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

Kyle J. Gaulton (Lead / Corresponding author), Teresa Ferreira, Yeji Lee, Anne Raimondo, Reedik Mägi, Michael E. Reschen, Anubha Mahajan, Adam Locke, N. William Rayner, Neil Robertson, Robert A. Scott, Inga Prokopenko, Laura J. Scott, Todd Green, Thomas Sparso, Dorothee Thuillier, Loic Yengo, Harald Grallert, Simone Wahl, Mattias Frånberg & 29 others Rona J. Strawbridge, Hans Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Lu Qi, Lennart C. Karssen, Elisabeth M. van Leeuwen, Sara M. Willems, Man Li, Han Chen, Christian Fuchsberger, Phoenix Kwan, Clement Ma, Michael Linderman, Yingchang Lu, Soren K. Thomsen, Jana K. Rundle, Nicola L. Beer, Martijn van de Bunt, Anil Chalisey, Hyun Min Kang, Benjamin F. Voight, Alex S. F. Doney, Andrew D. Morris, Colin N. A. Palmer, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

    Research output: Contribution to journalArticle

    146 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1415-1425
    Number of pages11
    JournalNature Genetics
    Volume47
    Issue number12
    Early online date9 Nov 2015
    DOIs
    Publication statusPublished - Dec 2015

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    Type 2 Diabetes Mellitus
    Alleles
    Islets of Langerhans
    Chromatin Immunoprecipitation
    Liver
    Single Nucleotide Polymorphism
    Binding Sites
    Genes

    Cite this

    Gaulton, K. J., Ferreira, T., Lee, Y., Raimondo, A., Mägi, R., Reschen, M. E., ... DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium (2015). Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nature Genetics, 47(12), 1415-1425. https://doi.org/10.1038/ng.3437
    Gaulton, Kyle J. ; Ferreira, Teresa ; Lee, Yeji ; Raimondo, Anne ; Mägi, Reedik ; Reschen, Michael E. ; Mahajan, Anubha ; Locke, Adam ; William Rayner, N. ; Robertson, Neil ; Scott, Robert A. ; Prokopenko, Inga ; Scott, Laura J. ; Green, Todd ; Sparso, Thomas ; Thuillier, Dorothee ; Yengo, Loic ; Grallert, Harald ; Wahl, Simone ; Frånberg, Mattias ; Strawbridge, Rona J. ; Kestler, Hans ; Chheda, Himanshu ; Eisele, Lewin ; Gustafsson, Stefan ; Steinthorsdottir, Valgerdur ; Thorleifsson, Gudmar ; Qi, Lu ; Karssen, Lennart C. ; van Leeuwen, Elisabeth M. ; Willems, Sara M. ; Li, Man ; Chen, Han ; Fuchsberger, Christian ; Kwan, Phoenix ; Ma, Clement ; Linderman, Michael ; Lu, Yingchang ; Thomsen, Soren K. ; Rundle, Jana K. ; Beer, Nicola L. ; van de Bunt, Martijn ; Chalisey, Anil ; Kang, Hyun Min ; Voight, Benjamin F. ; Doney, Alex S. F. ; Morris, Andrew D. ; Palmer, Colin N. A. ; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. / Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. In: Nature Genetics. 2015 ; Vol. 47, No. 12. pp. 1415-1425.
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    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.",
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    Gaulton, KJ, Ferreira, T, Lee, Y, Raimondo, A, Mägi, R, Reschen, ME, Mahajan, A, Locke, A, William Rayner, N, Robertson, N, Scott, RA, Prokopenko, I, Scott, LJ, Green, T, Sparso, T, Thuillier, D, Yengo, L, Grallert, H, Wahl, S, Frånberg, 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, Doney, ASF, Morris, AD, Palmer, CNA & DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium 2015, 'Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci', Nature Genetics, vol. 47, no. 12, pp. 1415-1425. https://doi.org/10.1038/ng.3437

    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. / Gaulton, Kyle J. (Lead / Corresponding author); Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E.; Mahajan, Anubha; Locke, Adam; William Rayner, N.; Robertson, Neil; Scott, Robert A.; Prokopenko, Inga; Scott, Laura J.; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J.; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C.; van Leeuwen, Elisabeth M.; Willems, Sara M.; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K.; Rundle, Jana K.; Beer, Nicola L.; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F.; Doney, Alex S. F. ; Morris, Andrew D.; Palmer, Colin N. A.; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium.

    In: Nature Genetics, Vol. 47, No. 12, 12.2015, p. 1415-1425.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

    AU - Gaulton, Kyle J.

    AU - Ferreira, Teresa

    AU - Lee, Yeji

    AU - Raimondo, Anne

    AU - Mägi, Reedik

    AU - Reschen, Michael E.

    AU - Mahajan, Anubha

    AU - Locke, Adam

    AU - William Rayner, N.

    AU - Robertson, Neil

    AU - Scott, Robert A.

    AU - Prokopenko, Inga

    AU - Scott, Laura J.

    AU - Green, Todd

    AU - Sparso, Thomas

    AU - Thuillier, Dorothee

    AU - Yengo, Loic

    AU - Grallert, Harald

    AU - Wahl, Simone

    AU - Frånberg, Mattias

    AU - Strawbridge, Rona J.

    AU - Kestler, Hans

    AU - Chheda, Himanshu

    AU - Eisele, Lewin

    AU - Gustafsson, Stefan

    AU - Steinthorsdottir, Valgerdur

    AU - Thorleifsson, Gudmar

    AU - Qi, Lu

    AU - Karssen, Lennart C.

    AU - van Leeuwen, Elisabeth M.

    AU - Willems, Sara M.

    AU - Li, Man

    AU - Chen, Han

    AU - Fuchsberger, Christian

    AU - Kwan, Phoenix

    AU - Ma, Clement

    AU - Linderman, Michael

    AU - Lu, Yingchang

    AU - Thomsen, Soren K.

    AU - Rundle, Jana K.

    AU - Beer, Nicola L.

    AU - van de Bunt, Martijn

    AU - Chalisey, Anil

    AU - Kang, Hyun Min

    AU - Voight, Benjamin F.

    AU - Doney, Alex S. F.

    AU - Morris, Andrew D.

    AU - Palmer, Colin N. A.

    AU - DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

    AU - Doney, Alex

    AU - Palmer, Colin

    PY - 2015/12

    Y1 - 2015/12

    N2 - 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.

    AB - 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.

    U2 - 10.1038/ng.3437

    DO - 10.1038/ng.3437

    M3 - Article

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    EP - 1425

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

    IS - 12

    ER -