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

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

Am J Psychiatry 2015 Jan 31;172(1):82-93. Epub 2014 Oct 31.

From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women's Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Lo

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.

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Source
http://dx.doi.org/10.1176/appi.ajp.2014.13101306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282594PMC
January 2015
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