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

Watson, H. J.; Yilmaz, Z.; Thornton, L. M.; Hubel, C.; Coleman, J. R. I.; Gaspar, H. A.; Bryois, J.; Hinney, A.; Leppa, V. M.; Mattheisen, M.; Medland, S. E.; Ripke, S.; Yao, S.; Giusti-Rodriguez, P.; Hanscombe, K. B.; Purves, K. L.; Adan, R. A. H.; Alfredsson, L.; Ando, T.; Andreassen, O. A.; Baker, J. H.; Berrettini, W. H.; Boehm, I.; Boni, C.; Perica, V. B.; Buehren, K.; Burghardt, R.; Cassina, M.; Cichon, S.; Clementi, M.; Cone, R. D.; Courtet, P.; Crow, S.; Crowley, J. J.; Danner, U. N.; Davis, O. S. P.; de Zwaan, M.; Dedoussis, G.; Degortes, D.; Desocio, J. E.; Dick, D. M.; Dikeos, D.; Dina, C.; Dmitrzak-Weglarz, M.; Docampo, E.; Duncan, L. E.; Egberts, K.; Ehrlich, S.; Escaramis, G.; Esko, T.; Estivill, X.; Farmer, A.; Favaro, A.; Fernandez-Aranda, F.; Fichter, M. M.; Fischer, K.; Focker, M.; Foretova, L.; Forstner, A. J.; Forzan, M.; Franklin, C. S.; Gallinger, S.; Giegling, I.; Giuranna, J.; Gonidakis, F.; Gorwood, P.; Mayora, M. G.; Guillaume, S.; Guo, Y.; Hakonarson, H.; Hatzikotoulas, K.; Hauser, J.; Hebebrand, J.; Helder, S. G.; Herms, S.; Herpertz-Dahlmann, B.; Herzog, W.; Huckins, L. M.; Hudson, J. I.; Imgart, H.; Inoko, H.; Janout, V.; Jimenez-Murcia, S.; Julia, A.; Kalsi, G.; Kaminska, D.; Kaprio, J.; Karhunen, L.; Karwautz, A.; Kas, M. J. H.; Kennedy, J. L.; Keski-Rahkonen, A.; Kiezebrink, K.; Kim, Y. -R.; Klareskog, L.; Klump, K. L.; Knudsen, G. P. S.; La Via, M. C.; Le Hellard, S.; Levitan, R. D.; Li, D.; Lilenfeld, L.; Lin, B. D.; Lissowska, J.; Luykx, J.; Magistretti, P. J.; Maj, M.; Mannik, K.; Marsal, S.; Marshall, C. R.; Mattingsdal, M.; Mcdevitt, S.; Mcguffin, P.; Metspalu, A.; Meulenbelt, I.; Micali, N.; Mitchell, K.; Monteleone, A. M.; Monteleone, P.; Munn-Chernoff, M. A.; Nacmias, B.; Navratilova, M.; Ntalla, I.; O'Toole, J. K.; Ophoff, R. A.; Padyukov, L.; Palotie, A.; Pantel, J.; Papezova, H.; Pinto, D.; Rabionet, R.; Raevuori, A.; Ramoz, N.; Reichborn-Kjennerud, T.; Ricca, V.; Ripatti, S.; Ritschel, F.; Roberts, M.; Rotondo, A.; Rujescu, D.; Rybakowski, F.; Santonastaso, P.; Scherag, A.; Scherer, S. W.; Schmidt, U.; Schork, N. J.; Schosser, A.; Seitz, J.; Slachtova, L.; Slagboom, P. E.; Slof-Op 't Landt, M. C. T.; Slopien, A.; Sorbi, S.; Swiatkowska, B.; Szatkiewicz, J. P.; Tachmazidou, I.; Tenconi, E.; Tortorella, A.; Tozzi, F.; Treasure, J.; Tsitsika, A.; Tyszkiewicz-Nwafor, M.; Tziouvas, K.; van Elburg, A. A.; van Furth, E. F.; Wagner, G.; Walton, E.; Widen, E.; Zeggini, E.; Zerwas, S.; Zipfel, S.; Bergen, A. W.; Boden, J. M.; Brandt, H.; Crawford, S.; Halmi, K. A.; Horwood, L. J.; Johnson, C.; Kaplan, A. S.; Kaye, W. H.; Mitchell, J. E.; Olsen, C. M.; Pearson, J. F.; Pedersen, N. L.; Strober, M.; Werge, T.; Whiteman, D. C.; Woodside, D. B.; Stuber, G. D.; Gordon, S.; Grove, J.; Henders, A. K.; Jureus, A.; Kirk, K. M.; Larsen, J. T.; Parker, R.; Petersen, L.; Jordan, J.; Kennedy, M.; Montgomery, G. W.; Wade, T. D.; Birgegard, A.; Lichtenstein, P.; Norring, C.; Landen, M.; Martin, N. G.; Mortensen, P. B.; Sullivan, P. F.; Breen, G.; Bulik, C. M.

doi:10.1038/s41588-019-0439-2

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.