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, Laramie Duncan, Zeynep Yilmaz, Héléna Gaspar, Raymond Walters, Jackie GoldsteinVerneri Anttila, Brendan Bulik-Sullivan, Stephan Ripke, Roger Adan, Lars Alfredsson, Tetsuya Ando, Ole Andreassen, Harald 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, James Mitchell, 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, Laura Thornton, Anke Hinney, Mark Daly, Patrick F. Sullivan, Eleftheria Zeggini, Gerome Breen, Cynthia M. Bulik

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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 (US)
Pages (from-to)850-858
Number of pages9
JournalAmerican Journal of Psychiatry
Volume174
Issue number9
DOIs
StatePublished - Sep 1 2017

Bibliographical note

Funding Information:
Funding for this project was provided to 56 investigators contributing to this report as follows: Laramie Duncan: NIMH 5U01MH094432-04, NIMH 3U01MH094432-03S1; Stephan Ripke: NIMH MH109528, NARSAD 23545; Mark Daly: NIMH MH109528; Youl-Ri Kim: Research of Korea Centers for Disease Control and Prevention Fund (code HD16A1351); Susana Jiménez-Murcia: Instituto de Salud Carlos III (FIS PI14/290 and CIBERobn); Fernando Fernández-Aranda: Instituto de Salud Carlos III (FIS PI14/290 and CIBERobn); Philip Gorwood: EC Framework V “Factors in Healthy Eating” from INRA/INSERM (4M406D), PHRC ENDANO (2008-A01636-49); Paolo Santonastaso (for PAUDA Group): Veneto Region Grant BIOVEDA, contract grant number DGR 3984/08; Leila Karhunen: Academy of Finland (28327); Anu Raevuori: Academy of Finland grant number 259764; André Scherag: Federal Ministry of Education and Research, Germany, FKZ 01EO1502; Andrew Bergen: Professional Services Agreement with the Regents of the University of California; Stephanie Le Hellard: Bergen Research Foundation, NFR (NORMENT-SFF), K.G. Jebsen Foundation, Norwegian Cognitive NeuroGenetics, the University of Bergen, Dr. Einar Martens Fund, the Research Council of Norway, to Stephanie Le Hellard, Vidar Steen, and Thomas Espeseth; Hakon Hakonarson: Institutional Development Fund to the Center for Applied Genomics from Children’s Hospital of Philadelphia, Electronic Medical Records and Genomics (eMERGE) Network (U01 HG006830) from the NationalHumanGenomeResearchInstitute,NIH,KurbertFamily;DongLi: Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research Award; Yiran Guo: Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research Award; Shuyang Yao: China Scholarship Council; Sietske Helder: European Commission (2008–2011) Early Stage Researcher from the Research Training Network INTACT (Individually Tailored Stepped Care for Women with Eating Disorders) in the Marie Curie Program (MRTN-CT-2006-035988); Stephen Scherer: Genome Canada, the government of Ontario, the Canadian Institutes of Health Research, University of Toronto McLaughlin Centre; Martina de Zwaan: Federal Ministry for Education and Research, Germany, 01GV0601 and 01GV0624; Anke Hinney: Ministry for Education and Research, Germany (National Genome Research Net-Plus 01GS0820) and the German Research Foundation (HI865/2-1); Tracey Wade: Grants 324715 and 480420 from the National Health and Medical Research Council (NHMRC), Australian Twin Registry supported by Enabling Grant (ID 310667) from the NHMRC (University of Melbourne); Hana Papezova: Internal Grant Agency of the Ministry of Health of the Czech Republic IGA MZ CR≤ NT 14094-3/2013; Karen Mitchell: K01MH093750; Jessica Baker: K01MH106675; Zeynep Yilmaz: K01MH109782; Danielle Dick: K02AA018755-06, R01AA015416-08, National Institute on Alcohol Abuse and Alcoholism; Mikael Landén: Klarman Family Foundation; Sarah Cohen-Woods: Matthew Flinders Fellowship, Flinders University, Australia; Matthias Tschöp: Alexander von Humboldt Foundation, Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases throughtheInitiativeandNetworkingFundoftheHelmholtzAssociation, the Helmholtz cross-program topic “Metabolic Dysfunction,” German Research Foundation (DFG-TS226/1-1 and TS226/3-1, European Research Council Consolidator Grant (HepatpMetaboPath); Beate Herpertz-Dahlmann: Ministry for Research and Education, Germany; Nicole Soranzo: Wellcome Trust (grant codes WT098051 and WT091310), EU FP7 (EPIGENESYS grant code 257082 and BLUEPRINT grant code HEALTH-F5-2011-282510), National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge in partnership with NHS Blood and Transplant; Allan Kaplan: Ontario Mental Health Foundation, Ministry of Health of Ontario AFP Innovation Fund; Wade Berrettini: Price Foundation; Marion Roberts: Psychiatry Research Trust (registered charity no. 284286); Patrick Sullivan: R01 MH109528, D0886501, Swedish Research Council; Thomas Espeseth: Research Council of Norway, and South-East Norway Regional Health Authority; Michael Strober: Resnick Family Chair in Eating Disorders; Xavier Estivill: Spanish Ministry of Economy and Competitiveness no. SAF2013-49108-R, the Generalitat de Catalunya AGAUR 2014 SGR-1138, the European Commission Seventh Framework Program (FP7/2007-2013) 262055 (ESGI); Lenka Foretova: MH CZ-DRO (MMCI, 00209805);

Funding Information:
Ole Andreassen: Research Council of Norway (248778, 223273), KG Jebsen Foundation; Timo Müller: Helmholtz Alliance ICEMED–Imaging and Curing Environmental Metabolic Diseases through the Initiative and Networking Fund of the Helmholtz Association, Helmholtz cross-program topic “Metabolic Dysfunction,” German Research Foundation (DFG-TS226/1-1 and TS226/3-1); Cynthia Bulik: the Klarman Family Foundation, Wellcome Trust WT088827/Z/09, Swedish Research Council (VR Dnr: 538-2013-8864); Preben Mortensen: the Klarman Family Foundation, unrestricted grant from the Lundbeck Foundation, iPSYCH (Initiative for Integrative Psychiatric Research), Aarhus University for CIRRAU (Centre of Integrated Register-Based Research); Walter Kaye: the Price Foundation, NIMH R01 MH092793; Ted Reichborn-Kjennerud: Norwegian Research Council, Norwegian Foundation for Health and Rehabilitation; Eleftheria Zeggini: the Wellcome Trust (WT098051); Martien Kas: ZonMW VIDI Grant (91786327) from the Netherlands Organization for Scientific Research (NWO); Tonu Esko: EU H2020 grants 692145, 676550, 654248, Estonian Research Council Grant IUT20-60, NIASC, EIT–Health and NIH-BMI grant 2R01DK075787-06A1, and the European Union through the European Regional Development Fund (project no. 2014-2020.4.01.15-0012 GENTRANSMED; Stefan Ehrlich: German Research Foundation (EH 367/5-1 and SFB 940), Swiss Anorexia Nervosa Foundation; Esther Walton: German Research Foundation (EH 367/5-1 and SFB 940), Swiss Anorexia Nervosa Foundation; Ulrike Schmidt: National Institutes of Health Research Mental Health Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London; Martin Kennedy: University of Otago Research Grant; Johannes Hebebrand: German Ministry for Education and Research (National Genome Research Net-Plus 01GS0820 and 01KU0903), German Research Foundation (DFG; HI865/2-1), European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement no. 245009 and no. 262055; Stephan Zipfel: German Ministry for Education and Research (ANTOP-study project, no. 01GV0624); Gerome Breen: the UK Medical Research Council (G0901245), the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and King’s College London, as well as support from NIMH (U01MH109528). The authors thank the study participants, the study coordinators, volunteers, and research staff who enabled this work, the Wellcome Trust, the Price Family Collaborative Group, NIMH, and the computational infrastructure provided by the Psychiatric Genomics Consortium. The authors from the Children’s Hospital of Philadelphia/Price Foundation Collaborative Group thank the Price Foundation for their support in recruiting patients, collecting clinical information, and providing DNA samples used in this study; the Klarman Family Foundation for supporting the study; the technical staff at the Center for Applied Genomics at Children’s Hospital of Philadelphia for generating genotypes used for analyses; and the nursing, medical assistant, and medical staff for their invaluable assistance with sample collection. Data on glycemic traits were contributed by the investigators from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) and were downloaded from www.magicinvestigators.org.

Funding Information:
This work represents independent research funded in part by the U.K. National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Funding Information:
Dr. Bulik-Sullivan is an employee and shareholder of Gritstone Oncology. Dr. Sullivan has served on a scientific advisory board for Pfizer and an advisory committee for Lundbeck and is a grant recipient from Roche. Dr. Breen has received grant funding from and served as a consultant to Eli Lilly and has received honoraria from Illumina. Dr. Bulik has received grant funding from and served as a consultant to Shire and has received royalties from Walker Books and Pearson. The other authors report no financial relationships with commercial interests. Disclosures for Working Group members: Dr. Dikeos has served as a speaker, consultant, or adviser for AstraZeneca, Boehringer, Bristol-Myers Squibb, Eli Lilly, Genesis Pharma, GlaxoSmithKline, Janssen, Lundbeck, Organon, Sanofi, UniPharma, and Wyeth, and he has received unrestricted grants from Eli Lilly and AstraZeneca as director of the Sleep Research Unit of Eginition Hospital (National and Kapodistrian University of Athens, Greece). Dr. Kaplan has served on the Shire Canada BED advisory board. Dr. Kennedy is an unpaid member of the scientific advisory board of AssurexHealth. Dr. Landén has received lecture honoraria from AstraZeneca, Biophausia Sweden, and Lundbeck and has served as a scientific consultant for EPID Research Oy. Dr. Treasure has received a speaking honorarium from Eli Lilly and royalties for a published book.

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