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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E; Mahajan, Anubha; Locke, Adam; William Rayner, N and Robertson, Neil, et al. (2015) In Nature Genetics 47(12). p.1415-1415
Abstract
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-... (More)
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. (Less)
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Nature Genetics
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47
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12
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1415 - 1415
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Nature Publishing Group
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  • pmid:26551672
  • wos:000365813200013
  • scopus:84948984088
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1546-1718
DOI
10.1038/ng.3437
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English
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yes
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88b7f53d-a3ef-4bf8-af45-e14cbfa9e205 (old id 8236899)
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@article{88b7f53d-a3ef-4bf8-af45-e14cbfa9e205,
  abstract     = {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.},
  author       = {Gaulton, Kyle J and Ferreira, Teresa and Lee, Yeji and Raimondo, Anne and Mägi, Reedik and Reschen, Michael E and Mahajan, Anubha and Locke, Adam and William Rayner, N and Robertson, Neil and Scott, Robert A and Prokopenko, Inga and Scott, Laura J and Green, Todd and Sparso, Thomas and Thuillier, Dorothee and Yengo, Loic and Grallert, Harald and Wahl, Simone and Frånberg, Mattias and Strawbridge, Rona J and Kestler, Hans and Chheda, Himanshu and Eisele, Lewin and Gustafsson, Stefan and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Qi, Lu and Karssen, Lennart C and van Leeuwen, Elisabeth M and Willems, Sara M and Li, Man and Chen, Han and Fuchsberger, Christian and Kwan, Phoenix and Ma, Clement and Linderman, Michael and Lu, Yingchang and Thomsen, Soren K and Rundle, Jana K and Beer, Nicola L and van de Bunt, Martijn and Chalisey, Anil and Kang, Hyun Min and Voight, Benjamin F and Abecasis, Gonçalo R and Almgren, Peter and Baldassarre, Damiano and Balkau, Beverley and Benediktsson, Rafn and Blüher, Matthias and Boeing, Heiner and Bonnycastle, Lori L and Bottinger, Erwin P and Burtt, Noël P and Carey, Jason and Charpentier, Guillaume and Chines, Peter S and Cornelis, Marilyn C and Couper, David J and Crenshaw, Andrew T and van Dam, Rob M and Doney, Alex S F and Dorkhan, Mozhgan and Edkins, Sarah and Eriksson, Johan G and Esko, Tonu and Eury, Elodie and Fadista, Joao and Flannick, Jason and Fontanillas, Pierre and Fox, Caroline and Franks, Paul and Gertow, Karl and Gieger, Christian and Gigante, Bruna and Gottesman, Omri and Grant, George B and Grarup, Niels and Groves, Christopher J and Hassinen, Maija and Have, Christian T and Herder, Christian and Holmen, Oddgeir L and Hreidarsson, Astradur B and Humphries, Steve E and Hunter, David J and Jackson, Anne U and Jonsson, Anna and Jørgensen, Marit E and Jørgensen, Torben and Kao, Wen-Hong L and Kerrison, Nicola D and Kinnunen, Leena and Klopp, Norman and Kong, Augustine and Kovacs, Peter and Kraft, Peter and Kravic, Jasmina and Langford, Cordelia and Leander, Karin and Liang, Liming and Lichtner, Peter and Lindgren, Cecilia M and Lindholm, Eero and Linneberg, Allan and Liu, Ching-Ti and Lobbens, Stéphane and Luan, Jian'an and Lyssenko, Valeriya and Männistö, Satu and McLeod, Olga and Meyer, Julia and Mihailov, Evelin and Mirza, Ghazala and Mühleisen, Thomas W and Müller-Nurasyid, Martina and Navarro, Carmen and Nöthen, Markus M and Oskolkov, Nikolay and Owen, Katharine R and Palli, Domenico and Pechlivanis, Sonali and Peltonen, Leena and Perry, John R B and Platou, Carl G P and Roden, Michael and Ruderfer, Douglas and Rybin, Denis and van der Schouw, Yvonne T and Sennblad, Bengt and Sigurðsson, Gunnar and Stančáková, Alena and Steinbach, Gerald and Storm, Petter and Strauch, Konstantin and Stringham, Heather M and Sun, Qi and Thorand, Barbara and Tikkanen, Emmi and Tonjes, Anke and Trakalo, Joseph and Tremoli, Elena and Tuomi, Tiinamaija and Wennauer, Roman and Wiltshire, Steven and Wood, Andrew R and Zeggini, Eleftheria and Dunham, Ian and Birney, Ewan and Pasquali, Lorenzo and Ferrer, Jorge and Loos, Ruth J F and Dupuis, Josée and Florez, Jose C and Boerwinkle, Eric and Pankow, James S and van Duijn, Cornelia and Sijbrands, Eric and Meigs, James B and Hu, Frank B and Thorsteinsdottir, Unnur and Stefansson, Kari and Lakka, Timo A and Rauramaa, Rainer and Stumvoll, Michael and Pedersen, Nancy L and Lind, Lars and Keinanen-Kiukaanniemi, Sirkka M and Korpi-Hyövälti, Eeva and Saaristo, Timo E and Saltevo, Juha and Kuusisto, Johanna and Laakso, Markku and Metspalu, Andres and Erbel, Raimund and Jöcke, Karl-Heinz and Moebus, Susanne and Ripatti, Samuli and Salomaa, Veikko and Ingelsson, Erik and Boehm, Bernhard O and Bergman, Richard N and Collins, Francis S and Mohlke, Karen L and Koistinen, Heikki and Tuomilehto, Jaakko and Hveem, Kristian and Njølstad, Inger and Deloukas, Panagiotis and Donnelly, Peter J and Frayling, Timothy M and Hattersley, Andrew T and de Faire, Ulf and Hamsten, Anders and Illig, Thomas and Peters, Annette and Cauchi, Stephane and Sladek, Rob and Froguel, Philippe and Hansen, Torben and Pedersen, Oluf and Morris, Andrew D and Palmer, Collin N A and Kathiresan, Sekar and Melander, Olle and Nilsson, Peter and Groop, Leif and Barroso, Inês and Langenberg, Claudia and Wareham, Nicholas J and O'Callaghan, Christopher A and Gloyn, Anna L and Altshuler, David and Boehnke, Michael and Teslovich, Tanya M and McCarthy, Mark I and Morris, Andrew P},
  issn         = {1546-1718},
  language     = {eng},
  number       = {12},
  pages        = {1415--1415},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.},
  url          = {http://dx.doi.org/10.1038/ng.3437},
  volume       = {47},
  year         = {2015},
}