Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Authors: Mahajan Anubha , Taliun Daniel , Thurner Matthias , Robertson Neil R , Torres Jason M , Rayner N William , Steinthorsdottir Valgerdur , Scott Robert A , Grarup Niels , Cook James P , Schmidt Ellen M , Wuttke Matthias , Sarnowski Chloé , Mägi Reedik , Nano Jana , Gieger Christian , Trompet Stella , Lecoeur Cécile , Preuss Michael , Prins Bram Peter , Guo Xiuqing , Bielak Lawrence F ,   DIAMANTE Consortium, Bennett Amanda J , Bork-Jensen Jette , Brummett Chad M , Canouil Mickaël , Eckardt Kai-Uwe , Fischer Krista , Kardia Sharon LR , Kronenberg Florian , Läll Kristi , Liu Ching-Ti , Locke Adam E , Luan Jian′an , Ntalla Ioanna , Nylander Vibe , Sch࿆nherr Sebastian , Schurmann Claudia , Yengo Loïc , Bottinger Erwin P , Brandslund Ivan , Christensen Cramer , Dedoussis George , Florez Jose C , Ford Ian , Franco Oscar H , Frayling Timothy M , Giedraitis Vilmantas , Hackinger Sophie , Hattersley Andrew T , Herder Christian , Ikram M Arfan , Ingelsson Martin , Jørgensen Marit E , Jørgensen Torben , Kriebel Jennifer , Kuusisto Johanna , Ligthart Symen , Lindgren Cecilia M , Linneberg Allan , Lyssenko Valeriya , Mamakou Vasiliki , Meitinger Thomas , Mohlke Karen L , Morris Andrew D , Nadkarni Girish , Pankow James S , Peters Annette , Sattar Naveed , Stančáková Alena , Strauch Konstantin , Taylor Kent D , Thorand Barbara , Thorleifsson Gudmar , Thorsteinsdottir Unnur , Tuomilehto Jaakko , Witte Daniel R , Dupuis Josée , Peyser Patricia A , Zeggini Eleftheria , Loos Ruth J F , Froguel Philippe , Ingelsson Erik , Lind Lars , Groop Leif , Laakso Markku , Collins Francis S , Jukema J Wouter , Palmer Colin N A , Grallert Harald , Metspalu Andres , Dehghan Abbas , Köttgen Anna , Abecasis Goncalo , Meigs James B , Rotter Jerome I , Marchini Jonathan , Pedersen Oluf , Hansen Torben , Langenberg Claudia , Wareham Nicholas J , Stefansson Kari , Gloyn Anna L , Morris Andrew P , Boehnke Michael , McCarthy Mark I 
Published: January 2018

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<5×10−8; 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.