Identifying Tissues Implicated in Anorexia Nervosa using Transcriptomic Imputation

Dr. Laura Huckins, Amanda Dobbyn, Whitney McFadden, Dr. Douglas Ruderfer, Weiqing Wang, Dr. Eric Gamazon, Dr. Virpi Leppa, Prof. Roger Adan, Dr. Tetsuya Ando, Dr. Jessica Baker, Dr. Andrew Bergen, Prof. Wade Berrettini, Dr. Andreas Birgegård, Dr. Claudette Boni, Dr. Vesna Boraska Perica, Dr. Harry Brandt, Dr. Roland Burghardt, Dr. Matteo Cassina, Carolyn Cesta, Prof. Maurizio Clementi, Dr. Jonathan Coleman, Prof. Roger Cone, Prof. Philippe Courtet, Dr. Steven Crawford, Prof. Scott Crow, Dr. James Crowley, Dr. Unna Danner, Dr. Oliver Davis, Prof. Martina de Zwaan, Prof. George Dedoussis, Dr. Daniela Degortes, Prof. Janiece DeSocio, Dr. Danielle Dick, Prof. Dimitirs Dikeos, Dr. Monika Dmitrzak-Weglarz, Dr. Elisa Docampo, Dr. Karin Egberts, Dr. Stefan Ehrlich, Dr. Geòrgia Escaramís, Dr. Tõnu Esko, Prof. Xavier Estivill, Prof. Angela Favaro, Prof. Fernando Fernández-Aranda, Prof. Manfred Fichter, Dr. Chris Finan, Dr. Krista Fischer, Dr. Manuel Föcker, Dr. Lenka Foretova, Dr. Monica Forzan, Dr. Christopher Franklin, Dr. Héléna Gaspar, Dr. Fragiskos Gonidakis, Prof. Philip Gorwood, Dr. Monica Gratacos, Prof. Sébastien Guillaume, Dr. Yiran Guo, Dr. Hakon Hakonarson, Prof. Katherine Halmi, Dr. Konstantinos Hatzikotoulas, Prof. Joanna Hauser, Prof. Johannes Hebebrand, Dr. Sietske Helder, Ms. Judith Hendriks, Prof. Beate Herpertz-Dahlmann, Prof. Wolfgang Herzog, Mr. Christopher Hilliard, Prof. Anke Hinney, Prof. James Hudson, Dr. Julia Huemer, Dr. Hartmut Imgart, Prof. Hidetoshi Inoko, Dr. Susana Jiménez-Murcia, Dr. Craig Johnson, Dr. Jenny Jordan, Dr. Anders Juréus, Dr. Gursharan Kalsi, Dr. Debora Kaminska, Prof. Allan Kaplan, Dr. Jaakko Kaprio, Dr. Leila Karhunen, Prof. Andreas Karwautz, Prof. Martien Kas, Prof. Walter Kaye, Dr. James Kennedy, Prof. Martin Kennedy, Dr. Anna Keski-Rahkonen, Dr. Kirsty Kiezebrink, Prof. Youl-Ri Kim, Prof. Kelly Klump, Dr. Gun Peggy Knudsen, Dr. Bobby Koeleman, Dr. Doris Koubek, Dr. Maria La Via, Prof. Mikael Landen, Prof. Robert Levitan, Dr. Dong Li, Dr. Paul Lichtenstein, Dr. Lisa Lilenfeld, Dr. Jolanta Lissowska, Pierre Magistretti, Prof. Mario Maj, Dr. Katrin Mannik, Nicholas Martin, Dr. Sara McDevitt, Prof. Peter McGuffin, Dr. Elisabeth Merl, Prof. Andres Metspalu, Dr. Ingrid Meulenbelt, Dr. Nadia Micali, Prof. James Mitchell, Dr. Karen Mitchell, Prof. Palmiero Monteleone, Alessio Maria Monteleone, Preben Mortensen, Dr. Melissa Munn-Chernoff, Prof. Benedetta Nacmias, Dr. Ida Nilsson, Prof. Claes Norring, Dr. Ioanna Ntalla, Dr. Julie O'Toole, Dr. Jacques Pantel, Prof. Hana Papezova, Mr. Richard Parker, Dr. Raquel Rabionet, Dr. Anu Raevuori, Prof. Andrzej Rajewski, Dr. Nicolas Ramoz, Dr. N.William Rayner, Prof. Ted Reichborn-Kjennerud, Valdo Ricca, Dr. Stephan Ripke, Ms. Franziska Ritschel, Dr. Marion Roberts, Dr. Alessandro Rotondo, Prof. Filip Rybakowski, Prof. Paolo Santonastaso, Prof. André Scherag, Prof. Ulrike Schmidt, Dr. Nicholas Schork, Dr. Alexandra Schosser, Dr. Jochen Seitz, Dr. Lenka Slachtova, Prof. P. Eline Slagboom, Dr. Margarita Slof-Op 't Landt, Dr. Agnieszka Slopien, Dr. Tosha Smith, Prof. Sandro Sorbi, Eric Strengman, Prof. Michael Strober, Prof. Patrick Sullivan, Jin Szatkiewicz, Prof. Neonila Szeszenia-Dabrowska, Dr. Ioanna Tachmazidou, Dr. Elena Tenconi, Dr. Laura Thornton, Dr. Alfonso Tortorella, Dr. Federica Tozzi, Prof. Janet Treasure, Dr. Artemis Tsitsika, Dr. Konstantinos Tziouvas, Dr. Annemarie van Elburg, Prof. Eric van Furth, Prof. Tracey Wade, Dr. Gudrun Wagner, Dr. Esther Walton, Dr. Hunna Watson, Prof. D.Blake Woodside, Ms. Shuyang Yao, Dr. Zeynep Yilmaz, Prof. Eleftheria Zeggini, Dr. Stephanie Zerwas, Prof. Stephan Zipfel, Prof. Lars Alfredsson, Prof. Ole Andreassen, Prof. Harald Aschauer, Dr. Jeffrey Barrett, Prof. Vladimir Bencko, Dr. Laura Carlberg, Prof. Sven Cichon, Dr. Sarah Cohen-Woods, Dr. Christian Dina, Dr. Bo Ding, Thomas Espeseth, Dr. James Floyd, Dr. Steven Gallinger, Prof. Giovanni Gambaro, Dr. Ina Giegling, Dr. Stefan Herms, Prof. Vladimir Janout, Dr. Antonio Julià, Prof. Lars Klareskog, Prof. Stephanie Le Hellard, Dr. Marion Leboyer, Prof. Astri Lundervold, Dr. Sara Marsal, Dr. Morten Mattingsdal, Prof. Marie Navratilova, Prof. Roel Ophoff, Prof. Aarno Palotie, Dr. Dalila Pinto, Prof. Samuli Ripatti, Dr. Dan Rujescu, Prof. Stephen Scherer, Prof. Laura Scott, Dr. Robert Sladek, Prof. Nicole Soranzo, Dr. Lorraine Southam, Dr. Vidar Steen, Prof. H-Erich Wichmann, Dr. Elisabeth Widen, Prof. Bernie Devlin, Dr. Solveig Sieberts, Nancy Cox, Dr. Hae Kyung Im, Dr. Gerome Breen, Dr. Pamela Sklar, Dr. Cynthia M Bulik, Dr. Eli Stahl

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Received: 22nd February 18

Anorexia nervosa (AN) is a complex and serious eating disorder, occurring in ~1% of individuals. Despite having the highest mortality rate of any psychiatric disorder, little is known about the aetiology of AN, and few effective treatments exist. 

Global efforts to collect large sample sizes of individuals with AN have been highly successful, and a recent study consequently identified the first genome-wide significant locus involved in AN. This result, coupled with other recent studies and epidemiological evidence, suggest that previous characterizations of AN as a purely psychiatric disorder are over-simplified. Rather, both neurological and metabolic pathways may also be involved. 

In order to elucidate more of the system-specific aetiology of AN, we applied transcriptomic imputation methods to 3,495 cases and 10,982 controls, collected by the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). Transcriptomic Imputation (TI) methods approaches use machine-learning methods to impute tissue-specific gene expression from large genotype data using curated eQTL reference panels. These offer an exciting opportunity to compare gene associations across neurological and metabolic tissues. Here, we applied CommonMind Consortium (CMC) and GTEx-derived gene expression prediction models for 13 brain tissues and 12 tissues with potential metabolic involvement (adipose, adrenal gland, 2 colon, 3 esophagus, liver, pancreas, small intestine, spleen, stomach). 

We identified 35 significant gene-tissue associations within the large chromosome 12 region described in the recent PGC-ED GWAS. We applied forward stepwise conditional analyses and FINEMAP to associations within this locus to identify putatively causal signals. We identified four independently associated genes; RPS26, C12orf49, SUOX, and RDH16. We also identified two further genome-wide significant gene-tissue associations, both in brain tissues; REEP5, in the dorso-lateral pre-frontal cortex (DLPFC; p=8.52x10-07), and CUL3, in the caudate basal ganglia (p=1.8x10-06). These genes are significantly enriched for associations with anthropometric phenotypes in the UK BioBank, as well as multiple psychiatric, addiction, and appetite/satiety pathways. Our results support a model of AN risk influenced by both metabolic and psychiatric factors.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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