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Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

By Laramie Duncan, Zeynep Yilmaz, Raymond Walters, Jackie Goldstein, Verneri Anttila, Brendan Bulik-Sullivan, Stephan Ripke, Roger Adan, Lars Alfredsson, Tetsuya Ando, Ole Andreassen, Harald Aschauer, Jessica Baker, Jeffrey Barrett, Vladimir Bencko, Andrew Bergen, Wade Berrettini, Andreas Birgegard, Claudette Boni, Vesna Boraska Perica, Harry Brandt, Roland Bughardt, Laura Carlberg, Matteo Cassina, Carolyn Cesta, Sven Cichon, Maurizio Clementi, Sarah Cohen-Woods, Joni Coleman, Roger Cone, Philippe Courtet, Steven Crawford, Scott Crow, Jim Crowley, Unna Danner, Oliver Davis, Martia de Zaan, George Dedoussis, Daniela Degortes, Janiece DeSocio, Danielle Dick, Dimitris Dikeos, Christian Dina, Bo Ding, Monika Dmitrzak-Weglarz, Elisa Docampo, Karin Egberts, Stefan Ehrlich, Georgia Escaramis, Tonu Esko, Thomas Espeseth, Xavier Estivill, Angela Favaro, Fernando Fernandez-Aranda, Manfred Fichter, Chris Finan, Krista Fischer, James Floyd, Manuel Focker, Lenka Foretova, Monica Forzan, Caroline Fox, Christopher Franklin, Valerie Bagorieau, Steven Gallinger, Giovanni Gambaro, Helena Gaspar, Ina Giegling, Fragiskos Gonidakis, Philip Gorwood, Monica Gratacos, Sebastien Guillaume, Yiran Guo, Hakon Hakonarson, Katherine Halmi, Rebecca Harrison, Konstantinos Hatzikotoulas, Hoanna Hauser, Johannes Hebebrand, Sietske Helder, Judith Hendriks, Stefan Herms, Beate Herpertz-Dahlmann, Wolfgang Herzog, Christopher Hilliard, Laura Huckins, James Hudson, Julia Huemer, Hartmut Imgart, Hidetoshi Inoko, Sigrid Jall, Vladimir Janout, Susana Jimenez-Murcia, Jenny Jordan, Antonio Julia, Anders Jureus, Gursharan Kalsi, Allan Kaplan, Leila Karhunen, Andreas Karwautz, Martien Kas, Walter Kaye, Martin Kennedy, James Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Lars Klareskog, Kelly Klump, Gun Peggy Knudsen, Bobby Koeleman, Doris Koubek, Maria La Via, Mikael Landen, Stephanie Le Hellard, Robert Levitan, Dong Li, Paul Lichtenstein, Lisa Lilenfeld, Jolanta Lissowska, Astri Lundervold, Pierre Magistretti, Mario Maj, Katrin Mannik, Debora Kaminska, Nicholas Martin, Morten Mattingsdal, 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, Timo Muller, Benedetta Nacmias, Marie Navratilova, Ida Nilsson, Claes Norring, Ioanna Ntalla, Roel Ophoff, Julie O'Toole, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, Dalila Pinto, Raquel Rabionet, Anu Raevuori, Andrzej Rajewski, Nicolas Ramoz, N William Rayner, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Alessandro Rotondo, Dan Rujescu, Filip Rybakowski, Paolo Santonastaso, Andre Scherag, Stephen Scherer, Ulrike Schmidt, Nicholas Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, Robert Sladek, P. Eline Slagboom, Margarita Slof-Op 't Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar Steen, Michael Strober, Jin Szatkiewicz, Neonila Szeszenia-Dabrowska, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Matthias Tschop, Artemis Tsitsika, Konstantinos Tziouvas, Annemarie van Elburg, Eric van Furth, Tracey Wade, Gudrun Wagner, Esther Walton, Hunna Watson, H-Erich Wichmann, Elisabeth Widen, D. Blake Woodside, Jack Yanovski, Shuyang Yao, Stephanie Zerwas, Stephan Zipfel, Laura Thornton, Anke Hinney, Mark Daly, Patrick Sullivan, Eleftheria Zeggini, Gerome Breen, Cynthia Bulik

Posted 25 Nov 2016
bioRxiv DOI: 10.1101/088815

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females(1,2), and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality(2). Twin studies support a genetic basis for the observed aggregation of AN in families(3), with heritability estimates of 48%-74%(4). Although initial genome-wide association studies (GWASs) were underpowered(5,6), evidence suggested that signals for AN would be detected with increased power(5). We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability (h_SNP^2) of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

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