Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Anubha Mahajan, Jennifer Wessel, Sara M. Willems, Wei Zhao, Neil R. Robertson, Audrey Y. Chu, Wei Gan, Hidetoshi Kitajima, Daniel Taliun, N. William Rayner, Xiuqing Guo, Yingchang Lu, Man Li, Richard A. Jensen, Yao Hu, Shaofeng Huo, Kurt K. Lohman, Weihua Zhang, James P. Cook, Bram Peter PrinsJason Flannick, Niels Grarup, Vassily Vladimirovich Trubetskoy, Jasmina Kravic, Young Jin Kim, Denis V. Rybin, Hanieh Yaghootkar, Martina Müller-Nurasyid, Karina Meidtner, Ruifang Li-Gao, Tibor V. Varga, Jonathan Marten, Jin Li, Albert Vernon Smith, Ping An, Symen Ligthart, Stefan Gustafsson, Giovanni Malerba, Ayse Demirkan, Juan Fernandez Tajes, Valgerdur Steinthorsdottir, Matthias Wuttke, Cécile Lecoeur, Michael Preuss, Lawrence F. Bielak, Marielisa Graff, Heather M. Highland, Anne E. Justice, Dajiang J. Liu, Eirini Marouli, Gina Marie Peloso, Helen R. Warren, Saima Afaq, Shoaib Afzal, Emma Ahlqvist, Peter Almgren, Najaf Amin, Lia B. Bang, Alain G. Bertoni, Cristina Bombieri, Jette Bork-Jensen, Ivan Brandslund, Jennifer A. Brody, Noël P. Burtt, Mickaël Canouil, Yii-Der Ida Chen, Yoon Shin Cho, Cramer Christensen, Sophie V. Eastwood, Kai-Uwe Eckardt, Krista Fischer, Giovanni Gambaro, Vilmantas Giedraitis, Megan L. Grove, Hugoline G. de Haan, Sophie Hackinger, Yang Hai, Sohee Han, Anne Tybjærg-Hansen, Marie-France Hivert, Bo Isomaa, Susanne Jäger, Marit E. Jørgensen, Torben Jørgensen, Annemari Käräjämäki, Bong-Jo Kim, Sung Soo Kim, Heikki A. Koistinen, Peter Kovacs, Jennifer Kriebel, Florian Kronenberg, Kristi Läll, Leslie A. Lange, Jung-Jin Lee, Benjamin Lehne, Huaixing Li, Keng-Hung Lin, Allan Linneberg, Ching-Ti Liu, Jun Liu, Marie Loh, Reedik Mägi, Vasiliki Mamakou, Roberta McKean-Cowdin, Girish Nadkarni, Matt Neville, Sune F. Nielsen, Ioanna Ntalla, Patricia A. Peyser, Wolfgang Rathmann, Kenneth Rice, Stephen S. Rich, Line Rode, Olov Rolandsson, Sebastian Schönherr, Elizabeth Selvin, Kerrin S. Small, Alena Stančáková, Praveen Surendran, Kent D. Taylor, Tanya M. Teslovich, Barbara Thorand, Gudmar Thorleifsson, Adrienne Tin, Anke Tönjes, Anette Varbo, Daniel R. Witte, Andrew R. Wood, Pranav Yajnik, Jie Yao, Loïc Yengo, Robin Young, Philippe Amouyel, Heiner Boeing, Eric Boerwinkle, Erwin P. Bottinger, Rajiv Chowdhury, Francis S. Collins, George Dedoussis, Abbas Dehghan, Panos Deloukas, Marco M. Ferrario, Jean Ferrières, Jose C. Florez, Philippe Frossard, Vilmundur Gudnason, Tamara B. Harris, Susan R. Heckbert, Joanna M. M. Howson, Martin Ingelsson, Sekar Kathiresan, Frank Kee, Johanna Kuusisto, Claudia Langenberg, Lenore J. Launer, Cecilia M. Lindgren, Satu Männistö, Thomas Meitinger, Olle Melander, Karen L. Mohlke, Marie Moitry, Andrew D. Morris, Alison D. Murray, Renée de Mutsert, Marju Orho-Melander, Katharine R. Owen, Markus Perola, Annette Peters, Michael A. Province, Asif Rasheed, Paul M. Ridker, Fernando Rivadineira, Frits R. Rosendaal, Anders H. Rosengren, Veikko Salomaa, Wayne H.-H. Sheu, Rob Sladek, Blair H. Smith, Konstantin Strauch, André G. Uitterlinden, Rohit Varma, Cristen J. Willer, Matthias Blüher, Adam S. Butterworth, John Campbell Chambers, Daniel I. Chasman, John Danesh, Cornelia van Duijn, Josée Dupuis, Oscar H. Franco, Paul W. Franks, Philippe Froguel, Harald Grallert, Leif Groop, Bok-Ghee Han, Torben Hansen, Andrew T. Hattersley, Caroline Hayward, Erik Ingelsson, Sharon L. R. Kardia, Fredrik Karpe, Jaspal Singh Kooner, Anna Köttgen, Kari Kuulasmaa, Markku Laakso, Xu Lin, Lars Lind, Yongmei Liu, Ruth J. F. Loos, Jonathan Marchini, Andres Metspalu, Dennis Mook-Kanamori, Børge G. Nordestgaard, Colin N. A. Palmer, James S. Pankow, Oluf Pedersen, Bruce M. Psaty, Rainer Rauramaa, Naveed Sattar, Matthias B. Schulze, Nicole Soranzo, Timothy D. Spector, Kari Stefansson, Michael Stumvoll, Unnur Thorsteinsdottir, Tiinamaija Tuomi, Jaakko Tuomilehto, Nicholas J. Wareham, James G. Wilson, Eleftheria Zeggini, Robert A. Scott, Inês Barroso, Timothy M. Frayling, Mark O. Goodarzi, James B. Meigs, Michael Boehnke, Danish Saleheen, Andrew P. Morris, Jerome I. Rotter, Mark I. McCarthy

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Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
Original languageEnglish
Pages (from-to)559-571
Number of pages13
JournalNature Genetics
Volume50
Issue number4
Early online date9 Apr 2018
DOIs
Publication statusPublished - 30 Apr 2018

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    Mahajan, A., Wessel, J., Willems, S. M., Zhao, W., Robertson, N. R., Chu, A. Y., Gan, W., Kitajima, H., Taliun, D., Rayner, N. W., Guo, X., Lu, Y., Li, M., Jensen, R. A., Hu, Y., Huo, S., Lohman, K. K., Zhang, W., Cook, J. P., ... McCarthy, M. I. (2018). Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nature Genetics, 50(4), 559-571. https://doi.org/10.1038/s41588-018-0084-1