Citations 2
Cross-definition GWAS of IBS in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms
Lorenzo, Biagio Di, Tavares, Letícia Camargo , Díaz-Muñoz, Cristian , Heredia-Fernández, Francisco , Bozzarelli, Isotta, Blanco, Cristina Esteban, Wang, Zhe, Smit, Roelof A J, Loos, Ruth J F, Hirbo, Jibril, Cox, Nancy J, Straub, Peter, Favé, Marie-Julie , Pozdeyev, Nikita, Gignoux, Christopher R, Gudbjartsson, Daniel F, Thorleifsson, Gudmar, Jónsdóttir, Ingileif , Stefansson, Kari, Palta, Priit, Sze, Gerald , John, Catherine, Richmond, Anne, McCartney, Daniel, Hayward, Caroline, Mulford, Ashley J, Sanders, Alan R, Dombrovska, Marija Simona, Capasso, Mario, Faro, Valeria Lo, Maya, Esteban Alexander Lopera, Zhernakova, A, Cohort, Lifelines, Martin, Alicia, Vanderwerff, Brett , Zöllner, Sebastian, Ferolito, Brian R. , Pereira, Alexander Castanho, Gaziano, J. Michael , Caruth, Lanna, Guare, Lindsay, Kripke, Colleen Morse , Rader, Daniel J, Verma, Shefali S, Verma, Anurag, BioBank, Penn Medicine, Saad, Chadi, Chao, Pei-Yu, Chen, Tzu-Ting, Lin, Yen-Feng, Feng, Yen‐Chen Anne , Khalili, Hamed , Andries, Aristomo , Ness‐Jensen, Eivind , Grover, Madhusudan , FinnGen, Lemmelä, Susanna, Abner, Erik , Challa, Prasanna K , Khalili, Hamed , Ness-Jensen, Eivind , Grover, Madhusudan , D'Amato, Mauro , Loos, Ruth J F , Camargo Tavares, Leticia , Lorenzo, Biagio Di , Smit, Roelof A. J. , Loos, Ruth J. F. , Hirbo, Jibril B , Cox, Nancy J., Awadalla, Philip , Pozdeyev, Nikita V. , Gignoux, Chris , Gudbjartsson, Daniel Fannar , Þorleifsson, Guðmar , Priit, Palta , Williams, Alexander T. , Coley, Kayesha , John, Catherine , Richmond, Anne , Mulford, Ashley J. , Pečulis, Raitis , Rovīte, Vita , Capasso, Mario , Faro, Valeria Lo , Sinha, Trishla , Lopera-Maya, Esteban A. , Zhernakova, Alexandra , Wang, Ying, Vanderwerff, Brett , Zöllner, Sebastian , Cho, Kelly , Guare, Lindsay A. , Rader, Daniel J , Verma, Shefali S. , Saad, Chadi , Mbarek, Hamdi , Brumpton, Ben , Lemmelä, Susanna M. , Sanna, Serena , Bonfiglio, Ferdinando , D’Amato, Mauro
Gut | July 9, 2026 | Volume: No volume available | Issue: No issue available | Pages: gutjnl-2026-338800
Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.
Shared genetic risk between eating disorder‐ and substance‐use‐related phenotypes: Evidence from genome‐wide association studies
Munn‐Chernoff, Melissa A. , Chou, Yi‐Ling, Coleman, Jonathan R. I. , Thornton, Laura M. , Walters, Raymond K. , Yılmaz, Zeynep , Baker, Jessica H. , Hübel, Christopher , Medland, Sarah E. , Hinney, Anke , Leppä, Virpi , Mattheisen, Manuel , Ripke, Stephan , Yao, Shuyang , Giusti‐Rodríguez, Paola , Hanscombe, Ken B. , Adan, Roger A.H. , Ando, Tetsuya , Berrettini, Wade H., Boehm, Ilka , Boni, Claudette, Perica, Vesna Boraska , Buehren, Katharina, Burghardt, Roland , Cassina, Matteo , Cichon, Sven , Clementi, Maurizio , Courtet, Philippe, Crowley, James J. , Danner, Unna N. , Davis, Oliver S. P. , Zwaan, Martina de, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dikeos, Dimitris, Dina, Christian , Dmitrzak‐Węglarz, Monika , Docampo, Elisa, Duncan, Laramie E. , Egberts, Karin , Ehrlich, Stefan , Escaramís, Geòrgia, Estivill, Xavier , Farmer, Anne, Favaro, Angela , Fernández‐Aranda, Fernando , Fichter, Manfred M., Fischer, Krista , Föcker, Manuel , Foretová, Lenka , Forstner, Andreas J. , Franklin, Christopher S., Gallinger, Steven , Giegling, Ina , Giuranna, Johanna, Gonidakis, Fragiskos , Gorwood, Philip , Mayora, Monica Gratacos, Guo, Yiran , Håkonarson, Håkon , Hatzikotoulas, Konstantinos , Hebebrand, Johannes , Helder, Sietske G., Herpertz‐Dahlmann, Beate, Herzog, Wolfgang , Huckins, Laura M. , Hudson, James I. , Imgart, Hartmut , Inoko, Hidetoshi , Janout, Vladimír , Jiménez‐Múrcia, Susana , Kalsi, Gursharan , Kaminská, Deborah , Karwautz, Andreas , Kas, Martien J. , Keski‐Rahkonen, Anna , Kiezebrink, Kirsty , Kim, Youl‐Ri , Klump, Kelly L. , Knudsen, Gun Peggy , Via, Maria C. La, Hellard, Stéphanie Le , Levitan, Robert D., Lilenfeld, Lisa , Lin, Bochao , Lissowska, Jolanta , Luykx, Jurjen J. , Magistretti, Pierre J. , Maj, Mario , Männik, Katrin , Marsal, Sara , Marshall, Christian R. , McDevitt, Sara , McGuffin, Peter, Meulenbelt, Ingrid, Navratilova, Marie, Ντάλλα, Ιωάννα , O’Toole, Julie K., Padyukov, Leonid , Palotie, Aarno , Pantel, Jacques , Papežová, Hana , Pinto, Dalila , Rabionet, Raquel , Raevuori, Anu , Ramoz, Nicolás , Reichborn‐Kjennerud, Ted , Ricca, Valdo , Ritschel, Franziska , Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip , Scherer, Stephen W. , Schmidt, Ulrike , Schork, Nicholas J. , Schosser, Alexandra , Šlachtová, Lenka , Landt, M , Slopien, Agnieszka, Sorbi, Sandro , Świątkowska, Beata , Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso , Tozzi, Federica, Treasure, Janet , Tziouvas, Konstantinos , Elburg, Annemarie , Furth, Eric F. van , Wagner, Gudrun , Walton, Esther , Widén, Elisabeth , Zerwas, Stephanie , Zipfel, Stephan, Bergen, Andrew W. , Brandt, Harry, Crawford, Steven , Halmi, Katherine A. , Johnson, Craig, Kaplan, Allan S. , Kaye, Walter H. , Mitchell, James E. , Olsen, Catherine M. , Pedersen, Nancy L. , Strober, Michael, Whiteman, David C. , Woodside, D. Blake , Grove, Jakob , Henders, Anjali K. , Larsen, Janne Tidselbak , Petersen, Liselotte , Jordan, Jennifer , Kennedy, Martin A. , Birgegård, Andreas , Landén, Mikael , Polimanti, Renato , McClintick, Jeanette N. , Adkins, Amy , Alıev, Fazil , Bacanu, Silviu‐Alin , Batzler, Anthony , Bertelsen, Sarah , Chen, Li‐Shiun , Degenhardt, Franziska , Docherty, Anna R. , Edwards, Alexis C. , Foo, Jerome C. , Fox, Louis , Frank, Josef , Hack, Laura M. , Hartmann, Annette M. , Hartz, Sarah M. , Hodgkinson, Colin A. , Hottenga, Jouke‐Jan, Konte, Bettina , Lahti, Jari , Lahti‐Pulkkinen, Marius , Ligthart, Lannie , Loukola, Anu , Maher, Brion S. , Mbarek, Hamdi , McIntosh, Andrew M. , McQueen, Matthew B. , Meyers, Jacquelyn L. , Milaneschi, Yuri , Palviainen, Teemu , Ryu, Euijung , Saccone, Nancy L. , Salvatore, Jessica E. , Streit, Fabian , Wang, Jen‐Chyong , Webb, Bradley T. , Wetherill, Leah , Wills, Amanda G. , Zhou, Hang , Boardman, Jason D., Chen, Danfeng , Copeland, William , Culverhouse, Robert , Dahmen, Norbert, Domingue, Benjamin W. , Frye, Mark A. , Gäebel, Wolfgang , Ising, Marcus, Keyes, Margaret A., Kiefer, Falk , Koller, Gabriele , Kuperman, Samuel , Lucae, Susanne , Lynskey, Michael T. , Maier, Wolfgang , Müller‐Myhsok, Bertram , Preuss, Ulrich W. , Räikkönen, Katri , Reynolds, Maureen , Ridinger, Monika , Schuckit, Marc A. , Soyka, Michael , Wodarz, Norbert , Zill, Peter , Adkins, Daniel E. , Bucholz, Kathleen K. , Diazgranados, Nancy , Goate, Alison , Goldman, David , Hancock, Dana B. , Hewitt, John K. , Johnson, Eric O. , 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. , Penninx, Brenda W.J.H. , Porjesz, Bernice , Rice, John P. , Rose, Richard J. , Shen, Pei‐Hong , Silberg, Judy L. , Tarter, Ralph E. , Vrieze, Scott , Zhao, Hongyu , Neale, Benjamin M. , Wade, Tracey , Sullivan, Patrick F., Kaprio, Jaakko , Breen, Gerome , Hottenga, Jouke‐Jan , Hakonarson, Hakon , Lissowska, Jolanta , Kennedy, Martin A , Ehrlich, Stefan , Hottenga, Jouke-Jan , Walton, Esther , Cichon, Sven , Luykx, Jurjen J , Nöthen, Markus M , Le Hellard, Stephanie , Penninx, Brenda W J H , Medland, Sarah E , Rabionet, Raquel , Estivil, Xavier , Padyukov, Leonid , Świątkowska, Beata , Dina, Christian , Palotie, Aarno V. , Ripke, Stephan , Whiteman, David C , Scherer, Stephen W , Tortorella, Alfonso , Streit, Fabian , Egberts, Karin , Goate, Alison M , Docherty, Anna R , Johnson, Eric O , Coleman, Jonathan Ri , Johnson, Emma C. , Gordon, Scott D. , Watson, Hunna J. , Gaspar, Héléna A. , Bryois, Julien , Alfredsson, Lars , Andreassen, Ole A. , Boehm, Ilka , Cone, Roger D. , Courtet, Philippe , Crow, Scott J. , Dedoussis, George , Dick, Danielle M. , Dikeos, Dimitris , Escaramís, Geòrgia , Esko, Tõnu , Forzan, Monica , Guillaume, Sébastien , Hauser, Joanna , Herms, Stefan , Herpertz-Dahlmann, Beate , Julià, Antonio , Karhunen, Leila J. , Kennedy, James L. , Li, Dong , Mattingsdal, Morten , Metspalu, Andres , Micali, Nadia , Mitchell, Karen S. , Monteleone, Alessio Maria , Monteleone, Palmiero , Nacmias, Benedetta , Ophoff, Roel A. , Ripatti, Samuli , Roberts, Marion , Santonastaso, Paolo , Scherag, André , Seitz, Jochen , Slagboom, P. Eline , Tenconi, Elena , Τσίτσικα, Άρτεμις , Tyszkiewicz‐Nwafor, Marta , Zeggini, Eleftheria , Boden, Joseph M. , Horwood, L. John , Pearson, John F , Werge, Thomas Mears , Parker, Richard , Lichtenstein, Paul , Norring, Claes E. A. , Mortensen, Preben Bo , Biernacka, Joanna M. , Bigdeli, Tim B. , Clarke, Toni‐Kim , Heilmann‐Heimbach, Stefanie , Hoffmann, Per , Lai, Dongbing , Peterson, Roseann Elizabeth , Sanchez-Roige, Sandra , Schwandt, Melanie L. , Sherva, Richard , Strohmaier, Jana , Thomas, Nathaniel , Wedow, Robbee , Boardman, Jason D., Choi, Doo‐Sup , Degenhardt, Louisa J , Hayward, Caroline , Kramer, John R. , Mann, Karl F , Männistö, Satu , Murray, Alison D. , Nurnberger, John I , Scherbaum, Norbert , Treutlein, Jens , Witt, Stephanie H. , Boomsma, Dorret I , Bierut, Laura Jean , Brown, Sandra A. , Costello, E. Jane , Wit, Harriet de , Eriksson, Johan G. , Farrer, Lindsay A. , Foroud, Tatiana , Gillespie, Nathan A. , Grucza, Richard A. , Harris, Kathleen Mullan , HESSELBROCK, VICTOR M. , Hopfer, Christian Jean , Iacono, William G. , Karpyak, Victor M. , Kendler, Kenneth S. , Kranzler, Henry R. , Palmer, Abraham A. , Rietschel, Marcella , Riley, Brien P. , Stallings, Michael C. , Vanyukov, Michael M. , Wall, Tamara L. , Whitfield, John B. , Heath, Andrew C. , Montgomery, Grant W. , Martin, Nicholas G. , Gelernter, Joel E. , Edenberg, Howard J , Bulik, Cynthia Marie , Agrawal, Arpana , Webb, Bradley T.
Addiction Biology | February 17, 2020 | Volume: 26 | Issue: 1 | Pages: No page available
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.