Examination of the shared genetic basis of anorexia nervosa and obsessive–compulsive disorder

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Abstract

Anorexia nervosa (AN) and obsessive–compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a cross-disorder GWAS meta-analysis of 3495 AN cases, 2688 OCD cases, and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg = 0.49 ± 0.13, p= 9.07 × 10−7) and a sizable SNP heritability (SNP h2 = 0.21 ± 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., rg = 0.36 with bipolar disorder and 0.34 with neuroticism) and negative genetic correlations with metabolic phenotypes (e.g., rg = −0.25 with body mass index and −0.20 with triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN–OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.

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Acknowledgements

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara.

Funding

Dr. Yilmaz is supported by NIH grant K01MH109782. Drs. Crowley and Mattheisen were supported by NIH grants R01MH105500 and R01MH110427. Dr. Bulik acknowledges funding from the Swedish Research Council (VR Dnr: 538-2013-8864). The OCD Collaborative Genetics Association Study (OCGAS) is a collaborative research study and was funded by the following NIMH Grant Numbers: MH071507 (GN), MH079489 (DAG), MH079487 (JM), MH079488 (AF) and MH079494 (JK). Dr. Kas was supported by a ZonMW VIDI Grant (91786327) from The Netherlands Organization for Scientific Research (NWO). Dr. Bryois is supported by the Swiss National Science Foundation.

Eating Disorders Working Group of the PGC

Roger Adan, Tetsuya Ando, Jessica Baker, Andrew Bergen, Wade Berrettini, Andreas Birgegård, Claudette Boni, Vesna Boraska Perica, Harry Brandt, Roland Burghardt, Matteo Cassina, Carolyn Cesta, Maurizio Clementi, Jonathan Coleman, Roger Cone, Philippe Courtet, Steven Crawford, Scott Crow, James Crowley, Unna Danner, Oliver Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece DeSocio, Danielle Dick, Dimitris Dikeos, Monika Dmitrzak-Weglarz, Elisa Docampo, Karin Egberts, Stefan Ehrlich, Geòrgia Escaramís, Tõnu Esko, Xavier Estivill, Angela Favaro, Fernando Fernández-Aranda, Manfred Fichter, Chris Finan, Krista Fischer, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher Franklin, Héléna Gaspar, Fragiskos Gonidakis, Philip Gorwood, Monica Gratacos, Sébastien Guillaume, Yiran Guo, Hakon Hakonarson, Katherine Halmi, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Sietske Helder, Judith Hendriks, Beate Herpertz-Dahlmann, Wolfgang Herzog, Christopher Hilliard, Anke Hinney, Laura Huckins, James Hudson, Julia Huemer, Hartmut Imgart, Hidetoshi Inoko, Susana Jiménez-Murcia, Craig Johnson, Jenny Jordan, Anders Juréus, Gursharan Kalsi, Debora Kaminska, Allan Kaplan, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien Kas, Walter Kaye, James Kennedy, Martin Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Kelly Klump, Gun Peggy Knudsen, Bobby Koeleman, Doris Koubek, Maria La Via, Mikael Landén, Robert Levitan, Dong Li, Paul Lichtenstein, Lisa Lilenfeld, Jolanta Lissowska, Pierre Magistretti, Mario Maj, Katrin Mannik, Nicholas Martin, Sara McDevitt, Peter McGuffin, Elisabeth Merl, Andres Metspalu, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Grant Montgomery, Preben Mortensen, Melissa Munn-Chernoff, Benedetta Nacmias, Ida Nilsson, Claes Norring, Ioanna Ntalla, Julie O’Toole, Jacques Pantel, Hana Papezova, Richard Parker, Raquel Rabionet, Anu Raevuori, Andrzej Rajewski, Nicolas Ramoz, N. William Rayner, Ted Reichborn-Kjennerud, Valdo Ricca, Stephan Ripke, Franziska Ritschel, Marion Roberts, Alessandro Rotondo, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita Slof-Op’t Landt, Agnieszka Slopien, Tosha Smith, Sandro Sorbi, Eric Strengman, Michael Strober, Patrick Sullivan, Jin Szatkiewicz, Neonila Szeszenia-Dabrowska, Ioanna Tachmazidou, Elena Tenconi, Laura Thornton, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Artemis Tsitsika, Konstantinos Tziouvas, Annemarie van Elburg, Eric van Furth, Tracey Wade, Gudrun Wagner, Esther Walton, Hunna Watson, D. Blake Woodside, Shuyang Yao, Zeynep Yilmaz, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Lars Alfredsson, Ole Andreassen, Harald Aschauer, Jeffrey Barrett, Vladimir Bencko, Laura Carlberg, Sven Cichon, Sarah Cohen-Woods, Christian Dina, Bo Ding, Thomas Espeseth, James Floyd, Steven Gallinger, Giovanni Gambaro, Ina Giegling, Stefan Herms, Vladimir Janout, Antonio Julià, Lars Klareskog, Stephanie Le Hellard, Marion Leboyer, Astri Lundervold, Sara Marsal, Morten Mattingsdal, Marie Navratilova, Roel Ophoff, Aarno Palotie, Dalila Pinto, Samuli Ripatti, Dan Rujescu, Stephen Scherer, Laura Scott, Robert Sladek, Nicole Soranzo, Lorraine Southam, Vidar Steen, H-Erich Wichmann, Elisabeth Widen, Gerome Breen, and Cynthia Bulik.

Tourette Syndrome/Obsessive Compulsive Disorder Working Group of the PGC

Paul D. Arnold, Kathleen D. Askland, Cristina Barlassina, Laura Bellodi, O.J. Bienvenu, Donald Black, Michael Bloch, Helena Brentani, Christie L. Burton, Beatriz Camarena, Carolina Cappi, Danielle Cath, Maria Cavallini, David Conti, Edwin Cook, Vladimir Coric, Bernadette A. Cullen, Danielle Cusi, Lea K. Davis, Richard Delorme, Damiaan Denys, Eske Derks, Valsamma Eapen, Christopher Edlund, Lauren Erdman, Peter Falkai, Martijn Figee, Abigail J. Fyer, Daniel A. Geller, Fernando S. Goes, Hans Grabe, Marcos A. Grados, Benjamin D. Greenberg, Edna Grünblatt, Wei Guo, Gregory L. Hanna, Sian Hemmings, Ana G. Hounie, Michael Jenicke, Clare Keenan, James Kennedy, Ekaterina A. Khramtsova, Anuar Konkashbaev, James A. Knowles, Janice Krasnow, Cristophe Lange, Nuria Lanzagorta, Marion Leboyer, Leonhard Lennertz, Bingbin Li, K.-Y. Liang, Christine Lochner, Fabio Macciardi, Brion Maher, Wolfgang Maier, Maurizio Marconi, Carol A. Mathews, Manuel Matthesien, James T. McCracken, Nicole C. McLaughlin, Euripedes C. Miguel, Rainald Moessner, Dennis L. Murphy, Benjamin Neale, Gerald Nestadt, Paul Nestadt, Humberto Nicolini, Ericka Nurmi, Lisa Osiecki, David L. Pauls, John Piacentini, Danielle Posthuma, Ann E. Pulver, H.-D. Qin, Steven A. Rasmussen, Scott Rauch, Margaret A. Richter, Mark A. Riddle, Stephan Ripke, Stephan Ruhrmann, Aline S. Sampaio, Jack F. Samuels, Jeremiah M. Scharf, Yin Yao Shugart, Jan Smit, Barbara Stranger, Daniel Stein, S. Evelyn Stewart, Maurizio Turiel, Homero Vallada, Jeremy Veenstra-VanderWeele, Michael Wagner, Susanne Walitza, Y. Wang, Jens Wendland, Nienke Vulink, Dongmei Yu, and Gwyneth Zai.

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Correspondence to James J. Crowley.

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Members of the “Eating Disorders Working Group of the Psychiatric Genomics Consortium” and “Tourette Syndrome/Obsessive–Compulsive Disorder Working Group of the Psychiatric Genomics Consortium” are listed below Acknowledgements.

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