Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann & 31 others Josee Dupuis, Lu Qi, Ayellet V. Segre, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Bostrom, Bert Bravenboer, Suzannah Bumpstead, Noisel P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S. F. Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Andrew D. Morris, Colin N. A. Palmer, GIANT Consortium, MAGIC Investigators

    Research output: Contribution to journalArticle

    1191 Citations (Scopus)

    Abstract

    By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

    Original languageEnglish
    Pages (from-to)579-U155
    Number of pages13
    JournalNature Genetics
    Volume42
    Issue number7
    DOIs
    Publication statusPublished - Jul 2010

    Keywords

    • GENOME-WIDE ASSOCIATION
    • C-REACTIVE PROTEIN
    • FASTING PLASMA-GLUCOSE
    • QT INTERVAL DURATION
    • INSULIN-RESISTANCE
    • COMMON VARIANTS
    • COMPLEX DISEASES
    • GENE-EXPRESSION
    • HNF1-ALPHA GENE
    • CROHNS-DISEASE

    Cite this

    Voight, B. F., Scott, L. J., Steinthorsdottir, V., Morris, A. P., Dina, C., Welch, R. P., ... GIANT Consortium, MAGIC Investigators (2010). Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics, 42(7), 579-U155. https://doi.org/10.1038/ng.609
    Voight, Benjamin F. ; Scott, Laura J. ; Steinthorsdottir, Valgerdur ; Morris, Andrew P. ; Dina, Christian ; Welch, Ryan P. ; Zeggini, Eleftheria ; Huth, Cornelia ; Aulchenko, Yurii S. ; Thorleifsson, Gudmar ; McCulloch, Laura J. ; Ferreira, Teresa ; Grallert, Harald ; Amin, Najaf ; Wu, Guanming ; Willer, Cristen J. ; Raychaudhuri, Soumya ; McCarroll, Steve A. ; Langenberg, Claudia ; Hofmann, Oliver M. ; Dupuis, Josee ; Qi, Lu ; Segre, Ayellet V. ; van Hoek, Mandy ; Navarro, Pau ; Ardlie, Kristin ; Balkau, Beverley ; Benediktsson, Rafn ; Bennett, Amanda J. ; Blagieva, Roza ; Boerwinkle, Eric ; Bonnycastle, Lori L. ; Bostrom, Kristina Bengtsson ; Bravenboer, Bert ; Bumpstead, Suzannah ; Burtt, Noisel P. ; Charpentier, Guillaume ; Chines, Peter S. ; Cornelis, Marilyn ; Couper, David J. ; Crawford, Gabe ; Doney, Alex S. F. ; Elliott, Katherine S. ; Elliott, Amanda L. ; Erdos, Michael R. ; Fox, Caroline S. ; Franklin, Christopher S. ; Ganser, Martha ; Morris, Andrew D. ; Palmer, Colin N. A. ; GIANT Consortium, MAGIC Investigators. / Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. In: Nature Genetics. 2010 ; Vol. 42, No. 7. pp. 579-U155.
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    abstract = "By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.",
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    author = "Voight, {Benjamin F.} and Scott, {Laura J.} and Valgerdur Steinthorsdottir and Morris, {Andrew P.} and Christian Dina and Welch, {Ryan P.} and Eleftheria Zeggini and Cornelia Huth and Aulchenko, {Yurii S.} and Gudmar Thorleifsson and McCulloch, {Laura J.} and Teresa Ferreira and Harald Grallert and Najaf Amin and Guanming Wu and Willer, {Cristen J.} and Soumya Raychaudhuri and McCarroll, {Steve A.} and Claudia Langenberg and Hofmann, {Oliver M.} and Josee Dupuis and Lu Qi and Segre, {Ayellet V.} and {van Hoek}, Mandy and Pau Navarro and Kristin Ardlie and Beverley Balkau and Rafn Benediktsson and Bennett, {Amanda J.} and Roza Blagieva and Eric Boerwinkle and Bonnycastle, {Lori L.} and Bostrom, {Kristina Bengtsson} and Bert Bravenboer and Suzannah Bumpstead and Burtt, {Noisel P.} and Guillaume Charpentier and Chines, {Peter S.} and Marilyn Cornelis and Couper, {David J.} and Gabe Crawford and Doney, {Alex S. F.} and Elliott, {Katherine S.} and Elliott, {Amanda L.} and Erdos, {Michael R.} and Fox, {Caroline S.} and Franklin, {Christopher S.} and Martha Ganser and Morris, {Andrew D.} and Palmer, {Colin N. A.} and {GIANT Consortium, MAGIC Investigators}",
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    pages = "579--U155",
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    Voight, BF, Scott, LJ, Steinthorsdottir, V, Morris, AP, Dina, C, Welch, RP, Zeggini, E, Huth, C, Aulchenko, YS, Thorleifsson, G, McCulloch, LJ, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, CJ, Raychaudhuri, S, McCarroll, SA, Langenberg, C, Hofmann, OM, Dupuis, J, Qi, L, Segre, AV, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, AJ, Blagieva, R, Boerwinkle, E, Bonnycastle, LL, Bostrom, KB, Bravenboer, B, Bumpstead, S, Burtt, NP, Charpentier, G, Chines, PS, Cornelis, M, Couper, DJ, Crawford, G, Doney, ASF, Elliott, KS, Elliott, AL, Erdos, MR, Fox, CS, Franklin, CS, Ganser, M, Morris, AD, Palmer, CNA & GIANT Consortium, MAGIC Investigators 2010, 'Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis', Nature Genetics, vol. 42, no. 7, pp. 579-U155. https://doi.org/10.1038/ng.609

    Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. / Voight, Benjamin F.; Scott, Laura J.; Steinthorsdottir, Valgerdur; Morris, Andrew P.; Dina, Christian; Welch, Ryan P.; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S.; Thorleifsson, Gudmar; McCulloch, Laura J.; Ferreira, Teresa; Grallert, Harald; Amin, Najaf; Wu, Guanming; Willer, Cristen J.; Raychaudhuri, Soumya; McCarroll, Steve A.; Langenberg, Claudia; Hofmann, Oliver M.; Dupuis, Josee; Qi, Lu; Segre, Ayellet V.; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin; Balkau, Beverley; Benediktsson, Rafn; Bennett, Amanda J.; Blagieva, Roza; Boerwinkle, Eric; Bonnycastle, Lori L.; Bostrom, Kristina Bengtsson; Bravenboer, Bert; Bumpstead, Suzannah; Burtt, Noisel P.; Charpentier, Guillaume; Chines, Peter S.; Cornelis, Marilyn; Couper, David J.; Crawford, Gabe; Doney, Alex S. F.; Elliott, Katherine S.; Elliott, Amanda L.; Erdos, Michael R.; Fox, Caroline S.; Franklin, Christopher S.; Ganser, Martha; Morris, Andrew D.; Palmer, Colin N. A.; GIANT Consortium, MAGIC Investigators.

    In: Nature Genetics, Vol. 42, No. 7, 07.2010, p. 579-U155.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

    AU - Voight, Benjamin F.

    AU - Scott, Laura J.

    AU - Steinthorsdottir, Valgerdur

    AU - Morris, Andrew P.

    AU - Dina, Christian

    AU - Welch, Ryan P.

    AU - Zeggini, Eleftheria

    AU - Huth, Cornelia

    AU - Aulchenko, Yurii S.

    AU - Thorleifsson, Gudmar

    AU - McCulloch, Laura J.

    AU - Ferreira, Teresa

    AU - Grallert, Harald

    AU - Amin, Najaf

    AU - Wu, Guanming

    AU - Willer, Cristen J.

    AU - Raychaudhuri, Soumya

    AU - McCarroll, Steve A.

    AU - Langenberg, Claudia

    AU - Hofmann, Oliver M.

    AU - Dupuis, Josee

    AU - Qi, Lu

    AU - Segre, Ayellet V.

    AU - van Hoek, Mandy

    AU - Navarro, Pau

    AU - Ardlie, Kristin

    AU - Balkau, Beverley

    AU - Benediktsson, Rafn

    AU - Bennett, Amanda J.

    AU - Blagieva, Roza

    AU - Boerwinkle, Eric

    AU - Bonnycastle, Lori L.

    AU - Bostrom, Kristina Bengtsson

    AU - Bravenboer, Bert

    AU - Bumpstead, Suzannah

    AU - Burtt, Noisel P.

    AU - Charpentier, Guillaume

    AU - Chines, Peter S.

    AU - Cornelis, Marilyn

    AU - Couper, David J.

    AU - Crawford, Gabe

    AU - Doney, Alex S. F.

    AU - Elliott, Katherine S.

    AU - Elliott, Amanda L.

    AU - Erdos, Michael R.

    AU - Fox, Caroline S.

    AU - Franklin, Christopher S.

    AU - Ganser, Martha

    AU - Morris, Andrew D.

    AU - Palmer, Colin N. A.

    AU - GIANT Consortium, MAGIC Investigators

    PY - 2010/7

    Y1 - 2010/7

    N2 - By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

    AB - By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

    KW - GENOME-WIDE ASSOCIATION

    KW - C-REACTIVE PROTEIN

    KW - FASTING PLASMA-GLUCOSE

    KW - QT INTERVAL DURATION

    KW - INSULIN-RESISTANCE

    KW - COMMON VARIANTS

    KW - COMPLEX DISEASES

    KW - GENE-EXPRESSION

    KW - HNF1-ALPHA GENE

    KW - CROHNS-DISEASE

    U2 - 10.1038/ng.609

    DO - 10.1038/ng.609

    M3 - Article

    VL - 42

    SP - 579-U155

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

    IS - 7

    ER -

    Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics. 2010 Jul;42(7):579-U155. https://doi.org/10.1038/ng.609