Genome-wide association study of Tourette Syndrome

Tourette 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

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

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

Copy number variation in obsessive-compulsive disorder and tourette syndrome: A cross-disorder study

Objective Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. Method The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Results Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p =.09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p =.08 in the current study, p =.025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Conclusion Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. the authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: the authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. in contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.David Judah FundNIHTourette Syndrome Association International Consortium for GeneticsTourette Syndrome AssociationOCD Collaborative Genetics Association StudyAmerican Academy of Child and Adolescent Psychiatry Early Investigator Research GrantAnxiety Disorders Association of America Junior Investigator Research GrantUniversity of British ColumbiaMichael Smith Foundation Clinical Research Scholar AwardAmerican Recovery and Reinvestment Act awardsUCLA Informatics Center for Neurogenetics and NeurogenomicsNew Jersey Center for Tourette Syndrome and Associated DisordersNIMHMedical Research Council of South AfricaNIH Genes, Environment, and Health Initiative [GEI]Gene Environment Association Studies (GENEVA) under GEL AssistanceGENEVA Coordinating CenterCollaborative Study on the Genetics of AlcoholismCollaborative Genetic Study of Nicotine DependenceFamily Study of Cocaine DependenceNIH GEINational Institute on Alcohol Abuse and AlcoholismNational Institute on Drug AbuseNIH contract High Throughput Genotyping for Studying the Genetic Contributions to Human DiseaseEuropean Union, HYPERGENESInterOmicsTourette Syndrome Association (TSA)Astra-ZenecaPsyadonAstraZenecaOtsukaU.S. national Tourette Syndrome AssociationMedtronicSimons FoundationAllison FoundationGerman Research FoundationFederal Ministry of Education, and Research GermanyGrifotsKlingenstein Third Generation FoundationPfizer Pharmaceuticals via the Duke University Clinical Research Instituteburette Syndrome AssociationPettit Family FoundationMedtronic and CyberonicsU.K. Tourette Syndrome AssociationU.S. Tourette Syndrome AssociationCOST/ESSTS (the European Society for the Study of Tourette Syndrome)RocheAMBRFBiocodexCiplaLundbeckNational Responsible Gambling FoundationNovartisServierSynapDxSeaside TherapeuticsForestPherin PharmaceuticalsTranscept PharmaceuticalsDNA GenotekBioMarinHarvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Dept Psychiat,Psychiat & Neur, Boston, MA 02138 USABroad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USAUniv Calif San Francisco, Dept Psychiat, San Francisco, CA USAMassachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USABrigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USAMassachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USAUniv Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USAUniv Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, NetherlandsUniv So Calif, Keck Sch Med, Dept Prevent Med, Div Biostat, Los Angeles, CA 90033 USANIA, Neurogenet Lab, Bethesda, MD 20892 USAFilarete Fdn, Genom & Bioinformat Unit, Milan, ItalyUniv Milan, Dept Hlth Sci, Grad Sch Nephrol, Milan, ItalyUniv Hlth Network, Toronto Western Res Inst, Toronto, ON, CanadaHosp Sick Children, Toronto, ON M5G 1X8, CanadaUniv Vita Salute San Raffaele, Milan, ItalyHadassah Hebrew Univ, Med Ctr, Herman Dana Div Child & Adolescent Psychiat, Jerusalem, IsraelUniv Pontificia Bolivariana, Univ Antioquia, Medellin, ColombiaJohns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USAUniv Iowa, Dept Psychiat, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USAYale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USAYale Univ, Sch Med, Dept Psychiat, New Haven, CT USAUniv São Paulo, Sch Med, Dept Psychiat, São Paulo, BrazilNorth Shore Long Isl Jewish Med Ctr, Manhasset, NY USANorth Shore Long Isl Jewish Hlth Syst, Manhasset, NY USANYU, Med Ctr, New York, NY 10016 USAHofstra Univ, Sch Med, Hempstead, NY 11550 USAInst Nacl Psiquiatria Ramon de la Fuente Muniz, Mexico City, DF, MexicoUCL, London, EnglandUniv Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R ChinaUniv Milan, Osped San Raffaele, I-20127 Milan, ItalyUniv Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USAUniv Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USAMcGill Univ, Montreal Neurol Inst, Montreal, PQ, CanadaUniv Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USAInst Pasteur, Paris, FranceFrench Natl Sci Fdn, Fdn FondaMental, Creteil, FranceHop Robert Debre, AP HP, Dept Child & Adolescent Psychiat, F-75019 Paris, FranceRoyal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Amsterdam, NetherlandsUniv Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, CanadaUniv New S Wales, Sydney, NSW 2052, AustraliaSouth West Sydney Local Hlth Dist AUCS, Acad Unit Child Psychiat, Sydney, NSW, AustraliaUniv Tubingen, Dept Child & Adolescent Psychiat & Psychotherapy, Tubingen, GermanyUniv Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-97070 Wurzburg, GermanyUniv Munich, Dept Psychiat & Psychotherapy, Munich, GermanyHosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa RicaClin Herrera Amighetti, San Jose, Costa RicaHarvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,OCD Program, Boston, MA USACincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USAUniv Cincinnati, Cincinnati, OH USAUniv Med Greffswatd, Hellos Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, GermanyButler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USAShaare Zedek Med Ctr, Neuropediat Unit, Jerusalem, IsraelUniv Zurich, Univ Clin Child Psychiat, Zurich, SwitzerlandUniv Zurich, Univ Clin Adolescent Psychiat, Zurich, SwitzerlandRutgers State Univ, Dept Genet, Human Genet Inst New Jersey, Piscataway, NJ USAUniv Stellenbosch, Dept Psychiat, ZA-7600 Stellenbosch, South AfricaUniv Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, NetherlandsBaylor Coll Med, Dept Neurol, Parkinsons Dis Ctr, Houston, TX 77030 USABaylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USACtr Addict & Mental Hlth, Neurogenet Sect, Toronto, ON, CanadaUniv Toronto, Dept Psychiat, Toronto, ON, CanadaOverlook Hosp, Atlantic Neurosci Inst, Summit, NJ USACarracci Med Grp, Mexico City, DF, MexicoInst Mondor Rech Biomed, Creteil, FranceUniv Bonn, Dept Psychiat & Psychotherapy, Bonn, GermanyUniv Illinois, Dept Psychiat, Inst Human Genet, Chicago, IL 60612 USAUniv Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7600 Stellenbosch, South AfricaUniv Cape Town, ZA-7700 Rondebosch, South AfricaUniv Calif Irvine, Sch Med, Dept Psychiat & Human Behav, Irvine, CA 92717 USAIRCCS San Raffaele Sci Inst, Milan, ItalyFdn IRCCS CaGranda Osped Maggiore Policlin, Ctr Transfus Med & Immunohematol, Milan, ItalyUniv Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USAColumbia Univ, Dept Biol Sci, New York, NY 10027 USAUniv Utah, Salt Lake City, UT USANIMH Intramural Res Program, Clin Sci Lab, Bethesda, MD USAMed City Dallas Hosp, Dept Clin Res, Dallas, TX USAUniv Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, NetherlandsUniv Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA USAYale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USAUniv So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USAPartners Psychiat, Boston, MA USAMcLean Hosp, Boston, MA USASunnybrook Hlth Sci Ctr, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON M4N 3M5, CanadaSt Georges Hosp & Med Sch, London, EnglandUniversidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit, São Paulo, BrazilWayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USADetroit Med Ctr, Detroit, MI USAUniv Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, GermanyStanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USAUniv Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, BrazilYouthdate Treatment Ctr, Toronto, ON, CanadaJohns Hopkins Univ, Sch Med, Baltimore, MD USAVrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, NetherlandsUniv Cape Town, ZA-7925 Cape Town, South AfricaUniv Med Ctr Utrecht, Dept Med Genet, Utrecht, NetherlandsUniv Milan, Dept Hlth Technol, Milan, ItalyVanderbilt Univ, Dept Psychiat, Kennedy Ctr Res Human Dev, Nashville, TN 37235 USAVanderbilt Univ, Dept Pediat, Kennedy Ctr Res Human Dev, Nashville, TN USAVanderbilt Univ, Dept Pharmacol, Kennedy Ctr Res Human Dev, Nashville, TN USAVanderbilt Univ, Inst Brain, Nashville, TN USAUniv Wurzburg, Dept Child & Adolescent Psychiat, D-97070 Wurzburg, GermanyWeill Cornell Med Ctr, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY USAKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, EnglandRoyal Netherlands Acad Arts & Sci, Acad Med Ctr, Dept Psychiat, Amsterdam, NetherlandsNIMH Intramural Res Program, Unit Stat Genom, Bethesda, MD USACarracci Med Grp, Natl Inst Genom Med SAP, Mexico City, DF, MexicoUniv Utrecht, Dept Clin & Hlth Psychol, Utrecht, NetherlandsUniv Utah, Dept Psychiat, Salt Lake City, UT USAVrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, NetherlandsVrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, NetherlandsErasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, NetherlandsErasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, NetherlandsMt Sinai Med Ctr, New York, NY 10029 USAGerman Ctr Neurodegenerat Dis, Tubingen, GermanyUniv Michigan, Dept Psychiat, Ann Arbor, MI 48109 USAHosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, CanadaUniv British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, CanadaUniversidade Federal de São Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit, São Paulo, BrazilNIH: NS40024NIH: NS16648NIH: MH079489NIH: MH073250NIH: NS037484NIH: MH085057NIH: MH079494NIH: MH71507American Recovery and Reinvestment Act awards: NS40024-0751American Recovery and Reinvestment Act awards: NS16648-29S1UCLA Informatics Center for Neurogenetics and Neurogenomics: R01 MH090937UCLA Informatics Center for Neurogenetics and Neurogenomics: P50MH094267UCLA Informatics Center for Neurogenetics and Neurogenomics: P30NS062691NIMH: R01MH092293NIH Genes, Environment, and Health Initiative [GEI]: U01 HG004422GENEVA Coordinating Center: U01 HG004446Collaborative Study on the Genetics of Alcoholism: U10 AA008401Collaborative Genetic Study of Nicotine Dependence: P01 CA089392Family Study of Cocaine Dependence: R01 DA013423NIH GEI: U01HG004438NIH contract High Throughput Genotyping for Studying the Genetic Contributions to Human Disease: HHSN268200782096CEuropean Union, HYPERGENES: FP7-HEALTH-2007-A-201550InterOmics: PB05Web of Scienc

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

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