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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 theNathan 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 NIHcontract 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.

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Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Publicat a:American Journal Of Psychiatry. 176 (3): 217-227 - 2019-03-01 176(3), DOI: 10.1176/appi.ajp.2018.18070857

Autors: Yu, Dongmei; Sul, Jae Hoon; Tsetsos, Fotis; Nawaz, Muhammad S.; Huang, Alden Y.; Zelaya, Ivette; Illmann, Cornelia; Osiecki, Lisa; Darrow, Sabrina M.; Hirschtritt, Matthew E.; Greenberg, Erica; Muller-Vahl, Kirsten R.; Stuhrmann, Manfred; Dion, Yves; Rouleau, Guy; Aschauer, Harald; Stamenkovic, Mara; Schloegelhofer, Monika; Sandor, Paul; Barr, Cathy L.; Grados, Marco; Singer, Harvey S.; Noethen, Markus M.; Hebebrand, Johannes; Hinney, Anke; King, Robert A.; Fernandez, Thomas, V; Barta, Csaba; Tarnok, Zsanett; Nagy, Peter; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Budman, Cathy L.; Rizzo, Renata; Lyon, Gholson J.; McMahon, William M.; Batterson, James R.; Cath, Danielle C.; Malaty, Irene A.; Okun, Michael S.; Berlin, Cheston; Woods, Douglas W.; Lee, Paul C.; Jankovic, Joseph; Robertson, Mary M.; Gilbert, Donald L.; Brown, Lawrence W.; Coffey, Barbara J.; Dietrich, Andrea; Hoekstra, Pieter J.; Kuperman, Samuel; Zinner, Samuel H.; Ludvigsson, Petur; Saemundsen, Evald; Thorarensen, Olafur; Atzmon, Gil; Barzilai, Nir; Wagner, Michael; Moessner, Rainald; Ophoff, Roel; Pato, Carlos N.; Pato, Michele T.; Knowles, James A.; Roffman, Joshua L.; Smoller, Jordan W.; Buckner, Randy L.; Willsey, A. Jeremy; Tischfield, Jay A.; Heiman, Gary A.; Stefansson, Hreinn; Stefansson, Kari; Posthuma, Danielle; Cox, Nancy J.; Pauls, David L.; Freimer, Nelson B.; Neale, Benjamin M.; Davis, Lea K.; Paschou, Peristera; Coppola, Giovanni; Mathews, Carol A.; Scharf, Jeremiah M.; Bruun, Ruth D.; Chouinard, Sylvain; Darrow, Sabrina; Grados, Marco A.; Kurlan, Roger; Leckman, James F.; Rouleau, Guy A.; Smit, Jan; Budman, Cathy; Konstantinidis, Anastasios; Wolanczyk, Tomasz; Bohnenpoll, Julia; Cheon, Keun-Ah; Elzerman, Lonneke; Frundt, Odette; Garcia-Delgar, Blanca; Grice, Dorothy E.; Hagstrom, Julie; Hedderly, Tammy; Heyman, Isobel; Hong, Hyun Ju; Huyser, Chaim; Ibanez-Gomez, Laura; Kim, Young Key; Kim, Young-Shin; Koh, Yun-Joo; Kook, Sodahm; Leventhal, Bennett L.; Ludolph, Andrea G.; Madruga-Garrido, Marcos; Maras, Athanasios; Mir, Pablo; Morer, Astrid; Munchau, Alexander; Murphy, Tara L.; Plessen, Kerstin J.; Richer, Petra; Roessner, Veit; Shin, Eun-Young; Song, Dong-Ho; Song, Jungeun; State, Matthew W.; Tubing, Jennifer; Visscher, Frank; Wanderer, Sina; Wang, Sheng; Woods, Martin;Tourette Assoc Amer Int Consortium; Gilles Tourette GWAS Replication I; Tourette Int Collaborative Genetic; Psychiat Genomics Consortium Toure

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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'sassociated 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.

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