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

Title: Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Authors: Gaulton, KJ
Ferreira, T
Lee, Y
Raimondo, A
Maegi, R
Reschen, ME
Mahajan, A
Locke, A
Rayner, NW
Robertson, N
Scott, RA
Prokopenko, I
Scott, LJ
Green, T
Sparso, T
Thuillier, D
Yengo, L
Grallert, H
Wahl, S
Franberg, 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
Abecasis, GR
Almgren, P
Baldassarre, D
Balkau, B
Benediktsson, R
Blueher, 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
Jorgensen, ME
Jorgensen, 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
Lyssenko, V
Mannisto, S
McLeod, O
Meyer, J
Mihailov, E
Mirza, G
Muehleisen, TW
Mueller-Nurasyid, M
Navarro, C
Noethen, 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
Sigurdsson, G
Stancakova, 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-Hyovalti, E
Saaristo, TE
Saltevo, J
Kuusisto, J
Laakso, M
Metspalu, A
Erbel, R
Joecke, K-H
Moebus, S
Ripatti, S
Salomaa, V
Ingelsson, E
Boehm, BO
Bergman, RN
Collins, FS
Mohlke, KL
Koistinen, H
Tuomilehto, J
Hveem, K
Njolstad, 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
Item Type: Journal Article
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.
Issue Date: 9-Nov-2015
Date of Acceptance: 7-Oct-2015
URI: http://hdl.handle.net/10044/1/60158
DOI: https://dx.doi.org/10.1038/ng.3437
ISSN: 1546-1718
Publisher: Nature Publishing Group
Start Page: 1415
End Page: 1425
Journal / Book Title: Nature Genetics
Volume: 47
Issue: 12
Copyright Statement: © 2015 Nature America, Inc. All rights reserved
Sponsor/Funder: Wellcome Trust
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 101033/C/13/Z
RDC03 79560
RDC03 79560
MR/L02036X/1
MR/L02036X/1
RDB03 79560
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
LARGE-SCALE ASSOCIATION
HUMAN PANCREATIC-ISLETS
WIDE ASSOCIATION
BETA-CELL
TRANSCRIPTION FACTORS
GLUCOSE-HOMEOSTASIS
GENOTYPE IMPUTATION
INSULIN-SECRETION
COMMON VARIANTS
GLYCEMIC TRAITS
Binding 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
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
11 Medical And Health Sciences
06 Biological Sciences
Developmental Biology
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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