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
Journal: American Journal of Psychiatry (2014)

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.