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Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

2018; Nature Portfolio; Volume: 50; Issue: 11 Linguagem: Inglês

10.1038/s41588-018-0241-6

1546-1718

Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R. Robertson, Jason Torres, Nigel W. Rayner, A. J. Payne, Valgerður Steinthórsdóttir, Robert A. Scott, Niels Grarup, James P. Cook, Ellen M. Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecœur, Michael Preuß, Bram P. Prins, Xiuqing Guo, Lawrence F. Bielak, Jennifer E. Below, Donald W. Bowden, John C. Chambers, Young Jin Kim, Maggie Ng, Lauren E. Petty, Xueling Sim, Weihua Zhang, Amanda J. Bennett, Jette Bork‐Jensen, Chad M. Brummett, Mickaël Canouil, Kai-Uwe Ec kardt, Krista Fischer, Sharon L. R. Kardia, Florian Kronenberg, Kristi Läll, Yongmei Liu, Adam E. Locke, Jian’an Luan, Ιωάννα Ντάλλα, Vibe Nylander, Sebastian Schönherr, Claudia Schurmann, Loïc Yengo, Erwin P. Böttinger, Ivan Brandslund, Cramer Christensen, George Dedoussis, José C. Florez, Ian Ford, Oscar H. Franco, Timothy M. Frayling, Vilmantas Giedraitis, Sophie Hackinger, Andrew T. Hattersley, Christian Herder, M. Arfan Ikram, Martin Ingelsson, Marit E. Jørgensen, Torben Jørgensen, Jennifer Kriebel, Johanna Kuusisto, Symen Ligthart, Cecilia M. Lindgren, Allan Linneberg, Valeriya Lyssenko, Vasiliki Mamakou, Thomas Meitinger, Karen L. Mohlke, Andrew D. Morris, Girish N. Nadkarni, James S. Pankow, Annette Peters, Naveed Sattar, Alena Stančáková, Konstantin Strauch, Kent D. Taylor, Barbara Thorand, Guðmar Þorleifsson, Unnur Þorsteinsdóttir, Jaakko Tuomilehto, Daniel R. Witte, Josée Dupuis, Patricia A. Peyser, Eleftheria Zeggini, Ruth J. F. Loos, Philippe Froguel, Erik Ingelsson, Lars Lind, Leif Groop, Markku Laakso, Francis S. Collins, J. Wouter Jukema, Nicholette D. Palmer, Harald Grallert, Andres Metspalu, Abbas Dehghan, Anna Köttgen, Gonçalo R. Abecasis, James B. Meigs, Jerome I. Rotter, Jonathan Marchini, Oluf Pedersen, Torben Hansen, Claudia Langenberg, Nicholas J. Wareham, Kári Stéfansson, Anna L. Gloyn, Andrew P. Morris, Michael Boehnke, Mark I. McCarthy,

Epigenetics and DNA Methylation

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence). Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.