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

Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R Robertson, Jason M Torres, N William Rayner, Anthony J Payne, Valgerdur Steinthorsdottir, Robert A Scott, Niels Grarup, James P Cook, Ellen M Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecoeur, Michael H PreussBram Peter Prins, Xiuqing Guo, Lawrence F Bielak, Jennifer E Below, Donald W Bowden, John Campbell Chambers, Young Jin Kim, Maggie C Y 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, Ching-Ti Liu, Adam E Locke, Jian'an Luan, Ioanna Ntalla, Vibe Nylander, Sebastian Schönherr, Claudia Schurmann, Loïc Yengo, Erwin P Bottinger, Ivan Brandslund, Cramer Christensen, George Dedoussis, Jose 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 Nadkarni, James S Pankow, Annette Peters, Naveed Sattar, Alena Stančáková, Konstantin Strauch, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, 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, Colin N A Palmer, Harald Grallert, Andres Metspalu, Abbas Dehghan, Anna Köttgen, Goncalo R Abecasis, James B Meigs, Jerome I Rotter, Jonathan Marchini, Oluf Pedersen, Torben Hansen, Claudia Langenberg, Nicholas J Wareham, Kari Stefansson, Anna L Gloyn, Andrew P Morris, Michael Boehnke, Mark I McCarthy

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Abstract

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 <5%, 14 with estimated allelic odds ratio >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).

Original languageEnglish
Pages (from-to)1505-1513
Number of pages9
JournalNature Genetics
Volume50
Issue number11
Early online date8 Oct 2018
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

  • Body Mass Index
  • Case-Control Studies
  • Chromosome Mapping/methods
  • Diabetes Mellitus, Type 2/epidemiology
  • Epigenesis, Genetic
  • European Continental Ancestry Group/genetics
  • Female
  • Gene Frequency
  • Genetic Loci/genetics
  • Genetic Predisposition to Disease
  • Genome, Human/genetics
  • Genome-Wide Association Study
  • High-Throughput Screening Assays/methods
  • Humans
  • Islets of Langerhans/metabolism
  • Linkage Disequilibrium
  • Male
  • Meta-Analysis as Topic
  • Polymorphism, Single Nucleotide
  • Sex Factors

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