TY - JOUR T1 - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. JF - Nat Genet Y1 - 2018 A1 - Mahajan, Anubha A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Zhao, Wei A1 - Robertson, Neil R A1 - Chu, Audrey Y A1 - Gan, Wei A1 - Kitajima, Hidetoshi A1 - Taliun, Daniel A1 - Rayner, N William A1 - Guo, Xiuqing A1 - Lu, Yingchang A1 - Li, Man A1 - Jensen, Richard A A1 - Hu, Yao A1 - Huo, Shaofeng A1 - Lohman, Kurt K A1 - Zhang, Weihua A1 - Cook, James P A1 - Prins, Bram Peter A1 - Flannick, Jason A1 - Grarup, Niels A1 - Trubetskoy, Vassily Vladimirovich A1 - Kravic, Jasmina A1 - Kim, Young Jin A1 - Rybin, Denis V A1 - Yaghootkar, Hanieh A1 - Müller-Nurasyid, Martina A1 - Meidtner, Karina A1 - Li-Gao, Ruifang A1 - Varga, Tibor V A1 - Marten, Jonathan A1 - Li, Jin A1 - Smith, Albert Vernon A1 - An, Ping A1 - Ligthart, Symen A1 - Gustafsson, Stefan A1 - Malerba, Giovanni A1 - Demirkan, Ayse A1 - Tajes, Juan Fernandez A1 - Steinthorsdottir, Valgerdur A1 - Wuttke, Matthias A1 - Lecoeur, Cécile A1 - Preuss, Michael A1 - Bielak, Lawrence F A1 - Graff, Marielisa A1 - Highland, Heather M A1 - Justice, Anne E A1 - Liu, Dajiang J A1 - Marouli, Eirini A1 - Peloso, Gina Marie A1 - Warren, Helen R A1 - Afaq, Saima A1 - Afzal, Shoaib A1 - Ahlqvist, Emma A1 - Almgren, Peter A1 - Amin, Najaf A1 - Bang, Lia B A1 - Bertoni, Alain G A1 - Bombieri, Cristina A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Burtt, Noel P A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Cho, Yoon Shin A1 - Christensen, Cramer A1 - Eastwood, Sophie V A1 - Eckardt, Kai-Uwe A1 - Fischer, Krista A1 - Gambaro, Giovanni A1 - Giedraitis, Vilmantas A1 - Grove, Megan L A1 - de Haan, Hugoline G A1 - Hackinger, Sophie A1 - Hai, Yang A1 - Han, Sohee A1 - Tybjærg-Hansen, Anne A1 - Hivert, Marie-France A1 - Isomaa, Bo A1 - Jäger, Susanne A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Käräjämäki, AnneMari A1 - Kim, Bong-Jo A1 - Kim, Sung Soo A1 - Koistinen, Heikki A A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Jung-Jin A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Lin, Keng-Hung A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jun A1 - Loh, Marie A1 - Mägi, Reedik A1 - Mamakou, Vasiliki A1 - McKean-Cowdin, Roberta A1 - Nadkarni, Girish A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Ntalla, Ioanna A1 - Peyser, Patricia A A1 - Rathmann, Wolfgang A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rode, Line A1 - Rolandsson, Olov A1 - Schönherr, Sebastian A1 - Selvin, Elizabeth A1 - Small, Kerrin S A1 - Stančáková, Alena A1 - Surendran, Praveen A1 - Taylor, Kent D A1 - Teslovich, Tanya M A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tin, Adrienne A1 - Tönjes, Anke A1 - Varbo, Anette A1 - Witte, Daniel R A1 - Wood, Andrew R A1 - Yajnik, Pranav A1 - Yao, Jie A1 - Yengo, Loic A1 - Young, Robin A1 - Amouyel, Philippe A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Chowdhury, Rajiv A1 - Collins, Francis S A1 - Dedoussis, George A1 - Dehghan, Abbas A1 - Deloukas, Panos A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Florez, Jose C A1 - Frossard, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Howson, Joanna M M A1 - Ingelsson, Martin A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lindgren, Cecilia M A1 - Männistö, Satu A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Moitry, Marie A1 - Morris, Andrew D A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Orho-Melander, Marju A1 - Owen, Katharine R A1 - Perola, Markus A1 - Peters, Annette A1 - Province, Michael A A1 - Rasheed, Asif A1 - Ridker, Paul M A1 - Rivadineira, Fernando A1 - Rosendaal, Frits R A1 - Rosengren, Anders H A1 - Salomaa, Veikko A1 - Sheu, Wayne H-H A1 - Sladek, Rob A1 - Smith, Blair H A1 - Strauch, Konstantin A1 - Uitterlinden, André G A1 - Varma, Rohit A1 - Willer, Cristen J A1 - Blüher, Matthias A1 - Butterworth, Adam S A1 - Chambers, John Campbell A1 - Chasman, Daniel I A1 - Danesh, John A1 - van Duijn, Cornelia A1 - Dupuis, Josée A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Grallert, Harald A1 - Groop, Leif A1 - Han, Bok-Ghee A1 - Hansen, Torben A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal Singh A1 - Köttgen, Anna A1 - Kuulasmaa, Kari A1 - Laakso, Markku A1 - Lin, Xu A1 - Lind, Lars A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Marchini, Jonathan A1 - Metspalu, Andres A1 - Mook-Kanamori, Dennis A1 - Nordestgaard, Børge G A1 - Palmer, Colin N A A1 - Pankow, James S A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Rauramaa, Rainer A1 - Sattar, Naveed A1 - Schulze, Matthias B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Thorsteinsdottir, Unnur A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Zeggini, Eleftheria A1 - Scott, Robert A A1 - Barroso, Inês A1 - Frayling, Timothy M A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Boehnke, Michael A1 - Saleheen, Danish A1 - Morris, Andrew P A1 - Rotter, Jerome I A1 - McCarthy, Mark I AB -

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); 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.

VL - 50 IS - 4 ER -