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

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1 , affecting 0.9–4% of women and 0.3% of men 2 – 4 , with twin-based heritability estimates of 50–60% 5 . Mortality rates are higher than those in other psychiatric disorders 6 , and outcomes are una...

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Published in	Nature genetics Vol. 51; no. 8; pp. 1207 - 1214
Main Authors	Hübel, Christopher, Bryois, Julien, Hinney, Anke, Leppä, Virpi M., Mattheisen, Manuel, Medland, Sarah E., Giusti-Rodríguez, Paola, Alfredsson, Lars, Berrettini, Wade H., Boni, Claudette, Burghardt, Roland, Cichon, Sven, Cone, Roger D., Courtet, Philippe, Crowley, James J., Davis, Oliver S. P., de Zwaan, Martina, Dikeos, Dimitris, Dina, Christian, Duncan, Laramie E., Egberts, Karin, Estivill, Xavier, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Forstner, Andreas J., Forzan, Monica, Franklin, Christopher S., Giegling, Ina, Guillaume, Sébastien, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Helder, Sietske G., Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M., Hudson, James I., Inoko, Hidetoshi, Janout, Vladimir, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Keski-Rahkonen, Anna, Kim, Youl-Ri, Knudsen, Gun Peggy S., La Via, Maria C., Levitan, Robert D., Lin, Bochao Danae, Luykx, Jurjen, Marsal, Sara, Marshall, Christian R., McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Monteleone, Alessio Maria, Monteleone, Palmiero, Munn-Chernoff, Melissa A., Navratilova, Marie, O’Toole, Julie K., Palotie, Aarno, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherer, Stephen W., Schmidt, Ulrike, Schosser, Alexandra, Slagboom, P. Eline, Sorbi, Sandro, Szatkiewicz, Jin P., Tenconi, Elena, Tortorella, Alfonso, Treasure, Janet, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Johnson, Craig, Kaye, Walter H., Mitchell, James E., Olsen, Catherine M., Woodside, D. Blake, Stuber, Garret D., Gordon, Scott, Henders, Anjali K., Juréus, Anders, Petersen, Liselotte, Wade, Tracey D., Landén, Mikael, Sullivan, Patrick F., Breen, Gerome
Format	Journal Article Web Resource
Language	English
Published	New York Nature Publishing Group US 01.08.2019 Nature Publishing Group
Subjects	631/208 631/337 631/477 Adult Agriculture Analysis Animal Genetics and Genomics Anorexia Anorexia nervosa Anorexia Nervosa - etiology Anorexia Nervosa - genetics Anorexia Nervosa - pathology Anthropometry Bioinformatics Biomedical and Life Sciences Biomedicine Body Mass Index Cancer Research Case-Control Studies Causes of Chromosomes Colorectal cancer comorbidity Consortia Diabetes Diagnosis Disorders Eating disorders Female Gene Function Gene loci Genetic aspects genetic correlations Genetic Predisposition to Disease Genetics Genetics & genetic processes Genetics & Heredity Genetik Genome-wide association studies Genome-Wide Association Study Genomes Genomics Genomics - methods Génétique & processus génétiques Heritability Human Genetics Humans insights ld score regression Letter Life Sciences Lipids Male Medicin och hälsovetenskap Mental disorders Mental Disorders - complications Mental Disorders - genetics Metabolic Diseases - complications Metabolic Diseases - genetics Metabolism myc Phenotype Physical activity polygenic prevalence Prognosis Quantitative Trait Loci risk Schizophrenia Sciences du vivant variants Working groups United States
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Summary:	Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1 , affecting 0.9–4% of women and 0.3% of men 2 – 4 , with twin-based heritability estimates of 50–60% 5 . Mortality rates are higher than those in other psychiatric disorders 6 , and outcomes are unacceptably poor 7 . 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. Genome-wide analyses identify eight independent loci associated with anorexia nervosa. Genetic correlations implicate both psychiatric and metabolic components in the etiology of this disorder, even after adjusting for the effects of common variants associated with body mass index.
Bibliography:	PMCID: PMC6779477 scopus-id:2-s2.0-85068455956 The members of this consortium are listed in the Supplementary Note These authors contributed equally to this work These authors jointly directed this project C.M.B. and P.F.S. conceived and designed the study. L.T., C.M.B., and G.B. performed overall study coordination. C.M.B. was lead PI of ANGI. P.F.S. was Co-Investigator of ANGI. N.G.M., M.L., and P.B.M. were site PIs of ANGI. H.J.W., Z.Y., J.R.I.C., C.H., J.B., H.A.G., S.Y., V.M.L., M.M., P.G-R. and S.E.M. performed the statistical analyses. H.J.W., Z.Y., C.H., J.R.I.C., H.A.G., J.B., A.H., P.G-R., P.F.S., G.B. and C.M.B. comprised the writing group. C.M.B. and G.B. were PGC-ED co-chairs. S.R. provided statistical consultation. A.H. assisted with data interpretation. A.W.B., C.M.B., J.J., M.K., K.M.K., P.L., G.M., C.N., R.P., L.T., and T.D.W. collected and managed the ANGI samples at sites and assisted with site-specific study co-ordination. A.W.B., J.M.B., H.B., S.C., K.A.H., L.J.H., C.J., A.S.K., W.K., J.M., C.M.O., J.F.P., N.L.P., M.S., T.W., D.C.W., and D.B.W. provided ANGI controls and extra samples. L.E.D provided data expertise. S.G., J.G., A.K.H., A.J., K.M.K., J.T.L., R.P., and L.P. contributed to the ANGI study. S.G., J.G., K.K., J.T.L., M.M., S.M., and L.P. were ANGI site analysts. K.B.H. and K.L.P. provided additional analysis for some secondary analyses. G.W.M., T.D.W., A.B., P.L., and C.N. were ANGI investigators. J.J. and M.K. assisted with ANGI recruitment in NZ. C.M.B., G.B., and P.F.S. supervised the study. H.J.W., C.M.B., Z.Y., C.H., G.B., J.R.I.C., H.A.G., S.Y., J.B., P.F.S., and P.G. wrote the manuscript. PGC-ED members and other individuals contributed to sample acquisition and made individual data from subjects available: R.A.H.A., L.A. T.A., O.A.A., J.H.B., A.W.B., W.H.B., A.B., I.B., C.B., J.M.B., H.B., G.B., K. B., C.M.B., R.B., M.C., S.C., M.C., J.R.I.C., R.D.C., P.C., S.C., S.C., J.C., U.N.D., O.S.P.D, M.D, G.D., D.D., J.E.D., D.M.D., D.D., C.D., M.D., E.D.M., K.E., S.E., G.E., T.E., X.E., A.F., A.F., F.F., M.M.F., K.F., M.F., L.F., A.J.F., M.F., S.G., I.G., J.G., F.G., S.G., P.G., M.G.M., J.G., S.G., K.A.H., K.H., J.H., J.H., S.G.H., A.K.H., S.H., B.H., W.H., A.H., L.J.H., J.I.H., H.I., H.I., V.J., S.J., C.J., J.J., A.J., A.J., G.K., D.K., A.S.K., J.K,. L.K., A.K., M.J.H.K., W.K., J.L.K., M.K., A.K., K.K., Y.K., L.K., G.S.K., M.C.L, M.L., S.L., R.D.L., P.L., L.L., B.L., J.L., J.L., P.M., M.M., K.M., S.M., C.M., N.G.M., M.M., S.M., P.M., A.M., I.M., N.M., J.M., A.M.M., P.M., P.M., M.A.M., B.N., M.N., C.N., I.N., C.M.O., J.K.O., R.A.O., L.P., A.P., J.P., H.P., N.L.P., J.F.P., D.P., R.R., A.R., N.R., T.R., V.R., S.R., F.R., M.R., A.R., D.R., F.R., P.S., S.W.S., U.S., A.S., J.S., L.S., P.E.S., M.C.T.S.L., A.S., S.S., M.S., P.F.S., B.Ś., J.P.S., I.T., E.T., A.T., F.T., J.T., A.T., M.T., K.T., A.A.V, E.F.V., T.D.W., G.W., E.W., H.J.W., T.W., D.C.W., E.W., D.B.W., G.S., S.Z., and S.Z. All authors critically reviewed the manuscript. Author contributions
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-019-0439-2