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

作者：Anubha Mahajan, Jennifer Wessel, Sara M. Willems, Wei Zhao, Neil R. Robertson, Audrey Y. Chu, Wei Gan, Hidetoshi Kitajima, Daniel Taliun, Nigel 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 Prins, Jason A. Flannick, Niels Grarup, Vassily Vladimirovich Trubetskoy, Jasmina Kravić, Young Jin Kim, Denis Rybin, Hanieh Yaghootkar, Martina Müller‐Nurasyid, Karina Meidtner, Ruifang Li‐Gao, Tibor V. Varga, Jonathan Marten, Jin Li, Albert V. Smith, Ping An, Symen Ligthart, Stefan Gustafsson, Giovanni Malerba, Ayşe Demirkan, Juan Fernández Tajes, Valgerður Steinthórsdóttir, Matthias Wuttke, Cécile Lecoeur, Michael H Preuss, Lawrence F. Bielak, Marielisa Graff, Heather M. Highland, Anne E. Justice, Dajiang J. Liu, Eirini Marouli, Gina Marie Peloso, Helen Elizabeth 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 Louis Kovacs, Jennifer Kriebel, Florian Kronenberg, Kristi Läll, Leslie A. Lange, Jung‐Jin Lee, Benjamin C. Lehne, Huaixing Li, Keng‐Hung Lin, Allan R Linneberg, Ching‐Ti Liu, Jun Liu, Marie Chiew Shia Loh, Reedik Mägi, Vasiliki Mamakou, Roberta McKean‐Cowdin, Girish N. Nadkarni, Matt J. Neville, Sune Fallgaard Nielsen, Ioanna Ntalla, Patricia A. Peyser, Wolfgang Rathmann, Kenneth M. Rice, Stephen S. Rich, Line Rode, Olov Rolandsson, Sebastian G. Schönherr, Elizabeth Selvin, Kerrin S. Small, Alena Stančáková, Praveen Surendran, Kent D. Taylor, Tanya M. Teslovich, Barbara Thorand, Guðmar Þorleifsson, 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. Böttinger, Rajiv Chowdhury, Francis S. Collins, George V. Dedoussis, Abbas Dehghan, Panos Deloukas, Maurizio Ferrario, Jean Ferrières, José C. Florez, Philippe Frossard, Vilmundur G. 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 Richard Rosendaal, Anders H. Rosengren, Veikko V Salomaa, Wayne H.-H. Sheu, Robert Sladek, Blair Hamilton Smith, Konstantin Strauch, André Gerardus Uitterlinden, Rohit Varma, Cristen J. Willer, Matthias Blüher, Adam S. Butterworth, John Campbell Chambers, Daniel I. Chasman, John Danesh, Cornelia M. van Duijn, Josée Dupuis, Oscar H. Franco, Paul W. Franks, Philippe Froguel, Harald Grallert, Leif Groop, Bok‐Ghee Han, Torben F. Hansen, Andrew Tym Hattersley, Caroline Hayward, Erik Ingelsson, Sharon L. R. Kardia, Fredrik Karpe, Jaspal Singh Kooner, Anna Köttgen, Kari Kuulasmaa, Markku Laakso, Lin Xu, Lars Lind, Ching‐Ti Liu, Ruth J. F. Loos, Jonathan Marchini, Andres Metspalu, Dennis O. Mook‐Kanamori, Børge Grønne Nordestgaard, Colin N. A. Palmer, James S. Pankow, Oluf Borbye Pedersen, Bruce M. Psaty, Rainer Rauramaa, Naveed A. Sattar, Matthias Bernd Schulze, Nicole Soranzo, Timothy D. Spector, Kāri Stefánsson, Michael Stümvoll, Unnur Arna Thorsteinsdottir, Tiinamaija Tuomi, Jaakko Tuomilehto, Nicholas J. Wareham, JAMES G. WILSON, Eleftheria Zeggini, Robert A. Scott, Inês Barroso, Timothy Mark Frayling, Mark O. Goodarzi, James B. Meigs, Michael Boehnke, Danish Saleheen, Andrew P. Morris, Jerome I. Rotter, Mark I. McCarthy · 发表于：Nature Genetics · 年份：2018 · DOI：10.1038/s41588-018-0084-1 · 被引用次数：473 · 研究领域：AI in cancer detection、Artificial Intelligence in Healthcare、Machine Learning in Healthcare

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. Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.