Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.
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- Davis, Lea K; Yu, Dongmei; Keenan, Clare L; Gamazon, Eric R; Konkashbaev, Anuar I; Derks, Eske M; Neale, Benjamin M; Yang, Jian; Lee, S Hong; Evans, Patrick; Barr, Cathy L; Bellodi, Laura; Benarroch, Fortu; Berrio, Gabriel Bedoya; Bienvenu, Oscar J; Bloch, Michael H; Blom, Rianne M; Bruun, Ruth D; Budman, Cathy L; Camarena, Beatriz; Campbell, Desmond; Cappi, Carolina; Cardona Silgado, Julio C; Cath, Danielle C; Cavallini, Maria C; Chavira, Denise A; Chouinard, Sylvain; Conti, David V; Cook, Edwin H; Coric, Vladimir; Cullen, Bernadette A; Deforce, Dieter; Delorme, Richard; Dion, Yves; Edlund, Christopher K; Egberts, Karin; Falkai, Peter; Fernandez, Thomas V; Gallagher, Patience J; Garrido, Helena; Geller, Daniel; Girard, Simon L; Grabe, Hans J; Grados, Marco A; Greenberg, Benjamin D; Gross-Tsur, Varda; Haddad, Stephen; Heiman, Gary A; Hemmings, Sian M J; Hounie, Ana G; Illmann, Cornelia; Jankovic, Joseph; Jenike, Michael A; Kennedy, James L; King, Robert A; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L; Macciardi, Fabio; McCracken, James T; McGrath, Lauren M; Mesa Restrepo, Sandra C; Moessner, Rainald; Morgan, Jubel; Muller, Heike; Murphy, Dennis L; Naarden, Allan L; Ochoa, William Cornejo; Ophoff, Roel A; Osiecki, Lisa; Pakstis, Andrew J; Pato, Michele T; Pato, Carlos N; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L; Renner, Tobias J; Reus, Victor I; Richter, Margaret A; Riddle, Mark A; Robertson, Mary M; Romero, Roxana; Rosàrio, Maria C; Rosenberg, David; Rouleau, Guy A; Ruhrmann, Stephan; Ruiz-Linares, Andres; Sampaio, Aline S; Samuels, Jack; Sandor, Paul; Sheppard, Brooke; Singer, Harvey S; Smit, Jan H; Stein, Dan J; Strengman, E; Tischfield, Jay A; Valencia Duarte, Ana V; Vallada, Homero; Van Nieuwerburgh, Filip; Veenstra-Vanderweele, Jeremy; Walitza, Susanne; Wang, Ying; Wendland, Jens R; Westenberg, Herman G M; Shugart, Yin Yao; Miguel, Euripedes C; McMahon, William; Wagner, Michael; Nicolini, Humberto; Posthuma, Danielle; Hanna, Gregory L; Heutink, Peter; Denys, Damiaan; Arnold, Paul D; Oostra, Ben A; Nestadt, Gerald; Freimer, Nelson B; Pauls, David L; Wray, Naomi R; Stewart, S Evelyn; Mathews, Carol A; Knowles, James A; Cox, Nancy J; Scharf, Jeremiah M
- Year
- 2013
- Journal
- PLoS genetics
- PMID
- 24204291
- DOI
- 10.1371/journal.pgen.1003864
- PMCID
- PMC3812053
The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
Tourette Syndrome heritability by chromosome.Heritability (y-axis) per chromosome is plotted against chromosome length (x-axis). The red line represents heritability regressed on chromosome length and the 95% confidence interval around the slope of the regression model is represented by the red dashed lines. The black line represents the expected heritability per chromosome (based on size) regressed on chromosome length. Chromosomes 2, 5, 11, 12, 16, and 20 fall outside of the 95% confidence interval and appear to account for more heritability than expected based on chromosome length.
LLM interpretation
This scatter plot shows Tourette Syndrome (TS) heritability plotted against chromosome length (Mb). A red regression line with a 95% confidence interval (dashed red lines) represents the observed heritability, while a black line represents the expected heritability based on chromosome size. Chromosomes 2, 5, 11, 12, 16, and 20 are positioned above the confidence interval, indicating higher than expected heritability.
Obsessive-compulsive disorder heritability by chromosome.Heritability (y-axis) per chromosome is plotted against chromosome length (x-axis). The red line represents heritability regressed on chromosome length and the 95% confidence interval around the slope of the regression model is represented by the red dashed lines. The black line represents the expected heritability per chromosome (based on size) regressed on chromosome length. Chromosome 15 is shown in red to highlight its extreme deviation from the expected heritability based on chromosome length. Chromosomes 3, 10, 13, and 17 are also outside of the 95% interval and appear to account for more heritability than expected based on chromosome length.
LLM interpretation
This scatter plot shows the heritability of obsessive-compulsive disorder (y-axis) plotted against chromosome length in Mb (x-axis). A black line represents the expected heritability based on size, while a red line and surrounding red dashed lines represent the regression of heritability on length and its 95% confidence interval. Chromosome 15 is highlighted in red as a significant outlier above the confidence interval, with chromosomes 3, 10, 13, and 17 also appearing above the interval.
Heritability by minor allele frequency.The x-axis represents all minor allele frequency bins tested while the y-axis represents resultant heritability in a given bin. Blue bars indicate TS and red bars indicate OCD. Error bars are shown.
LLM interpretation
This bar chart displays heritability across six minor allele frequency (MAF) bins for Tourette Syndrome (TS, blue bars) and Obsessive-Compulsive Disorder (OCD, red bars). The x-axis lists the MAF bins, and the y-axis represents the resultant heritability. TS generally shows higher heritability than OCD in most bins, particularly in the lowest and mid-to-high ranges, though both conditions exhibit substantial overlap in error bars.
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| Citation | PMID | DOI | Status |
|---|---|---|---|
| BoltonD, RijsdijkF, O'ConnorTG, PerrinS, EleyTC (2007) Obsessive-compulsive disorder, tics and anxiety in 6-year-old twins. Psychol Med 37: 39–48.1699987810.1017/S0033291706008816 | — | — | — |
| Consortium C-DGotPG (2013) Genetic relationships between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45 (9) 984–94.2393382110.1038/ng.2711PMC3800159 | — | — | — |
| DavisLK, GamazonER, Kistner-GriffinE, BadnerJA, LiuC, et al (2012) Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci. Mol Autism 3: 3.2259157610.1186/2040-2392-3-3PMC3484025 | — | — | — |
| DelahantyRJ, KangJQ, BruneCW, KistnerEO, CourchesneE, et al (2011) Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry 16: 86–96.1993573810.1038/mp.2009.118PMC3428055 | — | — | — |
| DoornbosM, Sikkema-RaddatzB, RuijvenkampCA, DijkhuizenT, BijlsmaEK, et al (2009) Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 52: 108–115.1932887210.1016/j.ejmg.2009.03.010 | — | — | — |
| EichlerEE, FlintJ, GibsonG, KongA, LealSM, et al (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11: 446–450.2047977410.1038/nrg2809PMC2942068 | — | — | — |
| ElbeinSC, GamazonER, DasSK, RasouliN, KernPA, et al (2012) Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture? Am J Hum Genet 91: 466–477.2295889910.1016/j.ajhg.2012.08.002PMC3512001 | — | — | — |
| ElbeinSC, KernPA, RasouliN, Yao-BorengasserA, SharmaNK, et al (2011) Global gene expression profiles of subcutaneous adipose and muscle from glucose-tolerant, insulin-sensitive, and insulin-resistant individuals matched for BMI. Diabetes 60: 1019–1029.2126633110.2337/db10-1270PMC3046820 | — | — | — |
| FerraoYA, MiguelE, SteinDJ (2009) Tourette's syndrome, trichotillomania, and obsessive-compulsive disorder: how closely are they related? Psychiatry Res 170: 32–42.1980117010.1016/j.psychres.2008.06.008 | — | — | — |
| Gamazon E, Im H, Liu C, Nicolae D, Cox N (2012) The convergence of functional genomics, heritability estimation, and polygenic modeling: Emerging spectrum of alleleic variation in bipolar disorder. arXiv:submit/0682261. | — | — | — |
| GamazonER, BadnerJA, ChengL, ZhangC, ZhangD, et al (2012) Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry 18 (3) 340–6.2221259610.1038/mp.2011.174PMC3601550 | — | — | — |
| Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43: 969–976.2192697410.1038/ng.940PMC3303194 | — | — | — |
| GradosMA, MathewsCA (2008) Latent class analysis of gilles de la tourette syndrome using comorbidities: clinical and genetic implications. Biol Psychiatry 64: 219–225.1835900810.1016/j.biopsych.2008.01.019PMC2596958 | — | — | — |
| GraybielAM (2008) Habits, rituals, and the evaluative brain. Annu Rev Neurosci 31: 359–387.1855886010.1146/annurev.neuro.29.051605.112851 | — | — | — |
| HannaGL, HimleJA, CurtisGC, GillespieBW (2005) A family study of obsessive-compulsive disorder with pediatric probands. Am J Med Genet B Neuropsychiatr Genet 134B: 13–19.1563569410.1002/ajmg.b.30138 | — | — | — |
| HarrisonBJ, PujolJ, CardonerN, DeusJ, AlonsoP, et al (2013) Brain corticostriatal systems and the major clinical symptom dimensions of obsessive-compulsive disorder. Biol Psychiatry 73: 321–328.2320052710.1016/j.biopsych.2012.10.006 | — | — | — |
| HebebrandJ, KlugB, FimmersR, SeuchterSA, Wettke-SchaferR, et al (1997) Rates for tic disorders and obsessive compulsive symptomatology in families of children and adolescents with Gilles de la Tourette syndrome. J Psychiatr Res 31: 519–530.936819410.1016/s0022-3956(97)00028-9 | — | — | — |
| JohnsonWE, LiC, RabinovicA (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8: 118–127.1663251510.1093/biostatistics/kxj037 | — | — | — |
| KanoY, OhtaM, NagaiY, PaulsDL, LeckmanJF (2001) A family study of Tourette syndrome in Japan. Am J Med Genet 105: 414–421.1144939210.1002/ajmg.1436 | — | — | — |
| KarnoM, GoldingJM, SorensonSB, BurnamMA (1988) The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry 45: 1094–1099.326414410.1001/archpsyc.1988.01800360042006 | — | — | — |
| KaterbergH, DelucchiKL, StewartSE, LochnerC, DenysDA, et al (2010) Symptom dimensions in OCD: item-level factor analysis and heritability estimates. Behav Genet 40: 505–517.2036124710.1007/s10519-010-9339-zPMC2886912 | — | — | — |
| KellerMF, SaadM, BrasJ, BettellaF, NicolaouN, et al (2012) Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease. Hum Mol Genet 21: 4996–5009.2289237210.1093/hmg/dds335PMC3576713 | — | — | — |
| KhalifaN, von KnorringAL (2003) Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Dev Med Child Neurol 45: 315–319.1272914510.1017/s0012162203000598 | — | — | — |
| KiddKK, HeimbuchRC, RecordsMA, OehlertG, WebsterRL (1980) Familial stuttering patterns are not related to one measure of severity. J Speech Hear Res 23: 539–545.742115710.1044/jshr.2303.539 | — | — | — |
| KiddKK, PrusoffBA, CohenDJ (1980) Familial pattern of Gilles de la Tourette syndrome. Arch Gen Psychiatry 37: 1336–1339.693471210.1001/archpsyc.1980.01780250022001 | — | — | — |
| KleiL, SandersSJ, MurthaMT, HusV, LoweJK, et al (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3: 9.2306755610.1186/2040-2392-3-9PMC3579743 | — | — | — |
| LanziG, ZambrinoCA, TermineC, PalestraM, Ferrari GinevraO, et al (2004) Prevalence of tic disorders among primary school students in the city of Pavia, Italy. Arch Dis Child 89: 45–47.14709503PMC1755911 | — | — | — |
| LeekJT, StoreyJD (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3: 1724–1735.1790780910.1371/journal.pgen.0030161PMC1994707 | — | — | — |
| LeeSH, HaroldD, NyholtDR, GoddardME, ZondervanKT, et al (2013) Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum Mol Genet 22: 832–841.2319319610.1093/hmg/dds491PMC3554206 | — | — | — |
| LeeSH, WrayNR, GoddardME, VisscherPM (2011) Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet 88: 294–305.2137630110.1016/j.ajhg.2011.02.002PMC3059431 | — | — | — |
| LeeSH, YangJ, GoddardME, VisscherPM, WrayNR (2012) Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics 28: 2540–2542.2284398210.1093/bioinformatics/bts474PMC3463125 | — | — | — |
| LichtensteinP, CarlstromE, RastamM, GillbergC, AnckarsaterH (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167: 1357–1363.2068618810.1176/appi.ajp.2010.10020223 | — | — | — |
| LiY, WillerC, SannaS, AbecasisG (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10: 387–406.1971544010.1146/annurev.genom.9.081307.164242PMC2925172 | — | — | — |
| LiY, WillerCJ, DingJ, ScheetP, AbecasisGR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34: 816–834.2105833410.1002/gepi.20533PMC3175618 | — | — | — |
| ManolioTA, CollinsFS, CoxNJ, GoldsteinDB, HindorffLA, et al (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.1981266610.1038/nature08494PMC2831613 | — | — | — |
| MathewsCA, GreenwoodT, WesselJ, AzzamA, GarridoH, et al (2008) Evidence for a heritable unidimensional symptom factor underlying obsessionality. Am J Med Genet B Neuropsychiatr Genet 147B: 676–685.1816338310.1002/ajmg.b.30660 | — | — | — |
| MiguelEC, BaerL, CoffeyBJ, RauchSL, SavageCR, et al (1997) Phenomenological differences appearing with repetitive behaviours in obsessive-compulsive disorder and Gilles de la Tourette's syndrome. Br J Psychiatry 170: 140–145.909350210.1192/bjp.170.2.140 | — | — | — |
| MiguelEC, do Rosario-CamposMC, PradoHS, do ValleR, RauchSL, et al (2000) Sensory phenomena in obsessive-compulsive disorder and Tourette's disorder. J Clin Psychiatry 61: 150–156; quiz 157.1073266710.4088/jcp.v61n0213 | — | — | — |
| NestadtG, SamuelsJ, RiddleM, BienvenuOJ3rd, LiangKY, et al (2000) A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 57: 358–363.1076869710.1001/archpsyc.57.4.358 | — | — | — |
| NestadtG, WangY, GradosMA, RiddleMA, GreenbergBD, et al (2012) Homeobox genes in obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 159B: 53–60.2209567810.1002/ajmg.b.32001PMC3250212 | — | — | — |
| O'RourkeJA, ScharfJM, YuD, PaulsDL (2009) The genetics of Tourette syndrome: a review. J Psychosom Res 67: 533–545.1991365810.1016/j.jpsychores.2009.06.006PMC2778609 | — | — | — |
| PattersonN, PriceAL, ReichD (2006) Population structure and eigenanalysis. PLoS Genet 2: e190.1719421810.1371/journal.pgen.0020190PMC1713260 | — | — | — |
| PaulsDL (1992) The genetics of obsessive compulsive disorder and Gilles de la Tourette's syndrome. Psychiatr Clin North Am 15: 759–766.1461793 | — | — | — |
| PaulsDL, RaymondCL, StevensonJM, LeckmanJF (1991) A family study of Gilles de la Tourette syndrome. Am J Hum Genet 48: 154–163.1985456PMC1682764 | — | — | — |
| PriceRA, KiddKK, CohenDJ, PaulsDL, LeckmanJF (1985) A twin study of Tourette syndrome. Arch Gen Psychiatry 42: 815–820.386019410.1001/archpsyc.1985.01790310077011 | — | — | — |
| PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.1770190110.1086/519795PMC1950838 | — | — | — |
| RossJ, BadnerJ, GarridoH, SheppardB, ChaviraDA, et al (2011) Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD. Hum Genet 130: 795–805.2169177410.1007/s00439-011-1033-6PMC4442699 | — | — | — |
| Scharf JM, Pauls D (2007) Genetics of tic disorders. In: D.L. R, M. CJ, R.E. P, R. KB, editors. Principles and Pracitices of Medical Genetics. 5th ed. New York: Elsevier. pp. 2737–2754. | — | — | — |
| ScharfJM, YuD, MathewsCA, NealeBM, StewartSE, et al (2012) Genome-wide association study of Tourette's syndrome. Mol Psychiatry 18 (6) 721–8.2288992410.1038/mp.2012.69PMC3605224 | — | — | — |
| ShaoY, CuccaroML, HauserER, RaifordKL, MenoldMM, et al (2003) Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. Am J Hum Genet 72: 539–548.1256732510.1086/367846PMC1180230 | — | — | — |
| ShugartYY, SamuelsJ, WillourVL, GradosMA, GreenbergBD, et al (2006) Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol Psychiatry 11: 763–770.1675527510.1038/sj.mp.4001847 | — | — | — |
| StewartSE, YuD, ScharfJM, NealeBM, FagernessJA, et al (2012) Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 18 (7) 788–98.2288992110.1038/mp.2012.85PMC4218751 | — | — | — |
| SwedoSE, LeonardHL, GarveyM, MittlemanB, AllenAJ, et al (1998) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155: 264–271.946420810.1176/ajp.155.2.264 | — | — | — |
| van GrootheestDS, CathD, HottengaJJ, BeekmanAT, BoomsmaDI (2009) Genetic factors underlie stability of obsessive-compulsive symptoms. Twin Res Hum Genet 12: 411–419.1980376810.1375/twin.12.5.411 | — | — | — |
| van GrootheestDS, CathDC, BeekmanAT, BoomsmaDI (2005) Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet 8: 450–458.1621283410.1375/183242705774310060 | — | — | — |
| WangHS, KuoMF (2003) Tourette's syndrome in Taiwan: an epidemiological study of tic disorders in an elementary school at Taipei County. Brain Dev 25 Suppl 1: S29–31.1498036910.1016/s0387-7604(03)90005-2 | — | — | — |
| WangK, LiM, HakonarsonH (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38: e164.2060168510.1093/nar/gkq603PMC2938201 | — | — | — |
| WangL, LeeDY, BaileyE, HartleinJM, GadoMH, et al (2007) Validity of large-deformation high dimensional brain mapping of the basal ganglia in adults with Tourette syndrome. Psychiatry Res 154: 181–190.1728935410.1016/j.pscychresns.2006.08.006PMC2859464 | — | — | — |
| YangJ, LeeSH, GoddardME, VisscherPM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88: 76–82.2116746810.1016/j.ajhg.2010.11.011PMC3014363 | — | — | — |
| YangJ, ManolioTA, PasqualeLR, BoerwinkleE, CaporasoN, et al (2011) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43: 519–525.2155226310.1038/ng.823PMC4295936 | — | — | — |
| ZukO, HechterE, SunyaevSR, LanderES (2012) The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci U S A 109: 1193–1198.2222366210.1073/pnas.1119675109PMC3268279 | — | — | — |
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genetics of Tourette Syndrome. | Fernandez TV | — | 2025 | → |
| Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. | Strom NI et al. | — | 2025 | → |
| Interneuron Loss and Microglia Activation by Transcriptome Analyses in the Basal Ganglia of Tourette Disorder. | Wang Y et al. | — | 2025 | → |
| Neuropsychiatric symptoms in siblings of children with Tourette syndrome in the EMTICS study. | Sidiropoulou O et al. | — | 2025 | → |
| Oligogenic risk score for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders. | Borczyk M et al. | — | 2025 | → |
| Recent advances in treating age-related macular degeneration and diabetic retinopathy: Current therapies and emerging novel approaches. | Antal R et al. | — | 2025 | → |
| Reply to: Methodological and Interpretational Issues in the PsyRiskMR Database. | Li X et al. | — | 2025 | → |
| Tourette syndrome and brain stimulation therapy: a systematic review and meta-analysis of current evidence. | Aloufi AK et al. | — | 2025 | → |
| A Family Genetic Study of Obsessive Compulsive Disorder in Youth. | Geller DA et al. | — | 2024 | → |
| A Genetic Analysis of Current Medication Use in the UK Biobank. | Rohde PD | — | 2024 | → |
| Developing a phenotype risk score for tic disorders in a large, clinical biobank. | Miller-Fleming TW et al. | — | 2024 | → |
| Endophenotype 2.0: updated definitions and criteria for endophenotypes of psychiatric disorders, incorporating new technologies and findings. | Liu C et al. | — | 2024 | → |
| Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population. | Strom NI et al. | — | 2024 | → |
| Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome. | Tsetsos F et al. | — | 2024 | → |
| Improved estimation of functional enrichment in SNP heritability using feasible generalized least squares. | Xiong Z et al. | — | 2024 | → |
| Interneuron loss and microglia activation by transcriptome analyses in the basal ganglia of Tourette syndrome | Wang Y et al. | — | 2024 | — |
| Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome. | Fichna JP et al. | — | 2024 | → |
| The role of neuroactive steroids in tic disorders. | Branca C et al. | — | 2024 | → |
| Abnormally Enhanced Midfrontal Theta Activity During Response Monitoring in Youths With Obsessive-Compulsive Disorder. | Suzuki T et al. | — | 2023 | → |
| Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics. | Morrill K et al. | — | 2023 | → |
| Direct additive genetics and maternal effect contribute to the risk of Tourette disorder. | Mahjani B et al. | — | 2023 | → |
| Exploring the underlying mechanisms of obesity and diabetes and the potential of Traditional Chinese Medicine: an overview of the literature. | Chen YK et al. | — | 2023 | → |
| Genomic variants and inferred biological processes in multiplex families with Tourette syndrome. | Fichna JP et al. | — | 2023 | → |
| Mice lacking Ptprd exhibit deficits in goal-directed behavior and female-specific impairments in sensorimotor gating. | Ho EV et al. | — | 2023 | → |
| Pediatric neuropsychiatric disorders with motor and nonmotor phenomena. | Younger DS | — | 2023 | → |
| Polygenic and environmental determinants of tics in the Avon Longitudinal Study of Parents and Children. | Abdulkadir M et al. | — | 2023 | → |
| Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome. | Jain P et al. | — | 2023 | → |
| Rhesus monkeys exhibiting spontaneous ritualistic behaviors resembling obsessive-compulsive disorder. | Zhai R et al. | — | 2023 | → |
| The identification of mediating effects using genome-based restricted maximum likelihood estimation. | Rietveld CA et al. | — | 2023 | → |
| Treatment of Tourette syndrome by acupuncture combined with Chinese medicine based on syndrome differentiation: A review. | Lin K et al. | — | 2023 | → |
| Anti-obesity drug discovery: advances and challenges. | Müller TD et al. | — | 2022 | → |
| Concordance and comorbidities among monozygotic twins with tic disorders. | Pedersen JH et al. | — | 2022 | → |
| European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I: assessment. | Szejko N et al. | — | 2022 | → |
| Examining the source of increased bipolar disorder and major depressive disorder common risk variation burden in multiplex schizophrenia families. | Ahangari M et al. | — | 2022 | → |
| Identity-by-descent analysis of a large Tourette's syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction. | Ryan N et al. | — | 2022 | → |
| Insights Into the Genomic Underpinnings of Psychopathology. | Kalin NH | — | 2022 | → |
| Relationship between adverse childhood experiences and symptom severity in adult men with Tourette Syndrome. | Yang K et al. | — | 2022 | → |
| The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum. | Mahjani B et al. | — | 2022 | → |
| Tourettic OCD: Current understanding and treatment challenges of a unique endophenotype. | Katz TC et al. | — | 2022 | → |
| A Comprehensive Review of Tic Disorders in Children. | Ueda K et al. | — | 2021 | → |
| A dimensional perspective on the genetics of obsessive-compulsive disorder. | Strom NI et al. | — | 2021 | → |
| A population-based family clustering study of tic-related obsessive-compulsive disorder. | Brander G et al. | — | 2021 | → |
| Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease. | Dennis JK et al. | — | 2021 | → |
| Contextualizing genetic risk score for disease screening and rare variant discovery. | Zhou D et al. | — | 2021 | → |
| Effect of maternal smoking during pregnancy on Tourette syndrome and chronic tic disorders among offspring: a systematic review and meta-analysis. | Ayubi E et al. | — | 2021 | → |
| Effects of Low-Frequency Repetitive Transcranial Magnetic Stimulation of the Bilateral Parietal Cortex in Patients With Tourette Syndrome. | Fu M et al. | — | 2021 | → |
| Efficient and effective control of confounding in eQTL mapping studies through joint differential expression and Mendelian randomization analyses. | Fan Y et al. | — | 2021 | → |
| Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree. | Halvorsen M et al. | — | 2021 | → |
| Elevated Expression of <i>SLC6A4</i> Encoding the Serotonin Transporter (SERT) in Gilles de la Tourette Syndrome. | Hildonen M et al. | — | 2021 | → |
| EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder. | Hildonen M et al. | — | 2021 | → |
| Genetics of obsessive-compulsive disorder. | Mahjani B et al. | — | 2021 | → |
| Genetics of OCD and Related Disorders; Searching for Shared Factors. | Grünblatt E | — | 2021 | → |
| Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder. | Burton CL et al. | — | 2021 | → |
| Genomics of Obsessive-Compulsive Disorder-Toward Personalized Medicine in the Era of Big Data. | Szejko N et al. | — | 2021 | → |
| Histamine, Neuroinflammation and Neurodevelopment: A Review. | Carthy E et al. | — | 2021 | → |
| Pharmacotherapeutic Strategies and New Targets in OCD. | Pittenger C | — | 2021 | → |
| Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis. | Strom NI et al. | — | 2021 | → |
| Recent progress on Tourette syndrome. | Ueda K et al. | — | 2021 | → |
| Specialty knowledge and competency standards for pharmacotherapy for adult obsessive-compulsive disorder. | Pittenger C et al. | — | 2021 | → |
| Synaptic processes and immune-related pathways implicated in Tourette syndrome. | Tsetsos F et al. | — | 2021 | → |
| Whole-exome sequencing identifies genes associated with Tourette's disorder in multiplex families. | Cao X et al. | — | 2021 | → |
| A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression. | Ndungu A et al. | — | 2020 | → |
| Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome. | Pagliaroli L et al. | — | 2020 | → |
| Heterogeneity and Polygenicity in Psychiatric Disorders: A Genome-Wide Perspective. | Wendt FR et al. | — | 2020 | → |
| Nordic OCD & Related Disorders Consortium: Rationale, design, and methods. | Mataix-Cols D et al. | — | 2020 | → |
| Quantifying genetic effects on disease mediated by assayed gene expression levels. | Yao DW et al. | — | 2020 | → |
| Serotonin system gene variants and regional brain volume differences in pediatric OCD. | Sinopoli VM et al. | — | 2020 | → |
| The histidine decarboxylase model of tic pathophysiology: a new focus on the histamine H<sub>3</sub> receptor. | Pittenger C | — | 2020 | → |
| Trichotillomania is more related to Tourette disorder than to obsessive-compulsive disorder. | Lamothe H et al. | — | 2020 | → |
| A Bayesian Account of the Sensory-Motor Interactions Underlying Symptoms of Tourette Syndrome. | Rae CL et al. | — | 2019 | → |
| Computational Approaches for Identification of Pleiotropic Biomarker Profiles in Psychiatry. | Cao H et al. | — | 2019 | → |
| Concordance of genetic variation that increases risk for tourette syndrome and that influences its underlying neurocircuitry. | Mufford M et al. | — | 2019 | → |
| Estimating Uterine Fibroid SNP-Based Heritability in European American Women with Imaging-Confirmed Fibroids. | Bray MJ et al. | — | 2019 | → |
| Heritability of Regional Brain Volumes in Large-Scale Neuroimaging and Genetic Studies. | Zhao B et al. | — | 2019 | → |
| Immunity in Gilles de la Tourette-Syndrome: Results From a Cerebrospinal Fluid Study. | Baumgaertel C et al. | — | 2019 | → |
| Initial findings of striatum tripartite model in OCD brain samples based on transcriptome analysis. | Lisboa BCG et al. | — | 2019 | → |
| Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies. | Yu D et al. | — | 2019 | → |
| Leveraging allelic imbalance to refine fine-mapping for eQTL studies. | Zou J et al. | — | 2019 | → |
| Parental Age and Differential Estimates of Risk for Neuropsychiatric Disorders: Findings From the Danish Birth Cohort. | Janecka M et al. | — | 2019 | → |
| Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort. | Abdulkadir M et al. | — | 2019 | → |
| Psychiatric genetics and the structure of psychopathology. | Smoller JW et al. | — | 2019 | → |
| Sex differences in the genetic architecture of obsessive-compulsive disorder. | Khramtsova EA et al. | — | 2019 | → |
| Assessing the evidence for shared genetic risks across psychiatric disorders and traits. | Martin J et al. | — | 2018 | → |
| Bridging the Great Divide: What Can Neurology Learn From Psychiatry? | Perez DL et al. | — | 2018 | → |
| Characterizing the Relation Between Expression QTLs and Complex Traits: Exploring the Role of Tissue Specificity. | Ip HF et al. | — | 2018 | → |
| Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome. | Hirschtritt ME et al. | — | 2018 | → |
| Genetic architecture of gene expression traits across diverse populations. | Mogil LS et al. | — | 2018 | → |
| Genetic susceptibility in obsessive-compulsive disorder. | Fernandez TV et al. | — | 2018 | → |
| Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. | Finucane HK et al. | — | 2018 | → |
| How can preclinical mouse models be used to gain insight into prefrontal cortex dysfunction in obsessive-compulsive disorder? | Manning EE et al. | — | 2018 | → |
| Impaired Antisaccades in Obsessive-Compulsive Disorder: Evidence From Meta-Analysis and a Large Empirical Study. | Bey K et al. | — | 2018 | → |
| Leveraging molecular quantitative trait loci to understand the genetic architecture of diseases and complex traits. | Hormozdiari F et al. | — | 2018 | → |
| Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study. | Brander G et al. | — | 2018 | → |
| Proteomic-genomic adjustments and their confluence for elucidation of pathways and networks during liver fibrosis. | Husain H et al. | — | 2018 | → |
| Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. | International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS) | — | 2018 | → |
| Systematic review of co-occurring OCD and TD: Evidence for a tic-related OCD subtype? | Kloft L et al. | — | 2018 | → |
| Tourette disorder and other tic disorders. | Fernandez TV et al. | — | 2018 | → |
| Tourette's syndrome and its borderland. | Stern JS | — | 2018 | → |
| Tourette syndrome: a disorder of the social decision-making network. | Albin RL | — | 2018 | → |
| Abnormalities in metabolite concentrations in tourette's disorder and obsessive-compulsive disorder-A proton magnetic resonance spectroscopy study. | Fan S et al. | — | 2017 | → |
| A hierarchical causal taxonomy of psychopathology across the life span. | Lahey BB et al. | — | 2017 | → |
| A search for the common ground between Tic; Obsessive-compulsive and Autism Spectrum Disorders: part I, Tic disorders. | Barnhill J et al. | — | 2017 | → |
| Autism Spectrum Symptoms in a Tourette's Disorder Sample. | Darrow SM et al. | — | 2017 | → |
| Centrality of prefrontal and motor preparation cortices to Tourette Syndrome revealed by meta-analysis of task-based neuroimaging studies. | Polyanska L et al. | — | 2017 | → |
| Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. | Hoffman JD et al. | — | 2017 | → |
| Classification of common human diseases derived from shared genetic and environmental determinants. | Wang K et al. | — | 2017 | → |
| Complex genetics of Tourette's Syndrome: Piecing the puzzle. | Wagle Shukla A et al. | — | 2017 | → |
| Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues. | Liu X et al. | — | 2017 | → |
| Genome Wide Association Study (GWAS) between Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD). | Ritter ML et al. | — | 2017 | → |
| Gilles de la Tourette syndrome. | Robertson MM et al. | — | 2017 | → |
| Heritability of tic disorders: a twin-family study. | Zilhão NR et al. | — | 2017 | → |
| Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions. | Pittenger C | — | 2017 | → |
| Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome. | Darrow SM et al. | — | 2017 | → |
| Integrative genetic analysis suggests that skin color modifies the genetic architecture of melanoma. | Hulur I et al. | — | 2017 | → |
| Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection. | Gazal S et al. | — | 2017 | → |
| Parental Psychopathology and Tourette Syndrome/Chronic Tic Disorder in Offspring: A Nationwide Case-Control Study. | Leivonen S et al. | — | 2017 | → |
| Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD. | Guo W et al. | — | 2017 | → |
| Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. | Huang AY et al. | — | 2017 | → |
| Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder. | Song M et al. | — | 2017 | → |
| Strain and sex based characterization of behavioral expressions in non-induced compulsive-like mice. | Mitra S et al. | — | 2017 | → |
| Analysis of Heritability Using Genome-Wide Data. | Hall JB et al. | — | 2016 | → |
| An integrated molecular landscape implicates the regulation of dendritic spine formation through insulin-related signalling in obsessive-compulsive disorder. | van de Vondervoort I et al. | — | 2016 | → |
| A Review and Update on Tourette Syndrome: Where Is the Field Headed? | Gunduz A et al. | — | 2016 | → |
| Clinical significance of psychiatric comorbidity in children and adolescents with obsessive-compulsive disorder: subtyping a complex disorder. | Ortiz AE et al. | — | 2016 | → |
| Cross-Disorder Genetic Analysis of Tic Disorders, Obsessive-Compulsive, and Hoarding Symptoms. | Zilhão NR et al. | — | 2016 | → |
| Differential contribution of genomic regions to marked genetic variation and prediction of quantitative traits in broiler chickens. | Abdollahi-Arpanahi R et al. | — | 2016 | → |
| Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia. | Costas J et al. | — | 2016 | → |
| From Genetics to Epigenetics: New Perspectives in Tourette Syndrome Research. | Pagliaroli L et al. | — | 2016 | → |
| Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation. | Frick L et al. | — | 2016 | → |
| Integrative approaches for large-scale transcriptome-wide association studies. | Gusev A et al. | — | 2016 | → |
| Investigation of SNP rs2060546 Immediately Upstream to <i>NTN4</i> in a Danish Gilles de la Tourette Syndrome Cohort. | Padmanabhuni SS et al. | — | 2016 | → |
| Limitations of GCTA as a solution to the missing heritability problem. | Krishna Kumar S et al. | — | 2016 | → |
| Neurobiology of rodent self-grooming and its value for translational neuroscience. | Kalueff AV et al. | — | 2016 | → |
| Obsessive-compulsive symptoms in a large population-based twin-family sample are predicted by clinically based polygenic scores and by genome-wide SNPs. | den Braber A et al. | — | 2016 | → |
| Parity in Tourette Syndrome: Reproducible Risk Factors for an Underrecognized Neurodevelopmental Disorder. | Scharf JM | — | 2016 | → |
| Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia. | Lee PH et al. | — | 2016 | → |
| Prenatal Maternal Smoking and Increased Risk for Tourette Syndrome and Chronic Tic Disorders. | Browne HA et al. | — | 2016 | → |
| Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease. | Traylor M et al. | — | 2016 | → |
| Survey of the Heritability and Sparse Architecture of Gene Expression Traits across Human Tissues. | Wheeler HE et al. | — | 2016 | → |
| The First World Congress on Tourette Syndrome and Tic Disorders: Controversies and Hot Topics in Etiology and Treatment. | Mathews CA et al. | — | 2016 | → |
| The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review. | Pérez-Vigil A et al. | — | 2016 | → |
| The need for inclusion of sex and age of onset variables in genetic association studies of obsessive-compulsive disorder: Overview. | Mattina GF et al. | — | 2016 | → |
| Top 10 Replicated Findings From Behavioral Genetics. | Plomin R et al. | — | 2016 | → |
| Understanding the covariation of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms: A population-based adult twin study. | Pinto R et al. | — | 2016 | → |
| A gene-based association method for mapping traits using reference transcriptome data. | Gamazon ER et al. | — | 2015 | → |
| A personal 35 year perspective on Gilles de la Tourette syndrome: assessment, investigations, and management. | Robertson MM | — | 2015 | → |
| A personal 35 year perspective on Gilles de la Tourette syndrome: prevalence, phenomenology, comorbidities, and coexistent psychopathologies. | Robertson MM | — | 2015 | → |
| A review of study designs and statistical methods for genomic epidemiology studies using next generation sequencing. | Wang Q et al. | — | 2015 | → |
| Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD. | Yu D et al. | — | 2015 | → |
| Do obsessive-compulsive disorder and Tourette syndrome share a common susceptibility gene? An association study of the BDNF Val66Met polymorphism in the Chinese Han population. | Liu S et al. | — | 2015 | → |
| Evolutionary behavioral genetics. | Zietsch BP et al. | — | 2015 | → |
| GDNF gene is associated with tourette syndrome in a family study. | Huertas-Fernández I et al. | — | 2015 | → |
| Genetic analyses benefit from using less heterogeneous phenotypes: an illustration with the hospital anxiety and depression scale (HADS). | Laurin CA et al. | — | 2015 | → |
| Genetic and environmental contributions to stability in adult obsessive compulsive behavior. | Zilhão NR et al. | — | 2015 | → |
| Genetics and genomics of psychiatric disease. | Geschwind DH et al. | — | 2015 | → |
| Genome-wide association and genome partitioning reveal novel genomic regions underlying variation in gastrointestinal nematode burden in a wild bird. | Wenzel MA et al. | — | 2015 | → |
| Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear. | Xu M et al. | — | 2015 | → |
| Homogeneous case subgroups increase power in genetic association studies. | Traylor M et al. | — | 2015 | → |
| Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis. | de Leeuw C et al. | — | 2015 | → |
| Partitioning heritability by functional annotation using genome-wide association summary statistics. | Finucane HK et al. | — | 2015 | → |
| Premonitory Urges in Patients with Gilles de la Tourette Syndrome: An Italian Translation and a 7-Year Follow-up. | Gulisano M et al. | — | 2015 | → |
| Single Nucleotide Polymorphism Heritability of Behavior Problems in Childhood: Genome-Wide Complex Trait Analysis. | Pappa I et al. | — | 2015 | → |
| Targeting dynamic interplay among disordered domains or endophenotypes to understand complex neuropsychiatric disorders: Translational lessons from preclinical models. | Kalueff AV et al. | — | 2015 | → |
| Tic symptom dimensions and their heritabilities in Tourette's syndrome. | de Haan MJ et al. | — | 2015 | → |
| Web-based phenotyping for Tourette Syndrome: Reliability of common co-morbid diagnoses. | Darrow SM et al. | — | 2015 | → |
| Commentary: Response to commentary by Rutter on Munafo et al. (2014). | Munafò MR et al. | — | 2014 | → |
| Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study. | McGrath LM et al. | — | 2014 | → |
| Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait. | Torres JM et al. | — | 2014 | → |
| Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome. | Rapanelli M et al. | — | 2014 | → |
| Genetic association signal near NTN4 in Tourette syndrome. | Paschou P et al. | — | 2014 | → |
| Genetics of obsessive-compulsive disorder and related disorders. | Browne HA et al. | — | 2014 | → |
| Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. | Baldan LC et al. | — | 2014 | → |
| Large-scale genomics unveils the genetic architecture of psychiatric disorders. | Gratten J et al. | — | 2014 | → |
| Neurobehavioral aspects, pathophysiology, and management of Tourette syndrome. | Shprecher DR et al. | — | 2014 | → |
| Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. | Pauls DL et al. | — | 2014 | → |
| Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. | Gusev A et al. | — | 2014 | → |
| Porcine SLITRK1: Molecular cloning and characterization. | Larsen K et al. | — | 2014 | → |
| Research review: Polygenic methods and their application to psychiatric traits. | Wray NR et al. | — | 2014 | → |
| Structural architecture of SNP effects on complex traits. | Gamazon ER et al. | — | 2014 | → |
| The Inheritance of Tourette Disorder: A review. | Pauls DL et al. | — | 2014 | → |
| The role of atypical antipsychotics for treatment of Tourette's syndrome: an overview. | Budman CL | — | 2014 | → |