A genome-wide association study of anorexia nervosa

V Boraska, C Franklin, J Floyd, M Thornton, L Huckins, L Southam, N Rayner, I Tachmazidou, K Klump, J Treasure, C Lewis, U Schmidt, F Tozzi, K Kiezebrink, J Hebebrand, P Gorwood, H Adan, M Kas, A Favaro, P SantonastasoF Fernández-Aranda, M Gratacos, F Rybakowski, M Dmitrzak-Weglarz, J Kaprio, A Keski-Rahkonen, A Raevuori, E Van Furth, Margarita Landt, James Hudson, Ted Reichborn-Kjennerud, Gun Knudsen, Palmiero Monteleone, Allan Kaplan, Adnreas Karwautz, Hakon Hakonarson, Wade Berrettini, Yiran Guo, Dong Li, Nicholas Schork, Gen Komaki, Tetsuya Ando, Hidetoshi Inoko, Tõnu Esko, Krista Fischer, Katrin Mannik, Andres Metspalu, Jessica Baker, Roger Cone, Jennifer Dackor, Janeice DeSocio, Christopher Hilliard, Julie O'Toole, Jaques Pantel, Jin Szatkiewicz, Chrysecollo Taico, Stephanie Zerwas, Sara Trace, Oliver Davis, Sietske Helder, Katharina Buhren, Roland Burghardt, Martina de Zwaan, Karin Egbert, Stefan Ehrlich, Beate Herpetz-Dahlmann, Wolfgang Herzog, Hartmut Imgart, Andre Scherag, Susann Scherag, Stephan Zipfell, Claudette Boni, Nicolas Ramoz, Audrey Versini, Marek Brandys, Unna Danner, Carlien de Koval, Judith Hendricks, Bobby Koeleman, Roel Ophoff, Eric Strengman, Annemarie van Elburg, Alice Bruson, Maurizio Clementi, Daniela Degortes, Monica Forzan, Elena Tenconi, Elisa Docampo, Georgia Escaramis, Susana Jimenez-Murcia, Jolanta Lissowska, Andrzej Rajewski, Neonila Szeszenia-Dabrowska, Agnieszka Slopien, Joanna Hauser, Lelia Karhunen, Ingrid Meulenbelt, Eline Slagboom, Alfonso Tortorella, Mario Maj, George Dedoussis, Dimitris Dikeos, Fragiskos Gonidakis, Konstantinos Tziouvas, Artemis Tsitsika, Hana Papezova, Lenka Slachtova, Debora Martaskova, James Kennedy, Robert Levitan, Zeynep Yilmaz, Julia Heumer, Doris Koubek, Elisabeth Merl, Gudrun Wagner, Paul Lichtenstein, Gerome Breen, Sarah Cohen-Woods, Anne Farmer, Peter McGuffin, Sven Cichon, Ina Giegling, Stefan Herms, Dan Rujescu, Stefan Schreiber, H. Erich Wichmann, Christian Dina, Rob Sladek, Giovanni Gambaro, Nicole Soranzo, Antonio Julia, Sara Marsal, Raquel Rabionet, Valerie Gaborieau, Danielle Dick, Aarno Palotie, Samuli Ripatti, Elisabeth Widen, Ole Andreassen, Thomas Espeseth, Astri Lundervold, Ivar Reinvang, Vidar Steen, Stephanie Le Hellard, Morten Mattingsdal, Ionna Ntalla, Vladimir Bencko, Lenka Faretova, Vladimir Janout, Marie Navratilova, Steven Gallinger, Dalila Pinto, Stephen Scherer, Harald Aschauer, Laura Carlberg, Alexandra Schosser, Lars Alfredsson, Bo Ding, Lars Klareskog, Leonid Padyukov, Chris Finan, Gursharan Kalsi, Marion Roberts, Darren Logan, Leena Peltonen, Graham Ritchie, Jeffrey Barrett, Xavier Estivill, Anke Hinney, Patrick Sullivan, David Collier, Eleftheria Zeggini, Cynthia Bulik

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    163 Citations (Scopus)

    Abstract

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P = 3.01 × 10-7) in SOX2OT and rs17030795 (P = 5.84 × 10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P = 5.76 × 10-6) between CUL3 and FAM124B and rs1886797 (P = 8.05 × 10-6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P = 4 × 10-6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

    Original languageEnglish
    Pages (from-to)1085-1094
    Number of pages10
    JournalMOLECULAR PSYCHIATRY
    Volume19
    Issue number10
    DOIs
    Publication statusPublished - 1 Oct 2014

    Keywords

    • Anorexia nervosa
    • Body mass index
    • Eating disorders
    • Genome-wide association study
    • GWAS
    • Metabolic

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  • Cite this

    Boraska, V., Franklin, C., Floyd, J., Thornton, M., Huckins, L., Southam, L., Rayner, N., Tachmazidou, I., Klump, K., Treasure, J., Lewis, C., Schmidt, U., Tozzi, F., Kiezebrink, K., Hebebrand, J., Gorwood, P., Adan, H., Kas, M., Favaro, A., ... Bulik, C. (2014). A genome-wide association study of anorexia nervosa. MOLECULAR PSYCHIATRY, 19(10), 1085-1094. https://doi.org/10.1038/mp.2013.187