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Epigenome-Wide Association Study of Tic Disorders

  • Nuno R. Zilhão (a1) (a2), Shanmukha S. Padmanabhuni (a3), Luca Pagliaroli (a4), Csaba Barta (a4), BIOS Consortium, Dirk J. A. Smit (a2), Danielle Cath (a2) (a5), Michel G. Nivard (a1), Bart M. L. Baselmans (a1), Jenny van Dongen (a1), Peristera Paschou (a3) and Dorret I. Boomsma (a1)...

Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 × 10−7). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 × 10−6). Several of the top ranking probes (p < 1 × 10−4) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 × 10−15) developmental process (GO:0032502, p = 2.96 × 10−12), and cellular developmental process (GO:0048869, p = 1.96 × 10−12). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder.

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Corresponding author
address for correspondence: Nuno Zilhão, VU University Amsterdam, Department of Biological Psychology, van der Boechorststraat 1, 1081 BT Amsterdam, the Netherlands. E-mail:
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Albin R. L., & Mink J. W. (2006). Recent advances in Tourette syndrome research. Trends in Neurosciences, 29, 175182.
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: Author.
Anckarsäter H., Lundström S., Kollberg L., Kerekes N., Palm C., Carlström E., . . . Bölte S. (2011). The child and adolescent twin study in Sweden (CATSS). Twin Research and Human Genetics, 14, 495508.
Awaad Y. (1999). Tics in Tourette syndrome: new treatment options. Journal of Child Neurology, 14, 316319.
Bibikova M., Barnes B., Tsan C., Ho V., Klotzle B., Le J. M., . . . Shen R. (2011). High density DNA methylation array with single CpG site resolution. Genomics, 98, 288295.
Bolton D., Rijsdijk F., O’Connor T. G., Perrin S., & Eley T. C. (2007). Obsessive–compulsive disorder, tics and anxiety in 6-year-old twins. Psychological Medicine, 37, 3948.
Chen Y. A., Lemire M., Choufani S., Butcher D. T., Grafodatskaya D., Zanke B. W., . . . Weksberg R. (2013). Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics, 8, 203209.
Christensen J. H., Elfving B., Muller H. K., Fryland T., Nyegaard M., Corydon T. J., . . . Borglum A. D. (2012). The schizophrenia and bipolar disorder associated BRD1 gene is regulated upon chronic restraint stress. European Neuropsychopharmacology, 22, 651656.
Davies M. N., Volta M., Pidsley R., Lunnon K., Dixit A., Lovestone S., . . . Mill J. (2012). Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biology, 13, R43.
de Haan M. J., Delucchi K. L., Mathews C. M., & Cath D. C. (2015). Tic symptom dimensions and their heritabilities in Tourette's syndrome. Psychiatric Genetics, 25, 112118.
Dempster E. L., Pidsley R., Schalkwyk L. C., Owens S., Georgiades A., Kane F., . . . Toulopoulou T. (2011). Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Human Molecular Genetics, 20, 47864796.
Doyon Y., Cayrou C., Ullah M., Landry A.-J., Côté V., Selleck W., . . . Côté J. (2006). ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Molecular Cell, 21, 5164.
Eden E., Navon R., Steinfeld I., Lipson D., & Yakhini Z. (2009). GOrilla: A tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics, 10, 48.
Fatemi S. H., Folsom T. D., Reutiman T. J., & Thuras P. D. (2009). Expression of GABAB receptors is altered in brains of subjects with autism. The Cerebellum, 8, 6469.
Feinberg A. P., & Irizarry R. A. (2010). Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proceedings of the National Academy of Sciences, 107 (Suppl. 1), 17571764.
Fortin J. P., Labbe A., Lemire M., Zanke B. W., Hudson T. J., Fertig E. J., . . . Hansen K. D. (2014). Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biology, 15, 503.
Genome of the Netherlands Consortium. (2014). Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nature Genetics, 46, 818825.
Hackett J. A., Sengupta R., Zylicz J. J., Murakami K., Lee C., Down T. A., . . . Surani M. A. (2013). Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science, 339, 448452.
Hafner A., Obermajer N., & Kos J. (2010). Gamma-1-syntrophin mediates trafficking of gamma-enolase towards the plasma membrane and enhances its neurotrophic activity. Neurosignals, 18, 246258.
Heard E., Clerc P., & Avner P. (1997). X-chromosome inactivation in mammals. Annual Review of Genetics, 31, 571610.
Hegyi H. (2013). GABBR1 has a HERV-W LTR in its regulatory region—A possible implication for schizophrenia. Biology Direct, 8 (5), 14.
Jeffries A. R., Perfect L. W., Ledderose J., Schalkwyk L. C., Bray N. J., Mill J., . . . Price J. (2012). Stochastic choice of allelic expression in human neural stem cells. Stem Cells, 30, 19381947.
Klein B. J., Lalonde M.-E., Côté J., Yang X.-J., & Kutateladze T. G. (2014). Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes. Epigenetics, 9, 186193.
Klengel T., Mehta D., Anacker C., Rex-Haffner M., Pruessner J. C., Pariante C. M., . . . Binder E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience, 16, 3341.
Leckman J. F., Riddle M. A., Hardin M. T., Ort S. I., Swartz K. L., Stevenson J., . . . Cohen D. J. (1989). The Yale Global Tic Severity Scale: Initial testing of a clinician-rated scale of tic severity. Journal of the American Academy of Child & Adolescent Psychiatry, 28, 566573.
Lee K. W., & Pausova Z. (2013). Cigarette smoking and DNA methylation. Frontiers in Genetics, 4, 132.
Lehalle D., Sanlaville D., Guimier A., Plouvier E., Leblanc T., Galmiche L., . . . Amiel J. (2014). Multiple congenital anomalies-intellectual disability (MCA-ID) and neuroblastoma in a patient harboring a de novo 14q23.1q23.3 deletion. American Journal of Medical Genetics, 164A, 13101317.
Leon C. A., Schumacher J., Kluck N., Herold C., Schulze T. G., Propping P., . . . Jamra R. A. (2011). Association study of the GRIA1 and CLINT1 (Epsin 4) genes in a German schizophrenia sample. Psychiatric Genetics, 21, 114.
Lichtenstein P., Carlström E., Råstam M., Gillberg C., & Anckarsäter H. (2010). The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. American Journal of Psychiatry, 167, 13571363.
Lichter D. G., Jackson L. A., & Schachter M. (1995). Clinical evidence of genomic imprinting in Tourette's syndrome. Neurology, 45, 924928.
Liu J., Morgan M., Hutchison K., & Calhoun V. D. (2010). A study of the influence of sex on genome wide methylation. PLoS One, 5, e10028.
Liu X., Cheng R., Verbitsky M., Kisselev S., Browne A., Mejia-Sanatana H., . . . Lee J. H. (2011). Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. BMC Medical Genetics, 12, 104.
Luo C., Rajput A., Robinson C., & Rajput A. (2012). Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor. Journal of Clinical Neuroscience, 19, 920921.
Lybaek H., Oyen N., Fauske L., & Houge G. (2008). A 2.1 Mb deletion adjacent but distal to a 14q21q23 paracentric inversion in a family with spherocytosis and severe learning difficulties. Clinical Genetics, 74, 553559.
Maier V., Jolicoeur C., Rayburn H., Takegahara N., Kumanogoh A., Kikutani H., . . . Friedel R. H. (2011). Semaphorin 4C and 4G are ligands of Plexin-B2 required in cerebellar development. Molecular and Cellular Neuroscience, 46, 419431.
Mathews C. A., & Grados M. A. (2011). Familiality of Tourette syndrome, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder: Heritability analysis in a large sib-pair sample. Journal of the American Academy of Child & Adolescent Psychiatry, 50, 4654.
Mill J., & Heijmans B. T. (2013). From promises to practical strategies in epigenetic epidemiology. Nature Reviews Genetics, 14, 585594.
Mink J. W. (2001). Basal ganglia dysfunction in Tourette's syndrome: A new hypothesis. Pediatric Neurology, 25, 190198.
Moore K., McKnight A. J., Craig D., & O’Neill F. (2014). Epigenome-wide association study for Parkinson's disease. Neuromolecular Medicine, 16, 845855.
Ooki S. (2005). Genetic and environmental influences on stuttering and tics in Japanese twin children. Twin Research and Human Genetics, 8, 6975.
Paschou P. (2013). The genetic basis of Gilles de la Tourette Syndrome. Neuroscience & Biobehavioral Reviews, 37, 10261039.
Pauls D. L., Fernandez T. V., Mathews C. A., State M. W., & Scharf J. M. (2014). The inheritance of Tourette disorder: A review. Journal of Obsessive-Compulsive and Related Disorders, 3, 380385.
Rakyan V. K., Down T. A., Balding D. J., & Beck S. (2011). Epigenome-wide association studies for common human diseases. Nature Reviews Genetics, 12, 529541.
Ribak C., Vaughn J., & Roberts E. (1979). The GABA neurons and their axon terminals in rat corpus striatum as demonstrated by GAD immunocytochemistry. Journal of Comparative Neurology, 187, 261283.
Richter M. A., de Jesus D. R., Hoppenbrouwers S., Daigle M., Deluce J., Ravindran L. N., . . . Daskalakis Z. J. (2012). Evidence for cortical inhibitory and excitatory dysfunction in obsessive compulsive disorder. Neuropsychopharmacology, 37, 11441151.
Sapountzi V., & Cote J. (2011). MYST-family histone acetyltransferases: beyond chromatin. Cellular and Molecular Life Sciences, 68, 11471156.
Schrötter A., Mastalski T., Nensa F. M., Neumann M., Loosse C., Pfeiffer K., . . . Theiss C. (2013). FE65 regulates and interacts with the Bloom syndrome protein in dynamic nuclear spheres-potential relevance to Alzheimer's disease. Journal of Cell Science, 126, 24802492.
Severinsen J., Bjarkam C. R., Kiar-Larsen S., Olsen I. M., Nielsen M. M., Blechingberg J., . . . Young B. D. (2006). Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder. Molecular Psychiatry, 11, 11261138.
Singer H. S., Wendlandt J., Krieger M., & Giuliano J. (2001). Baclofen treatment in Tourette syndrome a double-blind, placebo-controlled, crossover trial. Neurology, 56, 599604.
Sowell E. R., Kan E., Yoshii J., Thompson P. M., Bansal R., Xu D., . . . Peterson B. S. (2008). Thinning of sensorimotor cortices in children with Tourette syndrome. Nature Neuroscience, 11, 637639.
Tourette Syndrome Classification Study Group. (1993). Definitions and classification of tic disorders. The Tourette Syndrome Classification Study Group. Archives of Neurology, 50, 10131016.
Towbin K. (2010). Tic disorders. In Dulcan M. K. (Ed.), Dulcan's textbook of child and adolescent psychiatry (pp. 417433). Washington, DC: American Psychiatric Publishing.
Ullah M., Pelletier N., Xiao L., Zhao S. P., Wang K., Degerny C., . . . Yang X. J. (2008). Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Molecular and Cellular Biology, 28, 68286843.
Van Beijsterveldt C. E., Groen-Blokhuis M., Hottenga J. J., Franic S., Hudziak J. J., Lamb D., . . . Boomsma D. I. (2013). The Young Netherlands Twin Register (YNTR): Longitudinal twin and family studies in over 70,000 children. Twin Research and Human Genetics, 16, 252267.
Van Dongen J., Heijmans B. T., Nivard M. G., Willemsen G., Hottenga J.-J., Helmer Q., Dolan C. V., . . . Boomsma D. I. (2015). Genetic and environmental influences interact with age and sex in shaping the human methylome. Manuscript submitted for publication.
Van Iterson M., Tobi E. W., Slieker R. C., den Hollander W., Luijk R., Slagboom P. E., . . . Heijmans B. T. (2014). MethylAid: Visual and interactive quality control of large Illumina 450 k datasets. Bioinformatics, 30, 34353437.
Vassar R. (2013). ADAM10 prodomain mutations cause late-onset Alzheimer's disease: Not just the latest FAD. Neuron, 80, 250253.
Wang K. S., Liu X. F., & Aragam N. (2010). A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. Schizophrenia Research, 124, 192199.
Willemsen G., de Geus E. J., Bartels M., van Beijsterveldt C. E., Brooks A. I., Estourgie-van Burk G. F., . . . Boomsma D. I. (2010). The Netherlands twin register biobank: A resource for genetic epidemiological studies. Twin Research and Human Genetics, 13, 231245.
Willemsen G., Vink J. M., Abdellaoui A., den Braber A., van Beek J. H., Draisma H. H., . . . Boomsma D. I. (2013). The adult Netherlands twin register: Twenty-five years of survey and biological data collection. Twin Research and Human Genetics, 16, 271281.
Wockner L. F., Noble E. P., Lawford B. R., Young R. M., Morris C. P., Whitehall V. L., . . . Voisey J. (2014). Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Translational Psychiatry, 4, e339.
You L., Yan K., Zhou J., Zhao H., Bertos N. R., Park M., . . . Yang X. J. (2015). The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors. PLoS Genetics, 11, e1005034.
Zilhão N. R., Olthof R., Smit D., Mathews C. M., deLucchi K., Cath D. C., Boomsma D. I., . . . Dolan C. V. (2015). Heritability of tic disorders: A twin-family study. Manuscript submitted for publication.
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