التفاصيل البيبلوغرافية
| العنوان: |
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. |
| المؤلفون: |
Gaulton, KJ, Ferreira, T, Lee, Y, Raimondo, A, Maegi, R, Reschen, ME, Mahajan, A, Locke, A, Rayner, NW, Robertson, N, Scott, RA, Prokopenko, I, Scott, LJ, Green, T, Sparso, T, Thuillier, D, Yengo, L, Grallert, H, Wahl, S, Franberg, M, Strawbridge, RJ, Kestler, H, Chheda, H, Eisele, L, Gustafsson, S, Steinthorsdottir, V, Thorleifsson, G, Qi, L, Karssen, LC, Van Leeuwen, EM, Willems, SM, Li, M, Chen, H, Fuchsberger, C, Kwan, P, Ma, C, Linderman, M, Lu, Y, Thomsen, SK, Rundle, JK, Beer, NL, Van de Bunt, M, Chalisey, A, Kang, HM, Voight, BF, Abecasis, GR, Almgren, P, Baldassarre, D, Balkau, B, Benediktsson, R, Blueher, M, Boeing, H, Bonnycastle, LL, Bottinger, EP, Burtt, NP, Carey, J, Charpentier, G, Chines, PS, Cornelis, MC, Couper, DJ, Crenshaw, AT, Van Dam, RM, Doney, ASF, Dorkhan, M, Edkins, S, Eriksson, JG, Esko, T, Eury, E, Fadista, J, Flannick, J, Fontanillas, P, Fox, C, Franks, PW, Gertow, K, Gieger, C, Gigante, B, Gottesman, O, Grant, GB, Grarup, N, Groves, CJ, Hassinen, M, Have, CT, Herder, C, Holmen, OL, Hreidarsson, AB, Humphries, SE, Hunter, DJ, Jackson, AU, Jonsson, A, Jorgensen, ME, Jorgensen, T, Kao, W-HL, Kerrison, ND, Kinnunen, L, Klopp, N, Kong, A, Kovacs, P, Kraft, P, Kravic, J, Langford, C, Leander, K, Liang, L, Lichtner, P, Lindgren, CM, Lindholm, E, Linneberg, A, Liu, C-T, Lobbens, S, Luan, J, Lyssenko, V, Mannisto, S, McLeod, O, Meyer, J, Mihailov, E, Mirza, G, Muehleisen, TW, Mueller-Nurasyid, M, Navarro, C, Noethen, MM, Oskolkov, NN, Owen, KR, Palli, D, Pechlivanis, S, Peltonen, L, Perry, JRB, Platou, CGP, Roden, M, Ruderfer, D, Rybin, D, Van der Schouw, YT, Sennblad, B, Sigurdsson, G, Stancakova, A, Steinbach, G, Storm, P, Strauch, K, Stringham, HM, Sun, Q, Thorand, B, Tikkanen, E, Tonjes, A, Trakalo, J, Tremoli, E, Tuomi, T, Wennauer, R, Wiltshire, S, Wood, AR, Zeggini, E, Dunham, I, Birney, E, Pasquali, L, Ferrer, J, Loos, RJF, Dupuis, J, Florez, JC, Boerwinkle, E, Pankow, JS, Van Duijn, C, Sijbrands, E, Meigs, JB, Hu, FB, Thorsteinsdottir, U, Stefansson, K, Lakka, TA, Rauramaa, R, Stumvoll, M, Pedersen, NL, Lind, L, Keinanen-Kiukaanniemi, SM, Korpi-Hyovalti, E, Saaristo, TE, Saltevo, J, Kuusisto, J, Laakso, M, Metspalu, A, Erbel, R, Joecke, K-H, Moebus, S, Ripatti, S, Salomaa, V, Ingelsson, E, Boehm, BO, Bergman, RN, Collins, FS, Mohlke, KL, Koistinen, H, Tuomilehto, J, Hveem, K, Njolstad, I, Deloukas, P, Donnelly, PJ, Frayling, TM, Hattersley, AT, De Faire, U, Hamsten, A, Illig, T, Peters, A, Cauchi, S, Sladek, R, Froguel, P, Hansen, T, Pedersen, O, Morris, AD, Palmer, CNA, Kathiresan, S, Melander, O, Nilsson, PM, Groop, LC, Barroso, I, Langenberg, C, Wareham, NJ, O'Callaghan, CA, Gloyn, AL, Altshuler, D, Boehnke, M, Teslovich, TM, McCarthy, MI, Morris, AP |
| المساهمون: |
Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC) |
| المصدر: |
1425 ; 1415 |
| بيانات النشر: |
Nature Publishing Group |
| سنة النشر: |
2015 |
| المجموعة: |
Imperial College London: Spiral |
| مصطلحات موضوعية: |
Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, LARGE-SCALE ASSOCIATION, HUMAN PANCREATIC-ISLETS, WIDE ASSOCIATION, BETA-CELL, TRANSCRIPTION FACTORS, GLUCOSE-HOMEOSTASIS, GENOTYPE IMPUTATION, INSULIN-SECRETION, COMMON VARIANTS, GLYCEMIC TRAITS, Binding Sites, Case-Control Studies, Chromatin Immunoprecipitation, Chromosome Mapping, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Hepatocyte Nuclear Factor 3-beta, Humans, Islets of Langerhans, Liver, Molecular Sequence Annotation, Polymorphism |
| الوصف: |
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| تدمد: |
1546-1718 |
| العلاقة: |
Nature Genetics; http://hdl.handle.net/10044/1/60158Test; https://dx.doi.org/10.1038/ng.3437Test; 101033/C/13/Z; RDC03 79560; MR/L02036X/1; RDB03 79560 |
| DOI: |
10.1038/ng.3437 |
| الإتاحة: |
https://doi.org/10.1038/ng.3437Test
http://hdl.handle.net/10044/1/60158Test |
| حقوق: |
© 2015 Nature America, Inc. All rights reserved |
| رقم الانضمام: |
edsbas.E4BEA596 |
| قاعدة البيانات: |
BASE |
