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Refining The Accuracy Of Validated Target Identification Through Coding Variant Fine-Mapping In Type 2 Diabetes

By 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, Mark I. McCarthy, James P Cook, Bram Prins, Jason Flannick, Niels Grarup, Vassily Vladimirovich Trubetskoy, Jasmina Kravic, Young Jin Kim, Denis V Rybin, Hanieh Yaghootkar, Martina Mñller-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, ExomeBP Consortium, MAGIC Consortium, GIANT Consortium, 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, Josee 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 LR 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

Posted 31 May 2017
bioRxiv DOI: 10.1101/144410 (published DOI: 10.1038/s41588-018-0084-1)

Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p<2.2x10-7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency <5%, and we find no evidence for low-frequency variants with allelic odds ratio >1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the 'annotation-weighted' model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent 'false leads' and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.

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