@article {Mahajan245506, author = {Anubha Mahajan and Daniel Taliun and Matthias Thurner and Neil R Robertson and Jason M Torres and N William Rayner and Valgerdur Steinthorsdottir and Robert A Scott and Niels Grarup and James P Cook and Ellen M Schmidt and Matthias Wuttke and Chlo{\'e} Sarnowski and Reedik M{\"a}gi and Jana Nano and Christian Gieger and Stella Trompet and C{\'e}cile Lecoeur and Michael Preuss and Bram Peter Prins and Xiuqing Guo and Lawrence F Bielak and DIAMANTE Consortium and Amanda J Bennett and Jette Bork-Jensen and Chad M Brummett and Micka{\"e}l Canouil and Kai-Uwe Eckardt and Krista Fischer and Sharon LR Kardia and Florian Kronenberg and Kristi L{\"a}ll and Ching-Ti Liu and Adam E Locke and Jian'an Luan and Ioanna Ntalla and Vibe Nylander and Sebastian Sch࿆nherr and Claudia Schurmann and Lo{\"\i}c Yengo and Erwin P Bottinger and Ivan Brandslund and Cramer Christensen and George Dedoussis and Jose C Florez and Ian Ford and Oscar H Franco and Timothy M Frayling and Vilmantas Giedraitis and Sophie Hackinger and Andrew T Hattersley and Christian Herder and M Arfan Ikram and Martin Ingelsson and Marit E J{\o}rgensen and Torben J{\o}rgensen and Jennifer Kriebel and Johanna Kuusisto and Symen Ligthart and Cecilia M Lindgren and Allan Linneberg and Valeriya Lyssenko and Vasiliki Mamakou and Thomas Meitinger and Karen L Mohlke and Andrew D Morris and Girish Nadkarni and James S Pankow and Annette Peters and Naveed Sattar and Alena Stan{\v c}{\'a}kov{\'a} and Konstantin Strauch and Kent D Taylor and Barbara Thorand and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Jaakko Tuomilehto and Daniel R Witte and Jos{\'e}e Dupuis and Patricia A Peyser and Eleftheria Zeggini and Ruth J F Loos and Philippe Froguel and Erik Ingelsson and Lars Lind and Leif Groop and Markku Laakso and Francis S Collins and J Wouter Jukema and Colin N A Palmer and Harald Grallert and Andres Metspalu and Abbas Dehghan and Anna K{\"o}ttgen and Goncalo Abecasis and James B Meigs and Jerome I Rotter and Jonathan Marchini and Oluf Pedersen and Torben Hansen and Claudia Langenberg and Nicholas J Wareham and Kari Stefansson and Anna L Gloyn and Andrew P Morris and Michael Boehnke and Mark I McCarthy}, title = {Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps}, elocation-id = {245506}, year = {2018}, doi = {10.1101/245506}, publisher = {Cold Spring Harbor Laboratory}, abstract = {We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of \>30,000 sequenced haplotypes. Analysis of \~{}27M variants (\~{}21M with minor allele frequency [MAF]\<5\%), identified 243 genome-wide significant loci (p\<5{\texttimes}10-8; MAF 0.02\%-50\%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p\<10-5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5\%<=MAF\<5\%) and 24 rare (MAF\<0.5\%) index SNPs at 60 loci, including 14 with estimated allelic OR\>2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for \>80\% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99\%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA\>80\% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18\% of T2D-risk, and individuals in the 2.5\% extremes of a polygenic risk score generated from the GWAS data differed \>9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.}, URL = {https://www.biorxiv.org/content/early/2018/01/09/245506}, eprint = {https://www.biorxiv.org/content/early/2018/01/09/245506.full.pdf}, journal = {bioRxiv} }