {J. H.} and King, {R. A.} and Fernandez, {T. V.} and Leckman, {J. F.} and Kidd, {K. K.} and Kidd, {J. R.} and Pakstis, {A. J.} and State, {M. W.} and Herrera, {L. D.} and R. Romero and E. Fournier and P. Sandor and Barr, {C. L.} and N. Phan and V. Gross-Tsur and F. Benarroch and Y. Pollak and Budman, {C. L.} and Bruun, {R. D.} and G. Erenberg and Naarden, {A. L.} and Lee, {P. C.} and N. Weiss and B. Kremeyer and Berr{\'i}o, {G. B.} and Campbell, {D. D.} and {Cardona Silgado}, {J. C.} and Ochoa, {W. C.} and {Mesa Restrepo}, {S. C.} and H. Muller and {Valencia Duarte}, {A. V.} and Lyon, {G. J.} and M. Leppert and J. Morgan and R. Weiss and Grados, {M. A.} and K. Anderson and S. Davarya and H. Singer and J. Walkup and J. Jankovic and Tischfield, {J. A.} and Heiman, {G. A.} and Gilbert, {D. L.} and Hoekstra, {P. J.} and Robertson, {M. M.} and R. Kurlan and C. Liu and Gibbs, {J. R.} and A. Singleton and J. Hardy and E. Strengman and Ophoff, {R. A.} and M. Wagner and R. Moessner and Mirel, {D. B.} and D. Posthuma and C. Sabatti and E. Eskin and Conti, {D. V.} and Knowles, {J. A.} and A. Ruiz-Linares and Rouleau, {G. A.} and S. Purcell and P. Heutink and Oostra, {B. A.} and McMahon, {W. M.} and Freimer, {N. B.} and Cox, {N. J.} and Pauls, {D. L.}",

note = "Funding Information: We are grateful to all the patients with Tourette{\textquoteright}s syndrome who generously agreed to participate in this study. Furthermore, the members of the Tourette Syndrome Association International Consortium for Genetics are deeply indebted to the Tourette Syndrome Association for their guidance and support. We also thank Libby Bernier and Janelle Alabiso for their assistance in manuscript preparation and Stephan Ripke for help with meta-analysis figures. This work was supported by a grant from the Judah Foundation, NIH Grants NS40024 to DLP and the Tourette Syndrome Association International Consortium for Genetics, NIH Grant NS16648 and a grant from the Tourette Syndrome Association to DLP, NIH Grant NS037484 to NBF, NIH Grant NS043538 to AR-L, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, NIH Grant MH079489, and an American Academy of Neurology Foundation Grant and NIH Grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by Grant U54 RR020278 from the National Center for Research Resources. Support was also provided by the New Jersey Center for Tourette Syndrome & Associated Disorders (through New Jersey Department of Health and Senior Services: 08-1827-FS-N-0) to GAH and JAT and P01MH049351, R01MH061940, K05MH076273 and T32MH018268 to JFL. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. 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 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 (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; 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, the National Institute on Drug Abuse and the NIH contract {\textquoteleft}High throughput genotyping for studying the genetic contributions to human disease{\textquoteright} (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_ id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. None of the funding agencies for this project (NINDS, NIMH, the Tourette Syndrome Association and the Judah Foundation) had any influence or played any role in (1) the design or conduct of the study; (2) management, analysis or interpretation of the data; and (3) preparation, review or approval of the manuscript. Funding Information: Drs Pauls, Scharf, Mathews, Cox, Freimer, McMahon, Heutink, Oostra, Grados, King, Rouleau, Sandor and Budman have all received research support from the NIH and the Tourette Syndrome Association (TSA) on behalf of the TSA International Consortium for Genetics (TSAICG). Drs Scharf, Mathews and Grados have received honoraria and travel support from the TSA. Dr Mathews is a member of the TSA Medical Advisory Board. Dr Sandor has received support and consulting fees from Psyadon, Shire, Solway, UCB Pharma, Janssen, Eli Lilly, Pfizer and Prestwick. Dr Budman has been funded by Psyadon Pharmaceuticals, Otsuka Pharmaceuticals and NINDS and is a member of the National TSA Medical Advisory Board, LI TSA and LI CHADD Medical Advisory Boards. Dr Hoekstra has received honoraria for advice through Desitin, Eli Lilly and Shire. Dr Dion has received honoraria from Biovail Pharma, Pfizer and Eli Lilly. Dr Leckman has been funded by the NIH, the TSA, Talecris Biotherapeutics, Klingenstein Third Generation Foundation, John Wiley and Sons, McGraw Hill and Oxford University Press. Dr Walkup receives research support, travel support for paid and unpaid activities, serves in an unpaid position on the Medical Advisory Board and receives an honorarium for an Educational Meeting from the TSA. He receives royalties from Guilford Press and Oxford Press. He received free medication and placebo from Lilly, Pfizer and Abbott for NIH-funded studies. Dr Jankovic has received research grants from the following: Allergan, Allon Therapeutics, Ceregene, Chelsea Therapeutics, Diana Helis Henry Medical Research Foundation, EMD Serono, Huntington{\textquoteright}s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck, Medtronic, Merz Pharmaceuticals, Michael J Fox Foundation for Parkinson Research, National Institutes of Health, National Parkinson Foundation, Neurogen, St Jude Medical, Teva Pharmaceutical Industries, University of Rochester and Parkinson Study Group. He has served as a consultant or advisory committee member for Allergan, Chelsea Therapeutics, EMD Serono, Lundbeck, Merz Pharmaceuticals, Michael J Fox Foundation for Parkinson Research and Teva Pharmaceutical Industries. He also serves on the editorial boards for Elsevier, Medlink: Neurology, Neurology in Clinical Practice, Neurotoxin Institute, Scientiae and UpToDate. Dr Knowles is on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies, and is a technical advisor to SoftGenetics. Ms Anderson, Dr Barr, Dr Benarroch, Mr Berr{\'i}o, Dr Bruun, Mr Campbell, Dr Cath, Dr Chouinard, Dr Conti, Ms Crane, Mr Crenshaw, Ms Davarya, Dr Davis, Ms Duarte, Mr Edlund, Dr Erenberg, Dr Eskin, Dr Evans, Mr Fagerness, Dr Fernandez, Mr Fournier, Mr Gamazon, Mr Gibbs, Dr Gilbert, Dr Girard, Dr Gross-Tsur, Dr Han, Dr Hardy, Dr Heiman, Dr Herrera, Dr Heutink, Dr Illmann, Dr J Kidd, Dr K Kidd, Mr. Konkashbaev, Dr Kremeyer, Dr Kurlan, Dr Lee, Dr Leppert, Dr Liu, Dr Lowe, Dr Lyon, Dr Mirel, Dr Moessner, Ms Moorjani, Mr Morgan, Mr Muller, Dr Naarden, Dr Neale, Dr Ochoa, Dr Ophoff, Ms Osiecki, Dr Pakstis, Ms Parkin, Mr Phan, Dr Pluzhnikov, Dr Pollak, Dr Posthuma, Dr Purcell, Dr Rangel-Lugo, Dr Restrepo, Dr Reus, Ms Rivas, Dr Robertson, Ms Romero, Dr Ruiz-Linares, Dr Sabatti, Ms Service, Mr Silgado, Dr Singer, Dr Singleton, Dr Smit, Dr State, Dr Stewart, Mr. Strengman, Dr Tikhomirov, Dr Tischfield, Dr Wagner, Dr N Weiss, Dr R Weiss and Ms Yu declare no conflict of interest.",

year = "2013",

month = jun,

doi = "10.1038/mp.2012.69",

language = "English (US)",

volume = "18",

pages = "721--728",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "6",

}

TY - JOUR

T1 - Genome-wide association study of Tourette's syndrome

AU - Scharf, J. M.

AU - Yu, D.

AU - Mathews, C. A.

AU - Neale, B. M.

AU - Stewart, S. E.

AU - Fagerness, J. A.

AU - Evans, P.

AU - Gamazon, E.

AU - Edlund, C. K.

AU - Service, S. K.

AU - Tikhomirov, A.

AU - Osiecki, L.

AU - Illmann, C.

AU - Pluzhnikov, A.

AU - Konkashbaev, A.

AU - Davis, L. K.

AU - Han, B.

AU - Crane, J.

AU - Moorjani, P.

AU - Crenshaw, A. T.

AU - Parkin, M. A.

AU - Reus, V. I.

AU - Lowe, T. L.

AU - Rangel-Lugo, M.

AU - Chouinard, S.

AU - Dion, Y.

AU - Girard, S.

AU - Cath, D. C.

AU - Smit, J. H.

AU - King, R. A.

AU - Fernandez, T. V.

AU - Leckman, J. F.

AU - Kidd, K. K.

AU - Kidd, J. R.

AU - Pakstis, A. J.

AU - State, M. W.

AU - Herrera, L. D.

AU - Romero, R.

AU - Fournier, E.

AU - Sandor, P.

AU - Barr, C. L.

AU - Phan, N.

AU - Gross-Tsur, V.

AU - Benarroch, F.

AU - Pollak, Y.

AU - Budman, C. L.

AU - Bruun, R. D.

AU - Erenberg, G.

AU - Naarden, A. L.

AU - Lee, P. C.

AU - Weiss, N.

AU - Kremeyer, B.

AU - Berrío, G. B.

AU - Campbell, D. D.

AU - Cardona Silgado, J. C.

AU - Ochoa, W. C.

AU - Mesa Restrepo, S. C.

AU - Muller, H.

AU - Valencia Duarte, A. V.

AU - Lyon, G. J.

AU - Leppert, M.

AU - Morgan, J.

AU - Weiss, R.

AU - Grados, M. A.

AU - Anderson, K.

AU - Davarya, S.

AU - Singer, H.

AU - Walkup, J.

AU - Jankovic, J.

AU - Tischfield, J. A.

AU - Heiman, G. A.

AU - Gilbert, D. L.

AU - Hoekstra, P. J.

AU - Robertson, M. M.

AU - Kurlan, R.

AU - Liu, C.

AU - Gibbs, J. R.

AU - Singleton, A.

AU - Hardy, J.

AU - Strengman, E.

AU - Ophoff, R. A.

AU - Wagner, M.

AU - Moessner, R.

AU - Mirel, D. B.

AU - Posthuma, D.

AU - Sabatti, C.

AU - Eskin, E.

AU - Conti, D. V.

AU - Knowles, J. A.

AU - Ruiz-Linares, A.

AU - Rouleau, G. A.

AU - Purcell, S.

AU - Heutink, P.

AU - Oostra, B. A.

AU - McMahon, W. M.

AU - Freimer, N. B.

AU - Cox, N. J.

AU - Pauls, D. L.

N1 - Funding Information: We are grateful to all the patients with Tourette’s syndrome who generously agreed to participate in this study. Furthermore, the members of the Tourette Syndrome Association International Consortium for Genetics are deeply indebted to the Tourette Syndrome Association for their guidance and support. We also thank Libby Bernier and Janelle Alabiso for their assistance in manuscript preparation and Stephan Ripke for help with meta-analysis figures. This work was supported by a grant from the Judah Foundation, NIH Grants NS40024 to DLP and the Tourette Syndrome Association International Consortium for Genetics, NIH Grant NS16648 and a grant from the Tourette Syndrome Association to DLP, NIH Grant NS037484 to NBF, NIH Grant NS043538 to AR-L, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, NIH Grant MH079489, and an American Academy of Neurology Foundation Grant and NIH Grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by Grant U54 RR020278 from the National Center for Research Resources. Support was also provided by the New Jersey Center for Tourette Syndrome & Associated Disorders (through New Jersey Department of Health and Senior Services: 08-1827-FS-N-0) to GAH and JAT and P01MH049351, R01MH061940, K05MH076273 and T32MH018268 to JFL. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. 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 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 (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; 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, the National Institute on Drug Abuse and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_ id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. None of the funding agencies for this project (NINDS, NIMH, the Tourette Syndrome Association and the Judah Foundation) had any influence or played any role in (1) the design or conduct of the study; (2) management, analysis or interpretation of the data; and (3) preparation, review or approval of the manuscript. Funding Information: Drs Pauls, Scharf, Mathews, Cox, Freimer, McMahon, Heutink, Oostra, Grados, King, Rouleau, Sandor and Budman have all received research support from the NIH and the Tourette Syndrome Association (TSA) on behalf of the TSA International Consortium for Genetics (TSAICG). Drs Scharf, Mathews and Grados have received honoraria and travel support from the TSA. Dr Mathews is a member of the TSA Medical Advisory Board. Dr Sandor has received support and consulting fees from Psyadon, Shire, Solway, UCB Pharma, Janssen, Eli Lilly, Pfizer and Prestwick. Dr Budman has been funded by Psyadon Pharmaceuticals, Otsuka Pharmaceuticals and NINDS and is a member of the National TSA Medical Advisory Board, LI TSA and LI CHADD Medical Advisory Boards. Dr Hoekstra has received honoraria for advice through Desitin, Eli Lilly and Shire. Dr Dion has received honoraria from Biovail Pharma, Pfizer and Eli Lilly. Dr Leckman has been funded by the NIH, the TSA, Talecris Biotherapeutics, Klingenstein Third Generation Foundation, John Wiley and Sons, McGraw Hill and Oxford University Press. Dr Walkup receives research support, travel support for paid and unpaid activities, serves in an unpaid position on the Medical Advisory Board and receives an honorarium for an Educational Meeting from the TSA. He receives royalties from Guilford Press and Oxford Press. He received free medication and placebo from Lilly, Pfizer and Abbott for NIH-funded studies. Dr Jankovic has received research grants from the following: Allergan, Allon Therapeutics, Ceregene, Chelsea Therapeutics, Diana Helis Henry Medical Research Foundation, EMD Serono, Huntington’s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck, Medtronic, Merz Pharmaceuticals, Michael J Fox Foundation for Parkinson Research, National Institutes of Health, National Parkinson Foundation, Neurogen, St Jude Medical, Teva Pharmaceutical Industries, University of Rochester and Parkinson Study Group. He has served as a consultant or advisory committee member for Allergan, Chelsea Therapeutics, EMD Serono, Lundbeck, Merz Pharmaceuticals, Michael J Fox Foundation for Parkinson Research and Teva Pharmaceutical Industries. He also serves on the editorial boards for Elsevier, Medlink: Neurology, Neurology in Clinical Practice, Neurotoxin Institute, Scientiae and UpToDate. Dr Knowles is on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies, and is a technical advisor to SoftGenetics. Ms Anderson, Dr Barr, Dr Benarroch, Mr Berrío, Dr Bruun, Mr Campbell, Dr Cath, Dr Chouinard, Dr Conti, Ms Crane, Mr Crenshaw, Ms Davarya, Dr Davis, Ms Duarte, Mr Edlund, Dr Erenberg, Dr Eskin, Dr Evans, Mr Fagerness, Dr Fernandez, Mr Fournier, Mr Gamazon, Mr Gibbs, Dr Gilbert, Dr Girard, Dr Gross-Tsur, Dr Han, Dr Hardy, Dr Heiman, Dr Herrera, Dr Heutink, Dr Illmann, Dr J Kidd, Dr K Kidd, Mr. Konkashbaev, Dr Kremeyer, Dr Kurlan, Dr Lee, Dr Leppert, Dr Liu, Dr Lowe, Dr Lyon, Dr Mirel, Dr Moessner, Ms Moorjani, Mr Morgan, Mr Muller, Dr Naarden, Dr Neale, Dr Ochoa, Dr Ophoff, Ms Osiecki, Dr Pakstis, Ms Parkin, Mr Phan, Dr Pluzhnikov, Dr Pollak, Dr Posthuma, Dr Purcell, Dr Rangel-Lugo, Dr Restrepo, Dr Reus, Ms Rivas, Dr Robertson, Ms Romero, Dr Ruiz-Linares, Dr Sabatti, Ms Service, Mr Silgado, Dr Singer, Dr Singleton, Dr Smit, Dr State, Dr Stewart, Mr. Strengman, Dr Tikhomirov, Dr Tischfield, Dr Wagner, Dr N Weiss, Dr R Weiss and Ms Yu declare no conflict of interest.

PY - 2013/6

Y1 - 2013/6

N2 - Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10 -8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10 -6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10 -7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

AB - Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10 -8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10 -6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10 -7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

KW - GWAS

KW - Tourette's syndrome

KW - genetics

KW - neurodevelopmental disorder

KW - tics

UR - http://www.scopus.com/inward/record.url?scp=84878227013&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878227013&partnerID=8YFLogxK

U2 - 10.1038/mp.2012.69

DO - 10.1038/mp.2012.69

M3 - Article

C2 - 22889924

AN - SCOPUS:84878227013

VL - 18

SP - 721

EP - 728

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 6

ER -

Genome-wide association study of Tourette's syndrome

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