Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Melissa A. Munn-Chernoff, Emma C. Johnson, Yi Ling Chou, Jonathan R.I. Coleman, Laura M. Thornton, Raymond K. Walters, Zeynep Yilmaz, Jessica H. Baker, Christopher Hübel, Scott Gordon, Sarah E. Medland, Hunna J. Watson, Héléna A. Gaspar, Julien Bryois, Anke Hinney, Virpi M. Leppä, Manuel Mattheisen, Stephan Ripke, Shuyang Yao, Paola Giusti-RodríguezKen B. Hanscombe, Roger A.H. Adan, Lars Alfredsson, Tetsuya Ando, Ole A. Andreassen, 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, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, James L. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl Ri Kim, 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, 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 Mitchell, Catherine M. Olsen, John F. Pearson, Nancy L. Pedersen, Michael Strober, Thomas Werge, David C. Whiteman, D. Blake Woodside, Jakob Grove, Anjali K. Henders, Janne T. Larsen, Richard Parker, Liselotte V. Petersen, Jennifer Jordan, Martin A. Kennedy, Andreas Birgegård, Paul Lichtenstein, Claes Norring, Mikael Landén, Preben Bo Mortensen, Renato Polimanti, Jeanette N. McClintick, Amy E. Adkins, Fazil Aliev, Silviu Alin Bacanu, Anthony Batzler, Sarah Bertelsen, Joanna M. Biernacka, Tim B. Bigdeli, Li Shiun Chen, Toni Kim Clarke, Franziska Degenhardt, Anna R. Docherty, Alexis C. Edwards, Jerome C. Foo, Louis Fox, Josef Frank, Laura M. Hack, Annette M. Hartmann, Sarah M. Hartz, Stefanie Heilmann-Heimbach, Colin Hodgkinson, Per Hoffmann, Jouke Jan Hottenga, Bettina Konte, Jari Lahti, Marius Lahti-Pulkkinen, Dongbing Lai, Lannie Ligthart, Anu Loukola, Brion S. Maher, Hamdi Mbarek, Andrew M. McIntosh, Matthew B. McQueen, Jacquelyn L. Meyers, Yuri Milaneschi, Teemu Palviainen, Roseann E. Peterson, Euijung Ryu, Nancy L. Saccone, Jessica E. Salvatore, Sandra Sanchez-Roige, Melanie Schwandt, Richard Sherva, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen Chyong Wang, Bradley T. Webb, Robbee Wedow, Leah Wetherill, Amanda G. Wills, Hang Zhou, Jason D. Boardman, Danfeng Chen, Doo Sup Choi, William E. Copeland, Robert C. Culverhouse, Norbert Dahmen, Louisa Degenhardt, Benjamin W. Domingue, Mark A. Frye, Wolfgang Gäbel, Caroline Hayward, Marcus Ising, Margaret Keyes, Falk Kiefer, Gabriele Koller, John Kramer, Samuel Kuperman, Susanne Lucae, Michael T. Lynskey, Wolfgang Maier, Karl Mann, Satu Männistö, Bertram Müller-Myhsok, Alison D. Murray, John I. Nurnberger, Ulrich Preuss, Katri Räikkönen, Maureen D. Reynolds, Monika Ridinger, Norbert Scherbaum, Marc A. Schuckit, Michael Soyka, Jens Treutlein, Stephanie H. Witt, Norbert Wodarz, Peter Zill, Daniel E. Adkins, Dorret I. Boomsma, Laura J. Bierut, Sandra A. Brown, Kathleen K. Bucholz, E. Jane Costello, Harriet de Wit, Nancy Diazgranados, Johan G. Eriksson, Lindsay A. Farrer, Tatiana M. Foroud, Nathan A. Gillespie, Alison M. Goate, David Goldman, Richard A. Grucza, Dana B. Hancock, Kathleen Mullan Harris, Victor Hesselbrock, John K. Hewitt, Christian J. Hopfer, William G. Iacono, Eric O. Johnson, Victor M. Karpyak, Kenneth S. Kendler, Henry R. Kranzler, Kenneth Krauter, Penelope A. Lind, Matt McGue, James MacKillop, Pamela A.F. Madden, Hermine H. Maes, Patrik K.E. Magnusson, Elliot C. Nelson, Markus M. Nöthen, Abraham A. Palmer, Brenda W.J.H. Penninx, Bernice Porjesz, John P. Rice, Marcella Rietschel, Brien P. Riley, Richard J. Rose, Pei Hong Shen, Judy Silberg, Michael C. Stallings, Ralph E. Tarter, Michael M. Vanyukov, Scott Vrieze, Tamara L. Wall, John B. Whitfield, Hongyu Zhao, Benjamin M. Neale, Tracey D. Wade, Andrew C. Heath, Grant W. Montgomery, Nicholas G. Martin, Patrick F. Sullivan, Jaakko Kaprio, Gerome Breen, Joel Gelernter, Howard J. Edenberg, Cynthia M. Bulik, Arpana Agrawal

Research output: Contribution to journalArticlepeer-review

Abstract

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

Original languageEnglish (US)
Article numbere12880
JournalAddiction Biology
Volume26
Issue number1
DOIs
StatePublished - Jan 2021

Bibliographical note

Funding Information:
Grant support for individual authors can be found in Table S10. This study included summary statistics of a genetic study on cannabis use (Pasman et al [2018] Nature Neuroscience). We would like to acknowledge all participating groups of the International Cannabis Consortium, and in particular, the members of the working group including Joelle Pasman, Karin Verweij, Nathan Gillespie, Eske Derks, and Jacqueline Vink. Pasman et al (2018) included data from the UK Biobank resource under application numbers 9905, 16406, and 25331. We thank all study volunteers, study coordinators, and research staff who enabled this study. ANGI: The Anorexia Nervosa Genetics Initiative was an initiative of the Klarman Family Foundation. Additional support was offered by the National Institute of Mental Health. We acknowledge support from the North Carolina Translational and Clinical Sciences Institute (NC TraCS) and the Carolina Data Warehouse. PGC: We are deeply indebted to the investigators who comprise the PGC and to the hundreds of thousands of individuals who have shared their life experiences with PGC investigators and the contributing studies. We are grateful to the Children's Hospital of Philadelphia (CHOP), the Price Foundation Collaborative Group (PFCG), Genetic Consortium for Anorexia Nervosa (GCAN), Wellcome Trust Case-Control Consortium-3 (WTCCC-3), the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), the QSkin Sun and Health Study, Riks?t (Swedish National Quality Register for Eating Disorders), the Stockholm Center for Eating Disorders (SC?), LifeGene, the UK Biobank, and all PGC-ED members for their support in providing individual samples used in this study. We thank SURFsara (http://www.surf.nl) for support in using the Lisa Compute Cluster. We thank Max Lam, Institute of Mental Health, Singapore, for Ricopili consultation. This study also represents independent research partly funded by the English 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 author(s) and not necessarily those of the NHS, the NIHR, or the English Department of Health and Social Care. High performance computing facilities were funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). Research reported in this publication was supported by the National Institute of Mental Health of the US National Institutes of Health under Award Number U01MH109514. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. The PGC-SUD receives support from the National Institute on Drug Abuse and the National Institute of Mental Health via MH109532. We gratefully acknowledge prior support from the National Institute on Alcohol Abuse and Alcoholism. Statistical analyses for the PGC were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Cohort specific acknowledgements may be found in Walters et al (2018) Nature Neuroscience.

Keywords

  • eating disorders
  • genetic correlation
  • substance use

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