@article{Gaulton:2015:10.1038/ng.3437,
author = {Gaulton, KJ and Ferreira, T and Lee, Y and Raimondo, A and Maegi, R and Reschen, ME and Mahajan, A and Locke, A and Rayner, NW and Robertson, N and Scott, RA and Prokopenko, I and Scott, LJ and Green, T and Sparso, T and Thuillier, D and Yengo, L and Grallert, H and Wahl, S and Franberg, M and Strawbridge, RJ and Kestler, H and Chheda, H and Eisele, L and Gustafsson, S and Steinthorsdottir, V and Thorleifsson, G and Qi, L and Karssen, LC and van, Leeuwen EM and Willems, SM and Li, M and Chen, H and Fuchsberger, C and Kwan, P and Ma, C and Linderman, M and Lu, Y and Thomsen, SK and Rundle, JK and Beer, NL and van, de Bunt M and Chalisey, A and Kang, HM and Voight, BF and Abecasis, GR and Almgren, P and Baldassarre, D and Balkau, B and Benediktsson, R and Blueher, M and Boeing, H and Bonnycastle, LL and Bottinger, EP and Burtt, NP and Carey, J and Charpentier, G and Chines, PS and Cornelis, MC and Couper, DJ and Crenshaw, AT and van, Dam RM and Doney, ASF and Dorkhan, M and Edkins, S and},
doi = {10.1038/ng.3437},
journal = {Nature Genetics},
pages = {1415--1425},
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}
}

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TY  - JOUR
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.
AU  - Gaulton,KJ
AU  - Ferreira,T
AU  - Lee,Y
AU  - Raimondo,A
AU  - Maegi,R
AU  - Reschen,ME
AU  - Mahajan,A
AU  - Locke,A
AU  - Rayner,NW
AU  - Robertson,N
AU  - Scott,RA
AU  - Prokopenko,I
AU  - Scott,LJ
AU  - Green,T
AU  - Sparso,T
AU  - Thuillier,D
AU  - Yengo,L
AU  - Grallert,H
AU  - Wahl,S
AU  - Franberg,M
AU  - Strawbridge,RJ
AU  - Kestler,H
AU  - Chheda,H
AU  - Eisele,L
AU  - Gustafsson,S
AU  - Steinthorsdottir,V
AU  - Thorleifsson,G
AU  - Qi,L
AU  - Karssen,LC
AU  - van,Leeuwen EM
AU  - Willems,SM
AU  - Li,M
AU  - Chen,H
AU  - Fuchsberger,C
AU  - Kwan,P
AU  - Ma,C
AU  - Linderman,M
AU  - Lu,Y
AU  - Thomsen,SK
AU  - Rundle,JK
AU  - Beer,NL
AU  - van,de Bunt M
AU  - Chalisey,A
AU  - Kang,HM
AU  - Voight,BF
AU  - Abecasis,GR
AU  - Almgren,P
AU  - Baldassarre,D
AU  - Balkau,B
AU  - Benediktsson,R
AU  - Blueher,M
AU  - Boeing,H
AU  - Bonnycastle,LL
AU  - Bottinger,EP
AU  - Burtt,NP
AU  - Carey,J
AU  - Charpentier,G
AU  - Chines,PS
AU  - Cornelis,MC
AU  - Couper,DJ
AU  - Crenshaw,AT
AU  - van,Dam RM
AU  - Doney,ASF
AU  - Dorkhan,M
AU  - Edkins,S
AU  - Eriksson,JG
AU  - Esko,T
AU  - Eury,E
AU  - Fadista,J
AU  - Flannick,J
AU  - Fontanillas,P
AU  - Fox,C
AU  - Franks,PW
AU  - Gertow,K
AU  - Gieger,C
AU  - Gigante,B
AU  - Gottesman,O
AU  - Grant,GB
AU  - Grarup,N
AU  - Groves,CJ
AU  - Hassinen,M
AU  - Have,CT
AU  - Herder,C
AU  - Holmen,OL
AU  - Hreidarsson,AB
AU  - Humphries,SE
AU  - Hunter,DJ
AU  - Jackson,AU
AU  - Jonsson,A
AU  - Jorgensen,ME
AU  - Jorgensen,T
AU  - Kao,W-HL
AU  - Kerrison,ND
AU  - Kinnunen,L
AU  - Klopp,N
AU  - Kong,A
AU  - Kovacs,P
AU  - Kraft,P
AU  - Kravic,J
AU  - Langford,C
AU  - Leander,K
AU  - Liang,L
AU  - Lichtner,P
AU  - Lindgren,CM
AU  - Lindholm,E
AU  - Linneberg,A
AU  - Liu,C-T
AU  - Lobbens,S
AU  - Luan,J
AU  - Lyssenko,V
AU  - Mannisto,S
AU  - McLeod,O
AU  - Meyer,J
AU  - Mihailov,E
AU  - Mirza,G
AU  - Muehleisen,TW
AU  - Mueller-Nurasyid,M
AU  - Navarro,C
AU  - Noethen,MM
AU  - Oskolkov,NN
AU  - Owen,KR
AU  - Palli,D
AU  - Pechlivanis,S
AU  - Peltonen,L
AU  - Perry,JRB
AU  - Platou,CGP
AU  - Roden,M
AU  - Ruderfer,D
AU  - Rybin,D
AU  - van,der Schouw YT
AU  - Sennblad,B
AU  - Sigurdsson,G
AU  - Stancakova,A
AU  - Steinbach,G
AU  - Storm,P
AU  - Strauch,K
AU  - Stringham,HM
AU  - Sun,Q
AU  - Thorand,B
AU  - Tikkanen,E
AU  - Tonjes,A
AU  - Trakalo,J
AU  - Tremoli,E
AU  - Tuomi,T
AU  - Wennauer,R
AU  - Wiltshire,S
AU  - Wood,AR
AU  - Zeggini,E
AU  - Dunham,I
AU  - Birney,E
AU  - Pasquali,L
AU  - Ferrer,J
AU  - Loos,RJF
AU  - Dupuis,J
AU  - Florez,JC
AU  - Boerwinkle,E
AU  - Pankow,JS
AU  - van,Duijn C
AU  - Sijbrands,E
AU  - Meigs,JB
AU  - Hu,FB
AU  - Thorsteinsdottir,U
AU  - Stefansson,K
AU  - Lakka,TA
AU  - Rauramaa,R
AU  - Stumvoll,M
AU  - Pedersen,NL
AU  - Lind,L
AU  - Keinanen-Kiukaanniemi,SM
AU  - Korpi-Hyovalti,E
AU  - Saaristo,TE
AU  - Saltevo,J
AU  - Kuusisto,J
AU  - Laakso,M
DO  - 10.1038/ng.3437
EP  - 1425
PY  - 2015///
SN  - 1546-1718
SP  - 1415
TI  - Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
T2  - Nature Genetics
UR  - http://dx.doi.org/10.1038/ng.3437
UR  - http://hdl.handle.net/10044/1/60158
VL  - 47
ER  - 

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