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Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
- Source :
- Mahajan, A, Taliun, D, Thurner, M, Robertson, N R, Torres, J M, Rayner, N W, Payne, A J, Steinthorsdottir, V, Scott, R A, Grarup, N, Cook, J P, Schmidt, E M, Wuttke, M, Sarnowski, C, Mägi, R, Nano, J, Gieger, C, Trompet, S, Lecoeur, C, Preuss, M H, Prins, B P, Guo, X, Bielak, L F, Below, J E, Bowden, D W, Chambers, J C, Kim, Y J, Ng, M C Y, Petty, L E, Sim, X, Zhang, W, Bennett, A J, Bork-Jensen, J, Brummett, C M, Canouil, M, Ec Kardt, K-U, Fischer, K, Kardia, S L R, Kronenberg, F, Läll, K, Liu, C-T, Locke, A E, Luan, J, Ntalla, I, Nylander, V, Schönherr, S, Schurmann, C, Yengo, L, Bottinger, E P, Brandslund, I, Christensen, C, Dedoussis, G, Florez, J C, Ford, I, Franco, O H, Frayling, T M, Giedraitis, V, Hackinger, S, Hattersley, A T, Herder, C, Ikram, M A, Ingelsson, M, Jørgensen, M E, Jørgensen, T, Kriebel, J, Kuusisto, J, Ligthart, S, Lindgren, C M, Linneberg, A, Lyssenko, V, Mamakou, V, Meitinger, T, Mohlke, K L, Morris, A D, Nadkarni, G, Pankow, J S, Peters, A, Sattar, N, Stančáková, A, Strauch, K, Taylor, K D, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Tuomilehto, J, Witte, D R, Dupuis, J, Peyser, P A, Zeggini, E, Loos, R J F, Froguel, P, Ingelsson, E, Lind, L, Groop, L, Laakso, M, Collins, F S, Jukema, J W, Palmer, C N A, Grallert, H, Metspalu, A, Dehghan, A, Köttgen, A, Abecasis, G R, Meigs, J B, Rotter, J I, Marchini, J, Pedersen, O, Hansen, T, Langenberg, C, Wareham, N J, Stefansson, K, Gloyn, A L, Morris, A P, Boehnke, M & McCarthy, M I 2018, ' Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps ', Nature Genetics, vol. 50, no. 11, pp. 1505-1513 . https://doi.org/10.1038/s41588-018-0241-6
- Publication Year :
- 2018
-
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 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).
- Subjects :
- endocrine system diseases
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Mahajan, A, Taliun, D, Thurner, M, Robertson, N R, Torres, J M, Rayner, N W, Payne, A J, Steinthorsdottir, V, Scott, R A, Grarup, N, Cook, J P, Schmidt, E M, Wuttke, M, Sarnowski, C, Mägi, R, Nano, J, Gieger, C, Trompet, S, Lecoeur, C, Preuss, M H, Prins, B P, Guo, X, Bielak, L F, Below, J E, Bowden, D W, Chambers, J C, Kim, Y J, Ng, M C Y, Petty, L E, Sim, X, Zhang, W, Bennett, A J, Bork-Jensen, J, Brummett, C M, Canouil, M, Ec Kardt, K-U, Fischer, K, Kardia, S L R, Kronenberg, F, Läll, K, Liu, C-T, Locke, A E, Luan, J, Ntalla, I, Nylander, V, Schönherr, S, Schurmann, C, Yengo, L, Bottinger, E P, Brandslund, I, Christensen, C, Dedoussis, G, Florez, J C, Ford, I, Franco, O H, Frayling, T M, Giedraitis, V, Hackinger, S, Hattersley, A T, Herder, C, Ikram, M A, Ingelsson, M, Jørgensen, M E, Jørgensen, T, Kriebel, J, Kuusisto, J, Ligthart, S, Lindgren, C M, Linneberg, A, Lyssenko, V, Mamakou, V, Meitinger, T, Mohlke, K L, Morris, A D, Nadkarni, G, Pankow, J S, Peters, A, Sattar, N, Stančáková, A, Strauch, K, Taylor, K D, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Tuomilehto, J, Witte, D R, Dupuis, J, Peyser, P A, Zeggini, E, Loos, R J F, Froguel, P, Ingelsson, E, Lind, L, Groop, L, Laakso, M, Collins, F S, Jukema, J W, Palmer, C N A, Grallert, H, Metspalu, A, Dehghan, A, Köttgen, A, Abecasis, G R, Meigs, J B, Rotter, J I, Marchini, J, Pedersen, O, Hansen, T, Langenberg, C, Wareham, N J, Stefansson, K, Gloyn, A L, Morris, A P, Boehnke, M & McCarthy, M I 2018, ' Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps ', Nature Genetics, vol. 50, no. 11, pp. 1505-1513 . https://doi.org/10.1038/s41588-018-0241-6
- Accession number :
- edsair.pure.au.......4c8292b6070f0d4db60865ff05bcd506