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

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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; Boraska Perica, Vesna; 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; de Zwaan, Martina; 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; Gratacos Mayora, Monica; 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; La Via, Maria C; Le Hellard, Stephanie; 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; van Elburg, Annemarie A; van Furth, Eric F; 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; Gäebel, Wolfgang; Hayward, Caroline; Ising, Marcus; Keyes, Margaret; Kiefer, Falk; Koller, Gabriele; 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; de Wit, Harriet; 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
Year: 2021
Journal: Addiction biology
PMID: 32064741
DOI: 10.1111/adb.12880
PMCID: PMC7429266

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

#	Section	Preview
0	Method — Participants	We included summary statistics from two existing GWAS of eating disorder phenotypes where…
1	Method — Statistical Analysis	We used LDSC (Bulik-Sullivan et al., 2015a, Bulik-Sullivan et al., 2015b) to evaluate SNP-based rg…
2	Method — Statistical Analysis	Genetic correlations range from −1 to +1, where the sign indicates that the same genetic factors…
3	Method — Statistical Analysis	For significant rgs detected in LDSC where both the individual eating disorder and substance…
4	Results	The overall SNP-based heritability for the eating disorder phenotypes ranged from 0.1992 to 0.3911,…
5	Results	Significant positive rgs were observed for alcohol use- and cannabis use-related phenotypes. First,…
6	Results	Second, the significant rg between AN and cannabis initiation was 0.23 (SE=0.04, q<0.0001), and the…
7	Results	Conversely, for smoking phenotypes, significant correlations were only observed for the AN without…
8	Results	Because the AN GWAS and cannabis initiation GWAS each identified eight significant loci (Pasman et…
9	Discussion	Using existing GWAS data, we investigated genetic associations between liabilities to four eating…
10	Discussion	Three main patterns emerged. First, in line with prior twin studies, we observed a positive rg…
11	Discussion	Based on findings from twin studies, we hypothesized that: 1) the strongest SNP-based rg would be…
12	Discussion	Intriguingly, although we did not detect a significant rg for AN with binge-eating or the BN factor…
13	Discussion	2013, Volkow et al., 2013), and administration of Naltrexone, an opioid antagonist approved by the…
14	Discussion	The significant genetic associations between cannabis initiation and AN are novel, yet consistent…
15	Discussion	Further, the endocannabinoid anandamide has been shown to be elevated in individuals with acute AN…
16	Discussion	Finally, the significant negative rgs between three smoking phenotypes—smoking initiation, current…
17	Discussion	2011), and temporary weight gain does occur with smoking cessation (Filozof et al., 2004). However,…
18	Discussion	Another explanation for the negative genetic association is that it is due to a third, underlying…
19	Discussion	Substance use and substance use disorders are partially distinct, and although excessive substance…

Name	Type
1000 Genomes Phase 3 European ancestries sample local	cohort
alcohol	phenotype
alcohol-related phenotypes	phenotype
Alcohol Use	phenotype
Alcohol Use Disorder	phenotype
AN	phenotype
anandamide	drug
anorexia nervosa	phenotype
Anorexia Nervosa (AN) local	phenotype
Anorexia nervosa with binge-eating local	phenotype
Anorexia Nervosa with binge-eating subtype local	phenotype
Anorexia nervosa without binge-eating local	phenotype
Anorexia Nervosa without binge-eating local	phenotype
AN subtypes local	phenotype
AN with binge eating local	phenotype
AN with binge-eating local	phenotype
AN without binge eating local	phenotype
AN without binge-eating local	phenotype
AUD	phenotype
binge eating	phenotype
Binge-eating disorder local	phenotype
BMI	phenotype
BN	phenotype
BN factor local	phenotype
BN factor score local	phenotype
body mass index	phenotype
bulimia nervosa	phenotype
cachexia syndrome local	phenotype
cannabis initiation	phenotype
cannabis use	phenotype
cannabis use disorder	phenotype
cannabis use-related phenotypes local	phenotype
CB1 agonist	drug
CB1 receptor	drug
central nervous system	anatomy
cigarettes	phenotype
CUD	phenotype
current smoking	phenotype
delta-9-tetrahydrocannabinol	drug
Demontis et al., 2019 local	cohort
drinks per week	phenotype
eating disorder	phenotype
Eating disorder phenotypes with binge eating local	phenotype
eating disorders	phenotype
Eating Disorders and Substance Use Disorders Working Groups local	cohort
endocannabinoids	drug
fasting glucose	phenotype
food intake	phenotype
GSCAN cohort local	cohort
Hancock et al., 2017 local	cohort
HapMap3 EUR population local	cohort
HIV infection	phenotype
increased appetite	phenotype
Kranzler et al., 2019	cohort
Liu et al., 2019 local	cohort
major depressive disorder	phenotype
naltrexone	drug
nicotine	drug
nicotine addiction	phenotype
nicotine dependence	phenotype
Nicotine Dependence (ND) local	phenotype
obesity	phenotype
opioid	drug
opioid antagonist local	drug
Pasman et al., 2018 local	cohort
problematic alcohol use	phenotype
Psychiatric Genomics Consortium	cohort
restricting AN	phenotype
reward system	anatomy
rimonabant	drug
schizophrenia	phenotype
smoking	phenotype
smoking initiation	phenotype
Smoking Phenotypes (GSCAN) local	phenotype
SNPs (MAF>0.01) local	variant
study cohort	cohort
substance use	phenotype
substance use-related phenotype local	phenotype
Substance use-related phenotypes local	phenotype
tobacco use	phenotype
Twin cohort	cohort
type 2 diabetes	phenotype
Typical Alcohol Consumption (drinks per week) local	phenotype
UK Biobank	cohort
Wade et al., 2013 local	cohort
Walters et al., 2018	cohort
Walters et al. (2018) alcohol dependence GWAS local	cohort
Watson et al., in press local	cohort

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