Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Hunna J Watson, Zeynep Yilmaz, Laura M Thornton, Christopher Hübel, Jonathan R I Coleman, Héléna A Gaspar, Julien Bryois, Anke Hinney, Virpi M Leppä, Manuel Mattheisen, Sarah E Medland, Stephan Ripke, Shuyang Yao, Paola Giusti-Rodríguez, Anorexia Nervosa Genetics Initiative, Ken B Hanscombe, Kirstin L Purves, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Roger A H Adan, Lars Alfredsson, Tetsuya Ando, Ole A Andreassen, Jessica H Baker, Wade H Berrettini, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Matteo Cassina, Sven Cichon, Maurizio Clementi, Roger D Cone, Philippe Courtet, Scott Crow, James J Crowley, Unna N Danner, Oliver S P Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E DeSocio, Danielle M Dick, Dimitris Dikeos, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo, Laramie E Duncan, Karin Egberts, Stefan Ehrlich, Geòrgia Escaramís, Tõnu Esko, Xavier Estivill, Anne Farmer, Angela Favaro, Fernando Fernández-Aranda, Manfred M Fichter, Krista Fischer, Manuel Föcker, Lenka Foretova, Andreas J Forstner, Monica Forzan, Christopher S Franklin, Steven Gallinger, Ina Giegling, Johanna Giuranna, Fragiskos Gonidakis, Philip Gorwood, Monica Gratacos Mayora, Sébastien Guillaume, Yiran Guo, Hakon Hakonarson, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Sietske G Helder, Stefan Herms, Beate Herpertz-Dahlmann, Wolfgang Herzog, Laura M Huckins, James I Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Susana Jiménez-Murcia, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J H Kas, James L Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Lars Klareskog, Kelly L Klump, Gun Peggy S Knudsen, Maria C La Via, Stephanie Le Hellard, Robert D Levitan, Dong Li, Lisa Lilenfeld, Bochao Danae Lin, Jolanta Lissowska, Jurjen Luykx, Pierre J Magistretti, Mario Maj, Katrin Mannik, Sara Marsal, Christian R Marshall, Morten Mattingsdal, Sara McDevitt, Peter McGuffin, Andres Metspalu, Ingrid Meulenbelt, Nadia Micali, Karen Mitchell, Alessio Maria Monteleone, Palmiero Monteleone, Melissa A Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K O'Toole, Roel A Ophoff, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Dalila Pinto, Raquel Rabionet, Anu Raevuori, Nicolas Ramoz, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Alessandro Rotondo, Dan Rujescu, Filip Rybakowski, Paolo Santonastaso, André Scherag, Stephen W Scherer, Ulrike Schmidt, Nicholas J Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P Eline Slagboom, Margarita C T Slof-Op 't Landt, Agnieszka Slopien, Sandro Sorbi, Beata Świątkowska, Jin P Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A van Elburg, Eric F van Furth, Gudrun Wagner, Esther Walton, Elisabeth Widen, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Andrew W Bergen, Joseph M Boden, Harry Brandt, Steven Crawford, Katherine A Halmi, L John Horwood, Craig Johnson, Allan S Kaplan, Walter H Kaye, James E Mitchell, Catherine M Olsen, John F Pearson, Nancy L Pedersen, Michael Strober, Thomas Werge, David C Whiteman, D Blake Woodside, Garret D Stuber, Scott Gordon, Jakob Grove, Anjali K Henders, Anders Juréus, Katherine M Kirk, Janne T Larsen, Richard Parker, Liselotte Petersen, Jennifer Jordan, Martin Kennedy, Grant W Montgomery, Tracey D Wade, Andreas Birgegård, Paul Lichtenstein, Claes Norring, Mikael Landén, Nicholas G Martin, Preben Bo Mortensen, Patrick F Sullivan, Gerome Breen, Cynthia M Bulik, Hunna J Watson, Zeynep Yilmaz, Laura M Thornton, Christopher Hübel, Jonathan R I Coleman, Héléna A Gaspar, Julien Bryois, Anke Hinney, Virpi M Leppä, Manuel Mattheisen, Sarah E Medland, Stephan Ripke, Shuyang Yao, Paola Giusti-Rodríguez, Anorexia Nervosa Genetics Initiative, Ken B Hanscombe, Kirstin L Purves, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Roger A H Adan, Lars Alfredsson, Tetsuya Ando, Ole A Andreassen, Jessica H Baker, Wade H Berrettini, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Matteo Cassina, Sven Cichon, Maurizio Clementi, Roger D Cone, Philippe Courtet, Scott Crow, James J Crowley, Unna N Danner, Oliver S P Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E DeSocio, Danielle M Dick, Dimitris Dikeos, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo, Laramie E Duncan, Karin Egberts, Stefan Ehrlich, Geòrgia Escaramís, Tõnu Esko, Xavier Estivill, Anne Farmer, Angela Favaro, Fernando Fernández-Aranda, Manfred M Fichter, Krista Fischer, Manuel Föcker, Lenka Foretova, Andreas J Forstner, Monica Forzan, Christopher S Franklin, Steven Gallinger, Ina Giegling, Johanna Giuranna, Fragiskos Gonidakis, Philip Gorwood, Monica Gratacos Mayora, Sébastien Guillaume, Yiran Guo, Hakon Hakonarson, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Sietske G Helder, Stefan Herms, Beate Herpertz-Dahlmann, Wolfgang Herzog, Laura M Huckins, James I Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Susana Jiménez-Murcia, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J H Kas, James L Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Lars Klareskog, Kelly L Klump, Gun Peggy S Knudsen, Maria C La Via, Stephanie Le Hellard, Robert D Levitan, Dong Li, Lisa Lilenfeld, Bochao Danae Lin, Jolanta Lissowska, Jurjen Luykx, Pierre J Magistretti, Mario Maj, Katrin Mannik, Sara Marsal, Christian R Marshall, Morten Mattingsdal, Sara McDevitt, Peter McGuffin, Andres Metspalu, Ingrid Meulenbelt, Nadia Micali, Karen Mitchell, Alessio Maria Monteleone, Palmiero Monteleone, Melissa A Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K O'Toole, Roel A Ophoff, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Dalila Pinto, Raquel Rabionet, Anu Raevuori, Nicolas Ramoz, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Alessandro Rotondo, Dan Rujescu, Filip Rybakowski, Paolo Santonastaso, André Scherag, Stephen W Scherer, Ulrike Schmidt, Nicholas J Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P Eline Slagboom, Margarita C T Slof-Op 't Landt, Agnieszka Slopien, Sandro Sorbi, Beata Świątkowska, Jin P Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A van Elburg, Eric F van Furth, Gudrun Wagner, Esther Walton, Elisabeth Widen, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Andrew W Bergen, Joseph M Boden, Harry Brandt, Steven Crawford, Katherine A Halmi, L John Horwood, Craig Johnson, Allan S Kaplan, Walter H Kaye, James E Mitchell, Catherine M Olsen, John F Pearson, Nancy L Pedersen, Michael Strober, Thomas Werge, David C Whiteman, D Blake Woodside, Garret D Stuber, Scott Gordon, Jakob Grove, Anjali K Henders, Anders Juréus, Katherine M Kirk, Janne T Larsen, Richard Parker, Liselotte Petersen, Jennifer Jordan, Martin Kennedy, Grant W Montgomery, Tracey D Wade, Andreas Birgegård, Paul Lichtenstein, Claes Norring, Mikael Landén, Nicholas G Martin, Preben Bo Mortensen, Patrick F Sullivan, Gerome Breen, Cynthia M Bulik

Abstract

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Conflict of interest statement

Competing interests

The authors report the following potential competing interests. O.A.A. received a speaker’s honorarium from Lundbeck. G.B. received grant funding and consultancy fees in preclinical genetics from Eli Lilly, consultancy fees from Otsuka and has received honoraria from Illumina. C.M.B. is a grant recipient from Shire Pharmaceuticals and served on Shire Scientific Advisory Board; she receives author royalties from Pearson. D.D. served as a speaker and on advisory boards, and has received consultancy fees for participation in research from various pharmaceutical industry companies including: AstraZeneca, Boehringer, Bristol Myers Squibb, Eli Lilly, Genesis Pharma, GlaxoSmithKline, Janssen, Lundbeck, Organon, Sanofi, UniPharma, and Wyeth; he has received unrestricted grants from Lilly and AstraZeneca as director of the Sleep Research Unit of Eginition Hospital (National and Kapodistrian University of Athens, Greece). J.I.H. has received grant support from Shire and Sunovion, and has received consulting fees from DiaMentis, Shire, and Sunovion. A.S.K. is a member of the Shire Canadian BED Advisory Board and is on the steering committee for the Shire B/educated Educational Symposium: June 15-16, 2018. J.L.K. served as an unpaid member of the scientific advisory board of AssurexHealth Inc. M.L. declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as scientific consultant for EPID Research Oy. No other equity ownership, profit-sharing agreements, royalties, or patent. P.F.S. is on the Lundbeck advisory committee and is a Lundbeck grant recipient; he has served on the scientific advisory board for Pfizer, has received a consultation fee from Element Genomics, and a speaker reimbursement fee from Roche. J.T. has received an honorarium for participation in an EAP meeting and has received royalties from several books from Routledge, Wiley, and Oxford University press. T.W. has acted as a lecturer and scientific advisor to H. Lundbeck A/S. All other authors have no conflicts of interest to disclose.

Figures

Figure 1.. The Manhattan plot for the…
Figure 1.. The Manhattan plot for the primary genome-wide association meta-analysis of anorexia nervosa with 33 case-control samples (16,992 cases and 55,525 controls of European descent).
The −log10(P) values for the association tests (two-tailed) are shown on the y-axis and the chromosomes are ordered on the x-axis. Eight genetic loci surpassed genome-wide significance (−log10(P) > 7.3). The lead variant is indicated by a diamond and green circles show the variants in linkage-disequilibrium. The blue and red colors differentiate adjacent chromosomes.
Figure. 2.. Bonferroni-significant genetic correlations (SNP- r…
Figure. 2.. Bonferroni-significant genetic correlations (SNP-rgs) and standard errors (error bars) between anorexia nervosa and other phenotypes as estimated by LD score regression.
Only traits with significant P values following Bonferroni correction are shown. Correlations with 447 phenotypes were tested (Bonferroni-corrected significance threshold P > 1.11 × 10−4). Complete results are shown in Table S10. PGC = Psychiatric Genomics Consortium, UKB = UK Biobank, HOMA-IR = Homeostatic model assessment - insulin resistance.

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