Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

Laramie Duncan, Zeynep Yilmaz, Helena Gaspar, Raymond Walters, Jackie Goldstein, Verneri Anttila, Brendan Bulik-Sullivan, Stephan Ripke, Laura Thornton, Anke Hinney, Mark Daly, Patrick F. Sullivan, Eleftheria Zeggini, Gerome Breen, Cynthia M. Bulik, Héléna Gaspar, Roger Adan, Lars Alfredsson, Tetsuya Ando, Ole AndreassenHarald Aschauer, Jessica Baker, Jeffrey Barrett, Vladimir Bencko, Andrew Bergen, Wade Berrettini, Andreas Birgegård, Claudette Boni, Vesna Boraska Perica, Harry Brandt, Roland Burghardt, 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, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece DeSocio, Dick N. Danielle, Dimitris Dikeos, Christian Dina, Bo Ding, Monika Dmitrzak-Weglarz, Elisa Docampo, Karin Egberts, Stefan Ehrlich, Geòrgia Escaramís, Tõnu Esko, Thomas Espeseth, Xavier Estivill, Angela Favaro, Fernando Fernández-Aranda, Manfred Fichter, Chris Finan, Krista Fischer, James Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Caroline Fox, Christopher Franklin, Valerie Gaborieau, Steven Gallinger, Giovanni Gambaro, Ina Giegling, Fragiskos Gonidakis, Philip Gorwood, Monica Gratacos, Sébastien Guillaume, Yiran Guo, Hakon Hakonarson, Katherine Halmi, Rebecca Harrison, Konstantinos Hatzikotoulas, Joanna 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, Stephane Jamain, Vladimir Janout, Susana Jiménez-Murcia, Craig Johnson, Jenny Jordan, Antonio Julià, Anders Juréus, Gursharan Kalsi, Allan Kaplan, Jaakko Kaprio, 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 Landén, Stephanie Le Hellard, Marion Leboyer, Robert Levitan, Dong Li, Paul Lichtenstein, Lisa Lilenfeld, Jolanta Lissowska, Astri Lundervold, Pierre Magistretti, Mario Maj, Katrin Mannik, Sara Marsal, Debora Kaminska, Nicholas Martin, Morten Mattingsdal, Sara McDevitt, Peter McGuffin, Elisabeth Merl, Andres Metspalu, Ingrid Meulenbelt, Nadia Micali, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Grant Montgomery, Preben Mortensen, Melissa Munn-Chernoff, Timo Müller, 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, André Scherag, Stephen Scherer, Ulrike Schmidt, Nicholas Schork, Alexandra Schosser, Laura Scott, Jochen Seitz, Lenka Slachtova, Robert Sladek, P. Eline Slagboom, Margarita Slof-Op ’t Landt, Agnieszka Slopien, Tosha Smith, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar Steen, Eric Strengman, Michael Strober, Jin Szatkiewicz, Neonila Szeszenia-Dabrowska, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Matthias Tschöp, Artemis Tsitsika, Konstantinos Tziouvas, Annemarie van Elburg, Eric van Furth, Tracey Wade, Gudrun Wagner, Esther Walton, Hunna Watson, H. Erich Wichmann, Elisabeth Widen, Blake Woodside, Jack Yanovski, Shuyang Yao, Stephanie Zerwas, Stephan Zipfel

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Abstract

Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method: Following uniformquality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3, 495 anorexia nervosa cases and 10, 982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2 SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. Results: Results were obtained for 10, 641, 224 SNPs and insertion-deletion variants with minor allele frequencies.>1% and imputation quality scores >0.6. The h2 SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genomewide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.
Original languageEnglish
Pages (from-to)850-858
Number of pages9
JournalAmerican Journal of Psychiatry
Volume174
Issue number9
Early online date12 May 2017
DOIs
Publication statusPublished - 1 Sep 2017

Cite this

Duncan, L., Yilmaz, Z., Gaspar, H., Walters, R., Goldstein, J., Anttila, V., Bulik-Sullivan, B., Ripke, S., Thornton, L., Hinney, A., Daly, M., Sullivan, P. F., Zeggini, E., Breen, G., Bulik, C. M., Gaspar, H., Adan, R., Alfredsson, L., Ando, T., ... Zipfel, S. (2017). Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. American Journal of Psychiatry, 174(9), 850-858. https://doi.org/10.1176/appi.ajp.2017.16121402