Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Creators: name: Nano, J.
name: Kuusisto, J.
name: Lindgren, C.M.
name: Hansen, T.
name: Scott, R.A.
name: Franco, O.H.
name: Chambers, J.C.
name: Eckardt, K.-U.
name: Peters, A.
name: Fischer, K.
name: Yengo, L.
name: Mägi, R.
name: Thorand, B.
name: Wareham, N.J.
name: Nadkarni, G.
name: Köttgen, A.
name: Meigs, J.B.
name: Dedoussis, G.
name: Froguel, P.
name: Petty, L.E.
name: Jørgensen, M.E.
name: Laakso, M.
name: Metspalu, A.
name: Bowden, D.W.
name: Strauch, K.
name: Rotter, J.I.
name: Bennett, A.J.
name: Ingelsson, E.
name: Lecoeur, C.
name: Schmidt, E.M.
name: Palmer, C.N.A.
name: Thorsteinsdottir, U.
name: Torres, J.M.
name: Mahajan, A.
name: Taliun, D.
name: Witte, D.R.
name: Meitinger, T.
name: Peyser, P.A.
name: Frayling, T.M.
name: Ligthart, S.
name: Canouil, M.
name: Läll, K.
name: Guo, X.
name: Thurner, M.
name: Taylor, K.D.
name: Wuttke, M.
name: Luan, J.
name: Zhang, W.
name: Schönherr, S.
name: Pankow, J.S.
name: Christensen, C.
name: Sarnowski, C.
name: Payne, A.J.
name: Jukema, J.W.
name: Brandslund, I.
name: Sattar, N.
name: Kim, Y.J.
name: Mamakou, V.
name: Stefansson, K.
name: Morris, A.D.
name: Gieger, C.
name: Preuss, M.H.
name: Collins, F.S.
name: Linneberg, A.
name: Grarup, N.
name: Lind, L.
name: Langenberg, C.
name: Bielak, L.F.
name: Ingelsson, M.
name: Kronenberg, F.
name: Cook, J.P.
name: Giedraitis, V.
name: Zeggini, E.
name: Nylander, V.
name: Gloyn, A.L.
name: Morris, A.P.
name: Kriebel, J.
name: Bottinger, E.P.
name: Locke, A.E.
name: Hackinger, S.
name: McCarthy, M.I.
name: Grallert, H.
name: Schurmann, C.
name: Brummett, C.M.
name: Bork-Jensen, J.
name: Ntalla, I.
name: Trompet, S.
name: Ng, M.C.Y.
name: Loos, R.J.F.
name: Rayner, N.W.
name: Hattersley, A.T.
name: Jørgensen, T.
name: Marchini, J.
name: Steinthorsdottir, V.
name: Prins, B.P.
name: Dupuis, J.
name: Dehghan, A.
name: Below, J.E.
name: Sim, X.
name: Lyssenko, V.
name: Tuomilehto, J.
name: Abecasis, G.R.
name: Ikram, M.A.
name: Pedersen, O.
name: Stančáková, A.
name: Liu, C.-T.
name: Robertson, N.R.
name: Herder, C.
name: Florez, J.C.
name: Kardia, S.L.R.
name: Mohlke, K.L.
name: Groop, L.
name: Thorleifsson, G.
name: Boehnke, M.
name: Ford, I.
Publisher: name: Nature Publishing Group
Year: 2018

description: 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).