Identifying tissues implicated in Anorexia Nervosa using Transcriptomic Imputation
Authors: Huckins Laura M. , Dobbyn Amanda , McFadden Whitney , Ruderfer Douglas , Wang Weiqing , Gamazon Eric , Leppä Virpi , Adan Roger , Ando Tetsuya , Baker Jessica , Bergen Andrew , Berrettini Wade , Birgegård Andreas , Boni Claudette , Boraska Perica Vesna , Brandt Harry , Burghardt Roland , Cassina Matteo , Cesta Carolyn , Clementi Maurizio , Coleman Joni , Cone Roger , Courtet Philippe , Crawford Steven , Crow Scott , Crowley James , Danner Unna , Davis Oliver , de Zwaan Martina , Dedoussis George , Degortes Daniela , DeSocio Janiece , Dick Danielle , Dikeos Dimitris , Dmitrzak-Weglarz Monika , Docampo Elisa , Egberts Karin , Ehrlich Stefan , Escaramís Geòrgia , Esko Tonu , Estivill Xavier , Angela Favaro , Fernández-Aranda Fernando , Fichter Manfred , Finan Chris , Fischer Krista , Foretova Lenka , Forzan Monica , Franklin Christopher , Gaspar Héléna , Gonidakis Fragiskos , Gorwood Philip , Monica Gratacos , Guillaume Sébastien , Guo Yiran , Hakonarson Hakon , Halmi Katherine , Hatzikotoulas Konstantinos , Hauser Joanna , Hebebrand Johannes , Helder Sietske , Hendriks Judith , Herpertz-Dahlmann Beate , Herzog Wolfgang , Hilliard Christopher , Hinney Anke , Hudson James , Huemer Julia , Imgart Hartmut , Inoko Hidetoshi , Jiménez-Murcia Susana , Johnson Craig , Jordan Jenny , Juréus Anders , Kalsi Gursharan , Kaminska Debora , Kaplan Allan , Kaprio Jaakko , Karhunen Leila , Karwautz Andreas , Kas Martien , Kaye Walter , Kennedy James , Kennedy Martin , Keski-Rahkonen Anna , Kiezebrink Kirsty , Kim Youl-Ri , Klump Kelly , Knudsen Gun Peggy , Koeleman Bobby , Koubek Doris , La Via Maria , Landén Mikael , Levitan Robert , Li Dong , Lichtenstein Paul , Lilenfeld Lisa , Lissowska Jolanta , Magistretti Pierre , Maj Mario , Mannik Katrin , Martin Nicholas , McDevitt Sara , McGuffin Peter , Merl Elisabeth , Metspalu Andres , Meulenbelt Ingrid , Micali Nadia , Mitchell James , Mitchell Karen , Monteleone Palmiero , Monteleone Alessio Maria , Mortensen Preben , Munn-Chernoff Melissa , Nacmias Benedetta , Nilsson Ida , Norring Claes , Ntalla Ioanna , O'Toole Julie , Pantel Jacques , Papezova Hana , Parker Richard , Rabionet Raquel , Raevuori Anu , Rajewski Andrzej , Ramoz Nicolas , Rayner N. William , Reichborn-Kjennerud Ted , Ricca Valdo , Ripke Stephan , Ritschel Franziska , Roberts Marion , Rotondo Alessandro , Rybakowski Filip , Santonastaso Paolo , Scherag André , Schmidt Ulrike , Schork Nicholas , Schosser Alexandra , Seitz Jochen , Slachtova Lenka , Slagboom P. Eline , Slof-Op ’t Landt Margarita , Slopien Agnieszka , Smith Tosha , Sorbi Sandro , Strengman Eric , Strober Michael , Sullivan Patrick , Szatkiewicz Jin , Szeszenia-Dabrowska Neonila , Tachmazidou Ioanna , Tenconi Elena , Thornton Laura , Tortorella Alfonso , Tozzi Federica , Treasure Janet , Tsitsika Artemis , Tziouvas Konstantinos , van Elburg Annemarie , van Furth Eric , Wade Tracey , Wagner Gudrun , Walton Esther , Watson Hunna , Woodside D. Blake , Yao Shuyang , Yilmaz Zeynep , Zeggini Eleftheria , Zerwas Stephanie , Zipfel Stephan , Lars Alfredsson , Ole Andreassen , Aschauer Harald , Barrett Jeffrey , Bencko Vladimir , Carlberg Laura , Cichon Sven , Cohen-Woods Sarah , Dina Christian , Ding Bo , Espeseth Thomas , Floyd James , Gallinger Steven , Gambaro Giovanni , Giegling Ina , Herms Stefan , Janout Vladimir , Juliá Antonio , Klareskog Lars , Le Hellard Stephanie , Leboyer Marion , Lundervold Astri J. , Marsal Sara , Mattingsdal Morten , Navratilova Marie , Ophoff Roel , Palotie Aarno , Pinto Dalila , Ripatti Samuli , Rujescu Dan , Scherer Stephen , Scott Laura , Sladek Robert , Soranzo Nicole , Southam Lorraine , Steen Vidar , H-Erich Wichmann , Widen Elisabeth , Devlin Bernie , Sieberts Solveig K. , Cox Nancy , Kyung Im Hae , Breen Gerome , Sklar Pamela , Bulik Cynthia , Stahl Eli A. 
Published: February 2018

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, andRDH16.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=8.52×10−07), andCUL3, in the caudate basal ganglia (p=1.8×10−06). 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.