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

TitleGenetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Publication TypeJournal Article
Year of Publication2015
AuthorsGaulton, KJ, Ferreira, T, Lee, Y, Raimondo, A, Mägi, R, Reschen, ME, Mahajan, A, Locke, A, N Rayner, W, 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, HMin, Voight, BF, Abecasis, GR, Almgren, P, Baldassarre, D, Balkau, B, Benediktsson, R, Blüher, 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, Jørgensen, ME, Jørgensen, 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'an, Lyssenko, V, Männistö, S, McLeod, O, Meyer, J, Mihailov, E, Mirza, G, Mühleisen, TW, Müller-Nurasyid, M, Navarro, C, Nöthen, 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, Sigurðsson, G, Stančáková, 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-Hyövälti, E, Saaristo, TE, Saltevo, J, Kuusisto, J, Laakso, M, Metspalu, A, Erbel, R, Jöcke, K-H, Moebus, S, Ripatti, S, Salomaa, V, Ingelsson, E, Boehm, BO, Bergman, RN, Collins, FS, Mohlke, KL, Koistinen, H, Tuomilehto, J, Hveem, K, Njølstad, 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
Corporate Authors
JournalNat Genet
Volume47
Issue12
Pagination1415-25
Date Published2015 Dec
ISSN1546-1718
KeywordsBinding 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, Single Nucleotide, Receptor, Melatonin, MT2
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.

DOI10.1038/ng.3437
Alternate JournalNat. Genet.
PubMed ID26551672
PubMed Central IDPMC4666734
Grant ListR01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HL-64278 / HL / NHLBI NIH HHS / United States
WT098017 / WT / WETP NIH HHS / United States
AG04563 / AG / NIA NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
R01 DK073490 / DK / NIDDK NIH HHS / United States
G0000649 / / Medical Research Council / United Kingdom
WT098395 / WT / WETP NIH HHS / United States
/ / British Heart Foundation / United Kingdom
R01 DK058845 / DK / NIDDK NIH HHS / United States
MRC_G116/165 / / Medical Research Council / United Kingdom
BHF_PG/11/4/28645 / / British Heart Foundation / United Kingdom
N01-HG-65403 / HG / NHGRI NIH HHS / United States
K24DK080140 / DK / NIDDK NIH HHS / United States
GR072960 / / Wellcome Trust / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
AG10175 / AG / NIA NIH HHS / United States
U01 DK085545 / DK / NIDDK NIH HHS / United States
1 Z01 HG000024 / HG / NHGRI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
MRC_G0601261 / / Medical Research Council / United Kingdom
R01DK078616 / DK / NIDDK NIH HHS / United States
N01 HG65403 / HG / NHGRI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
WT101033 / WT / WETP NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
R01 DK098032 / DK / NIDDK NIH HHS / United States
HHSN268201100008 / HL / NHLBI NIH HHS / United States
U01DK085526 / DK / NIDDK NIH HHS / United States
MRC_MC_U106179472 / / Medical Research Council / United Kingdom
AG028555 / AG / NIA NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
WT072960 / WT / WETP NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
MRC_MC_UU_12015/1 / / Medical Research Council / United Kingdom
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
DK58845 / DK / NIDDK NIH HHS / United States
HHSN268201100005 / HL / NHLBI NIH HHS / United States
N01HC25195 / HC / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
U01HG004399 / HG / NHGRI NIH HHS / United States
1Z01HG000024 / HG / NHGRI NIH HHS / United States
R01DK062370 / DK / NIDDK NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
R01 DK062370 / DK / NIDDK NIH HHS / United States
WT090532 / WT / WETP NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
R01 DK101478 / DK / NIDDK NIH HHS / United States
R01 AG028555 / AG / NIA NIH HHS / United States
WT076113 / WT / WETP NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
MRC_MR/L02036X/1 / / Medical Research Council / United Kingdom
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
R01DK073490 / DK / NIDDK NIH HHS / United States
Z01 HG000024-13 / / Intramural NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
MRC_MC_U106179471 / / Medical Research Council / United Kingdom
U01 DK085526 / DK / NIDDK NIH HHS / United States
WT098381 / WT / WETP NIH HHS / United States
AG08861 / AG / NIA NIH HHS / United States
DK085545 / DK / NIDDK NIH HHS / United States
HHSN268201100011 / HL / NHLBI NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
AG08724 / AG / NIA NIH HHS / United States
DK098032 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01DK072193 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HC-25195 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
HHSN268201100009 / HL / NHLBI NIH HHS / United States
CA055075 / CA / NCI NIH HHS / United States
WT090367 / WT / WETP NIH HHS / United States
HL64278 / HL / NHLBI NIH HHS / United States
WT095101 / WT / WETP NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
WT086596 / WT / WETP NIH HHS / United States
R01 AG010175 / AG / NIA NIH HHS / United States
U01 HG004399 / HG / NHGRI NIH HHS / United States
WT083270 / WT / WETP NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
WT098051 / WT / WETP NIH HHS / United States
MRC_MC_UU_12015/2 / / Medical Research Council / United Kingdom
WT083948 / WT / WETP NIH HHS / United States