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

ABSTRACT: 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=2×10(-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 Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

SUBMITTER: Yu D

PROVIDER: S-EPMC4282594 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Yu Dongmei D Mathews Carol A CA Scharf Jeremiah M JM Neale Benjamin M BM Davis Lea K LK Gamazon Eric R ER Derks Eske M EM Evans Patrick P Edlund Christopher K CK Crane Jacquelyn J Fagerness Jesen A JA Osiecki Lisa L Gallagher Patience P Gerber Gloria G Haddad Stephen S Illmann Cornelia C McGrath Lauren M LM Mayerfeld Catherine C Arepalli Sampath S Barlassina Cristina C Barr Cathy L CL Bellodi Laura L Benarroch Fortu F Berrió Gabriel Bedoya GB Bienvenu O Joseph OJ Black Donald W DW Bloch Michael H MH Brentani Helena H Bruun Ruth D RD Budman Cathy L CL Camarena Beatriz B Campbell Desmond D DD Cappi Carolina C Silgado Julio C Cardona JC Cavallini Maria C MC Chavira Denise A DA Chouinard Sylvain S Cook Edwin H EH Cookson M R MR Coric Vladimir V Cullen Bernadette B Cusi Daniele D Delorme Richard R Denys Damiaan D Dion Yves Y Eapen Valsama V Egberts Karin K Falkai Peter P Fernandez Thomas T Fournier Eduardo E Garrido Helena H Geller Daniel D Gilbert Donald L DL Girard Simon L SL Grabe Hans J HJ Grados Marco A MA Greenberg Benjamin D BD Gross-Tsur Varda V Grünblatt Edna E Hardy John J Heiman Gary A GA Hemmings Sian M J SM Herrera Luis D LD Hezel Dianne M DM Hoekstra Pieter J PJ Jankovic Joseph J Kennedy James L JL King Robert A RA Konkashbaev Anuar I AI Kremeyer Barbara B Kurlan Roger R Lanzagorta Nuria N Leboyer Marion M Leckman James F JF Lennertz Leonhard L Liu Chunyu C Lochner Christine C Lowe Thomas L TL Lupoli Sara S Macciardi Fabio F Maier Wolfgang W Manunta Paolo P Marconi Maurizio M McCracken James T JT Mesa Restrepo Sandra C SC Moessner Rainald R Moorjani Priya P Morgan Jubel J Muller Heike H Murphy Dennis L DL Naarden Allan L AL Nurmi Erika E Ochoa William Cornejo WC Ophoff Roel A RA Pakstis Andrew J AJ Pato Michele T MT Pato Carlos N CN Piacentini John J Pittenger Christopher C Pollak Yehuda Y Rauch Scott L SL Renner Tobias T Reus Victor I VI Richter Margaret A MA Riddle Mark A MA Robertson Mary M MM Romero Roxana R Rosário Maria C MC Rosenberg David D Ruhrmann Stephan S Sabatti Chiara C Salvi Erika E Sampaio Aline S AS Samuels Jack J Sandor Paul P Service Susan K SK Sheppard Brooke B Singer Harvey S HS Smit Jan H JH Stein Dan J DJ Strengman Eric E Tischfield Jay A JA Turiel Maurizio M Valencia Duarte Ana V AV Vallada Homero H Veenstra-VanderWeele Jeremy J Walitza Susanne S Wang Ying Y Weale Mike M Weiss Robert R Wendland Jens R JR Westenberg Herman G M HG Shugart Yin Yao YY Hounie Ana G AG Miguel Euripedes C EC Nicolini Humberto H Wagner Michael M Ruiz-Linares Andres A Cath Danielle C DC McMahon William W Posthuma Danielle D Oostra Ben A BA Nestadt Gerald G Rouleau Guy A GA Purcell Shaun S Jenike Michael A MA Heutink Peter P Hanna Gregory L GL Conti David V DV Arnold Paul D PD Freimer Nelson B NB Stewart S Evelyn SE Knowles James A JA Cox Nancy J NJ Pauls David L DL

The American journal of psychiatry 20141031 1

<h4>Objective</h4>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.<h4>Method</h4>The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome ...[more]

PMID: 25158072

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Project description:Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics that can be considered motor responses to preceding inner urges. It has been shown that Tourette patients have inferior performance in some motor learning tasks and reduced synaptic plasticity induced by transcranial magnetic stimulation. However, it has not been investigated whether altered synaptic plasticity is directly linked to impaired motor skill acquisition in Tourette patients. In this study, cortical plasticity was assessed by measuring motor-evoked potentials before and after paired associative stimulation in 14 Tourette patients (13 male; age 18-39) and 15 healthy controls (12 male; age 18-33). Tic and urge severity were assessed using the Yale Global Tic Severity Scale and the Premonitory Urges for Tics Scale. Motor learning was assessed 45 minutes after inducing synaptic plasticity and 9 months later, using the rotary pursuit task. On average, long-term potentiation-like effects in response to the paired associative stimulation were present in healthy controls but not in patients. In Tourette patients, long-term potentiation-like effects were associated with more and long-term depression-like effects with less severe urges and tics. While motor learning did not differ between patients and healthy controls 45 minutes after inducing synaptic plasticity, the learning curve of the healthy controls started at a significantly higher level than the Tourette patients' 9 months later. Induced synaptic plasticity correlated positively with motor skills in healthy controls 9 months later. The present study confirms previously found long-term improvement in motor performance after paired associative stimulation in healthy controls but not in Tourette patients. Tourette patients did not show long-term potentiation in response to PAS and also showed reduced levels of motor skill consolidation after 9 months compared to healthy controls. Moreover, synaptic plasticity appears to be related to symptom severity.

Project description:The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was first implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 were subsequently reported in autism, schizophrenia and other psychiatric or neurological disorders. We aimed to comprehensively examine evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders, by the analysis of multiple classes of genetic variation in large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS for seven psychiatric disorders; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; and iv) conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated; nor did predicted functional SNPs yield significant results in meta-analysis across psychiatric disorders at either SNP-level or gene-level. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. Finally, in a CNV mircroarray study of an extended bipolar disorder family with 5 affected relatives we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site. Quantitative-PCR validation and segregation analysis of this CNV revealed imperfect segregation with BD. This large comprehensive study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.

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

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

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