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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.* ; Magill, 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.* ; Kardt, K.E.* ; Fischer, K.* ; Kardia, S.L.R.* ; Kronenberg, F.* ; Läll, K.* ; Liu, C.* ; Locke, A.E.* ; Luan, J.* ; Ntalla, L.* ; Nylander, V.* ; Schoenherr, S.* ; Schurmann, C.* ; Yengo, L.* ; Bottinger, E.P.* ; Brandslund, I.* ; Christensen, C.* ; Dedoussis, G.* ; Florez, J.C* ; Ford, I.* ; France, O.H.* ; Frayling, T.M.* ; Giedraitis, V.* ; Hackinger, S.* ; Hattersley, A.T.* ; Herder, C. ; Ikram, M.A.* ; Ingelsson, M.* ; Jorgensen, M.E.* ; Jorgensen, 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.* ; Stancáková, 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.* ; Koettgen, 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.*

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Nat. Genet. 50, 1505-1513 (2018)
Postprint DOI PMC
Open Access Green
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).
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Susceptibility Loci; Genetic Architecture; Disease; Identification; Expression; Metaanalysis; Phenotypes; Traits; Score
Language english
Publication Year 2018
HGF-reported in Year 2018
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 50, Issue: 11, Pages: 1505-1513 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504091-004
G-504000-002
G-504091-002
G-500700-001
G-504000-010
G-504100-001
G-501900-402
DOI 10.1038/s41588-018-0241-6
WOS ID WOS:000448398000006
PubMed ID 30297969
Erfassungsdatum 2018-11-13
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