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

16 Scopus citations

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 [r g ], 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 (r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r g = 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 (r gs = -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:
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.

Funding Information:
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, Riksät (Swedish National Quality Register for Eating Disorders), the Stockholm Center for Eating Disorders (SCÄ), 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.

Funding Information:
The authors report the following potential competing interests. O. Andreassen received a speaker's honorarium from Lundbeck. G. Breen received grant funding and consultancy fees in preclinical genetics from Eli Lilly, consultancy fees from Otsuka, and has received honoraria from Illumina. C. Bulik served on Shire Scientific Advisory Boards, is a consultant for Idorsia, and receives author royalties from Pearson. D. Degortes 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. Hudson has received grant support from Shire and Sunovion and has received consulting fees from DiaMentis, Shire, and Sunovion. A. Kaplan is a member of the Shire Canadian Binge‐Eating Disorder Advisory Board and was on the steering committee for the Shire B/educated Educational Symposium: 15 to 16 June 2018. J. Kennedy served as an unpaid member of the scientific advisory board of AssurexHealth Inc. M. Landén declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as scientific consultant for EPID Research Oy. S. Scherer is a member of the scientific advisory board for Deep Genomics. P. Sullivan 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. Treasure 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. Werge has acted as a lecturer and scientific advisor to H. Lundbeck A/S. L. Bierut, A. Goate, J. Rice, J.‐C. Wang, and the spouse of N. Saccone are listed as inventors on Issued US Patent 8080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. N. Wodarz has received funding from the German Research Foundation (DFG) and Federal Ministry of Education and Research Germany (BMBF); he has received speaker's honoraria and travel funds from Janssen‐Cilag, Mundipharma, and Indivior. He took part in industry‐sponsored multicenter randomized trials by D&A Pharma and Lundbeck. M. Ridinger received compensation from Lundbeck Switzerland and Lundbeck institute for advisory boards and expert meetings and from Lundbeck and Lilly Suisse for workshops and presentations. K. Mann received speaker fees from Janssen‐Cilag. H. Kranzler is a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was sponsored in the past 3 years by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. H. Kranzler and J. Gelernter are named as inventors on PCT patent application #15/878,640, entitled “Genotype‐guided dosing of opioid agonists,” filed 24 January 2018. J. MacKillop is a principal in BEAM Diagnostics, Inc. D.‐S. Choi is a scientific advisory member of Peptron Inc. M. Frye has received grant support from Assurex Health, Mayo Foundation, Myriad, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, and Pfizer; he has been a consultant for Intra‐Cellular Therapies, Inc., Janssen, Mitsubishi Tanabe Pharma Corporation, Myriad, Neuralstem Inc., Otsuka American Pharmaceutical, Sunovion, and Teva Pharmaceuticals. H. de Wit has received support from Insys Therapeutics and Indivior for studies unrelated to this project, and she has consulted for Marinus and Jazz Pharmaceuticals, also unrelated to this project. T. Wall has previously received funds from ABMRF. J. Nurnberger is an investigator for Janssen. M. Nöthen has received honoraria from the Lundbeck Foundation and the Robert Bosch Stiftung for membership on advisory boards. N. Scherbaum received honoraria for several activities (advisory boards, lectures, and manuscripts) by the factories Abbvie, Hexal, Janssen‐Cilag, MSD, Medice, Mundipharma, Reckitt‐Benckiser/Indivior, and Sanofi‐Aventis. W. Gäbel has received symposia support from Janssen‐Cilag GmbH, Neuss, Lilly Deutschland GmbH, Bad Homburg, and Servier, Munich and is a member of the Faculty of the Lundbeck International Neuroscience Foundation (LINF), Denmark. J. Kaprio has provided consultations on nicotine dependence for Pfizer (Finland) 2012 to 2015. In the past 3 years, L. Degenhardt has received investigator‐initiated untied educational grants for studies of opioid medications in Australia from Indivior, Mundipharma, and Seqirus. B. Neale is a member of the scientific advisory board for Deep Genomics and has consulted for Camp4 Therapeutics Corporation, Merck & Co., and Avanir Pharmaceuticals, Inc. A. Agrawal previously received peer‐reviewed funding and travel reimbursement from ABMRF for unrelated research. All other authors have no conflicts of interest, relevant to the contents of this paper, to disclose.

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.

Publisher Copyright:
© 2020 Society for the Study of Addiction

Keywords

  • eating disorders
  • genetic correlation
  • substance use
  • Genome-Wide Association Study
  • Tobacco Use Disorder/genetics
  • Feeding and Eating Disorders/genetics
  • Humans
  • Risk Factors
  • Substance-Related Disorders/genetics
  • Depressive Disorder, Major/genetics
  • Linkage Disequilibrium
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Schizophrenia/genetics
  • Alcoholism/genetics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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