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

Επιστημονική δημοσίευση - Άρθρο Περιοδικού uoadl:3085494 66 Αναγνώσεις

Μονάδα:
Ερευνητικό υλικό ΕΚΠΑ
Τίτλος:
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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). © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
Έτος δημοσίευσης:
2018
Συγγραφείς:
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.
Περιοδικό:
Nature Genetics
Εκδότης:
Nature Publishing Group
Τόμος:
50
Αριθμός / τεύχος:
11
Σελίδες:
1505-1513
Λέξεις-κλειδιά:
adult; Article; body mass; controlled study; disease predisposition; epigenetics; European; female; FTO gene; gene; gene frequency; gene locus; gene mapping; genetic association; genetic predisposition; genetic risk; genetic susceptibility; genetic trait; genetic variability; genome-wide association study; genotype; gnpda2 gene; haplotype; heritability; human; major clinical study; male; mc4r gene; middle aged; non insulin dependent diabetes mellitus; priority journal; sec16b gene; sex difference; single nucleotide polymorphism; tmem18 gene; case control study; Caucasian; chromosomal mapping; gene linkage disequilibrium; gene locus; genetic epigenesis; genetics; genome-wide association study; high throughput screening; human genome; meta analysis (topic); metabolism; non insulin dependent diabetes mellitus; pancreas islet; pathology; procedures; sex factor, Body Mass Index; Case-Control Studies; Chromosome Mapping; Diabetes Mellitus, Type 2; Epigenesis, Genetic; European Continental Ancestry Group; Female; Gene Frequency; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; High-Throughput Screening Assays; Humans; Islets of Langerhans; Linkage Disequilibrium; Male; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Sex Factors
Επίσημο URL (Εκδότης):
DOI:
10.1038/s41588-018-0241-6
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