Shared Genetic Risk between Eating Disorder- and Substance-Use-Related Phenotypes: Evidence from Genome-Wide Association Studies
Authors: Munn-Chernoff Melissa A. , Johnson Emma C. , Chou Yi-Ling , Coleman Jonathan R.I. , Thornton Laura M. , Walters Raymond K. , Yilmaz Zeynep , Baker Jessica H. , Hübel Christopher , Gordon Scott , Medland Sarah E. , Watson Hunna J. , Gaspar Héléna A. , Bryois Julien , Hinney Anke , Leppä Virpi M. , Mattheisen Manuel , Ripke Stephan , Yao Shuyang , Giusti-Rodríguez Paola , Hanscombe Ken B. , Adan Roger A.H. , Alfredsson Lars , Ando Tetsuya , Andreassen Ole A. , Berrettini Wade H. , Boehm Ilka , Boni Claudette , Perica Vesna Boraska , Buehren Katharina , Burghardt Roland , Cassina Matteo , Cichon Sven , Clementi Maurizio , Cone Roger D. , Courtet Philippe , Crow Scott , Crowley James J. , Danner Unna N. , Davis Oliver S.P. , Zwaan Martina de , Dedoussis George , Degortes Daniela , DeSocio Janiece E. , Dick Danielle M. , Dikeos Dimitris , Dina Christian , Dmitrzak-Weglarz Monika , Docampo Elisa , Duncan Laramie E. , Egberts Karin , Ehrlich Stefan , Escaramís Geòrgia , Esko Tõnu , Estivill Xavier , Farmer Anne , Favaro Angela , Fernández-Aranda Fernando , Fichter Manfred M. , Fischer Krista , Föcker Manuel , Foretova Lenka , Forstner Andreas J. , Forzan Monica , Franklin Christopher S. , Gallinger Steven , Giegling Ina , Giuranna Johanna , Gonidakis Fragiskos , Gorwood Philip , Mayora Monica Gratacos , Guillaume Sébastien , Guo Yiran , Hakonarson Hakon , Hatzikotoulas Konstantinos , Hauser Joanna , Hebebrand Johannes , Helder Sietske G. , Herms Stefan , Herpertz-Dahlmann Beate , Herzog Wolfgang , Huckins Laura M. , Hudson James I. , Imgart Hartmut , Inoko Hidetoshi , Janout Vladimir , Jiménez-Murcia Susana , Julià Antonio , Kalsi Gursharan , Kaminská Deborah , Karhunen Leila , Karwautz Andreas , Kas Martien J.H. , Kennedy James L. , Keski-Rahkonen Anna , Kiezebrink Kirsty , Kim Youl-Ri , Klump Kelly L. , Knudsen Gun Peggy S. , Via Maria C. La , Hellard Stephanie Le , Levitan Robert D. , Li Dong , Lilenfeld Lisa , Lin Bochao Danae , Lissowska Jolanta , Luykx Jurjen , Magistretti Pierre J. , Maj Mario , Mannik Katrin , Marsal Sara , Marshall Christian R. , Mattingsdal Morten , McDevitt Sara , McGuffin Peter , Metspalu Andres , Meulenbelt Ingrid , Micali Nadia , Mitchell Karen , Monteleone Alessio Maria , Monteleone Palmiero , Nacmias Benedetta , Navratilova Marie , Ntalla Ioanna , O’Toole Julie K. , Ophoff Roel A. , Padyukov Leonid , Palotie Aarno , Pantel Jacques , Papezova Hana , Pinto Dalila , Rabionet Raquel , Raevuori Anu , Ramoz Nicolas , Reichborn-Kjennerud Ted , Ricca Valdo , Ripatti Samuli , Ritschel Franziska , Roberts Marion , Rotondo Alessandro , Rujescu Dan , Rybakowski Filip , Santonastaso Paolo , Scherag André , Scherer Stephen W. , Schmidt Ulrike , Schork Nicholas J. , Schosser Alexandra , Seitz Jochen , Slachtova Lenka , Slagboom P. Eline , Slof-Op’t Landt Margarita C.T. , Slopien Agnieszka , Sorbi Sandro , Świątkowska Beata , Szatkiewicz Jin P. , Tachmazidou Ioanna , Tenconi Elena , Tortorella Alfonso , Tozzi Federica , Treasure Janet , Tsitsika Artemis , Tyszkiewicz-Nwafor Marta , Tziouvas Konstantinos , Elburg Annemarie A. van , Furth Eric F. van , Wagner Gudrun , Walton Esther , Widen Elisabeth , Zeggini Eleftheria , Zerwas Stephanie , Zipfel Stephan , Bergen Andrew W. , Boden Joseph M. , Brandt Harry , Crawford Steven , Halmi Katherine A. , Horwood L. John , Johnson Craig , Kaplan Allan S. , Kaye Walter H. , Mitchell James , Olsen Catherine M. , Pearson John F. , Pedersen Nancy L. , Strober Michael , Werge Thomas , Whiteman David C. , Woodside D. Blake , Grove Jakob , Henders Anjali K. , Larsen Janne T. , Parker Richard , Petersen Liselotte V. , Jordan Jennifer , Kennedy Martin A. , Birgegård Andreas , Lichtenstein Paul , Norring Claes , Landén Mikael , Mortensen Preben Bo , Polimanti Renato , McClintick Jeanette N. , Adkins Amy E. , Aliev Fazil , Bacanu Silviu-Alin , Batzler Anthony , Bertelsen Sarah , Biernacka Joanna M. , Bigdeli Tim B. , Chen Li-Shiun , Clarke Toni-Kim , Degenhardt Franziska , Docherty Anna R. , Edwards Alexis C. , Foo Jerome C. , Fox Louis , Frank Josef , Hack Laura M. , Hartmann Annette M. , Hartz Sarah M. , Heilmann-Heimbach Stefanie , Hodgkinson Colin , Hoffmann Per , Hottenga Jouke-Jan , Konte Bettina , Lahti Jari , Lahti-Pulkkinen Marius , Lai Dongbing , Ligthart Lannie , Loukola Anu , Maher Brion S. , Mbarek Hamdi , McIntosh Andrew M. , McQueen Matthew B. , Meyers Jacquelyn L. , Milaneschi Yuri , Palviainen Teemu , Peterson Roseann E. , Ryu Euijung , Saccone Nancy L. , Salvatore Jessica E. , Sanchez-Roige Sandra , Schwandt Melanie , Sherva Richard , Streit Fabian , Strohmaier Jana , Thomas Nathaniel , Wang Jen-Chyong , Webb Bradley T. , Wedow Robbee , Wetherill Leah , Wills Amanda G. , Zhou Hang , Boardman Jason D. , Chen Danfeng , Choi Doo-Sup , Copeland William E. , Culverhouse Robert C. , Dahmen Norbert , Degenhardt Louisa , Domingue Benjamin W. , Frye Mark A. , Gäbel Wolfgang , Hayward Caroline , Ising Marcus , Keyes Margaret , Kiefer Falk , Koller Gabrielle , Kramer John , Kuperman Samuel , Lucae Susanne , Lynskey Michael T. , Maier Wolfgang , Mann Karl , Männistö Satu , Müller-Myhsok Bertram , Murray Alison D. , Nurnberger John I. , Preuss Ulrich , Räikkönen Katri , Reynolds Maureen D. , Ridinger Monika , Scherbaum Norbert , Schuckit Marc A. , Soyka Michael , Treutlein Jens , Witt Stephanie H. , Wodarz Norbert , Zill Peter , Adkins Daniel E. , Boomsma Dorret I. , Bierut Laura J. , Brown Sandra A. , Bucholz Kathleen K. , Costello E. Jane , Wit Harriet de , Diazgranados Nancy , Eriksson Johan G. , Farrer Lindsay A. , Foroud Tatiana M. , Gillespie Nathan A. , Goate Alison M. , Goldman David , Grucza Richard A. , Hancock Dana B. , Harris Kathleen Mullan , Hesselbrock Victor , Hewitt John K. , Hopfer Christian J. , Iacono William G. , Johnson Eric O. , Karpyak Victor M. , Kendler Kenneth S. , Kranzler Henry R. , Krauter Kenneth , Lind Penelope A. , McGue Matt , MacKillop James , Madden Pamela A.F. , Maes Hermine H. , Magnusson Patrik K.E. , Nelson Elliot C. , Nöthen Markus M. , Palmer Abraham A. , Penninx Brenda W.J.H. , Porjesz Bernice , Rice John P. , Rietschel Marcella , Riley Brien P. , Rose Richard J. , Shen Pei-Hong , Silberg Judy , Stallings Michael C. , Tarter Ralph E. , Vanyukov Michael M. , Vrieze Scott , Wall Tamara L. , Whitfield John B. , Zhao Hongyu , Neale Benjamin M. , Wade Tracey D. , Heath Andrew C. , Montgomery Grant W. , Martin Nicholas G. , Sullivan Patrick F. , Kaprio Jaakko , Breen Gerome , Gelernter Joel , Edenberg Howard J. , Bulik Cynthia M. , Agrawal Arpana 
Published: August 2019

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 (BN) 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 BN 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 (MDD). Total sample sizes per phenotype ranged from ~2,400 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 non-diagnostic 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 MDD loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors.