Abstract
Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.
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Acknowledgements
We are grateful to all the patients with Tourette 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. This work was supported by a grant from the David Judah Fund, NIH grants NS40024 to DLP, JMS and the Tourette Syndrome Association International Consortium for Genetics, NIH grant NS16648 and a grant from the Tourette Syndrome Association to DLP, American Recovery and Reinvestment Act (ARRA) Grants NS40024-07S1 to DLP/JMS and NS16648-29S1 to DLP, NIH grant NS037484 to NBF 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. 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 GWAS 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 the 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. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). We gratefully acknowledge financial support by NWO via the Complexity project (645.000.003) and TOP ZonMW (40-00812-98-07-032). ABS and DP received funding from the HEALTH-2009-2.1.2-1 EU-FP7 Synsys project (grant number 242167).
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Drs Scharf and Mathews have received research support from the NIH and the Tourette Syndrome Association (TSA) on behalf of the TSA International Consortium for Genetics (TSAICG). Drs Scharf and Mathews have received honoraria and travel support from the TSA and are members of the TSA Medical Advisory Board (CAM) and Scientific Advisory Board (JMS).
None of the funding agencies for this project (NINDS, NIMH, the Tourette Syndrome Association and the David Judah Fund) had any influence or played any role in (a) the design or conduct of the study; (b) management, analysis or interpretation of the data; (c) preparation, review or approval of the manuscript. The remaining authors declare no conflict of interest.
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Tourette Syndrome Association International Consortium For Genetics (TSAICG) members and additional Tourette Syndrome GWAS contributors Massachusetts General Hospital: JM Scharf (Site PI), DL Pauls, D Yu, C Illmann, L Osiecki, BM Neale; UCSF: CA Mathews (Site PI), VI Reus, TL Lowe; UCLA: NB Freimer (Site PI), S Service; University of Chicago: NJ Cox (Site PI), LK Davis; University of Montreal: GA Rouleau (Site PI), S Chouinard, Y Dion, S Girard; Utrecht University/VU Medical Center, Amsterdam: DC Cath (Site PI), D Posthuma, JH Smit, P Heutink; Yale University: RA King (Site PI), T Fernandez, JF Leckman; University of Toronto: P Sandor (Site PI), CL Barr; University of Utah: W McMahon (Site PI), G Lyon, M Leppert, J Morgan, R Weiss; Johns Hopkins School of Medicine: MA Grados (Site PI), H Singer; Baylor College of Medicine: J Jankovic; Rutgers University: JA Tischfield (Site PI), GA Heiman (Site PI)
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de Leeuw, C., Goudriaan, A., Smit, A. et al. Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis. Eur J Hum Genet 23, 1519–1522 (2015). https://doi.org/10.1038/ejhg.2015.22
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DOI: https://doi.org/10.1038/ejhg.2015.22
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