Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/138839
Title: Fine-mapping 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
Payne, Anthony J.
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 H.
Prins, Bram Peter
Guo, Xiuqing
Bielak, Lawrence F.
Below, Jennifer E.
Bowden, Donald W.
Chambers, John Campbell
Kim, Young Jin
Ng, Maggie Chor Yin
Petty, Lauren E.
Sim, Xueling
Zhang, Weihua
Bennett, Amanda J.
Bork-Jensen, Jette
Brummett, Chad M.
Canouil, Mickaël
Ec Kardt, Kai-Uwe
Fischer, Krista
Kardia, Sharon L. R.
Kronenberg, Florian
Läll, Kristi
Liu, Ching-Ti
Locke, Adam E.
Luan, Jian'an
Ntalla, Ioanna
Nylander, Vibe
Schönherr, 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 R.
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.
Keywords: Science::Medicine
Issue Date: 2018
Source: Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., . . . McCarthy, M. I. (2018). Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nature Genetics, 50(11), 1505-1513. doi:10.1038/s41588-018-0241-6
Journal: Nature Genetics
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).
URI: https://hdl.handle.net/10356/138839
ISSN: 1061-4036
DOI: 10.1038/s41588-018-0241-6
Rights: © 2018 The Author(s), under exclusive licence to Springer Nature America, Inc. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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