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

Kyle J. Gaulton; 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; 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

doi:10.1038/ng.3437

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 FrånbergRona 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

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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.

Original language	English
Pages (from-to)	1415-1425
Number of pages	11
Journal	Nature Genetics
Volume	47
Issue number	12
Early online date	9 Nov 2015
DOIs	https://doi.org/10.1038/ng.3437
Publication status	Published - Dec 2015

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Gaulton, K. J., Ferreira, T., Lee, Y., Raimondo, A., Mägi, R., Reschen, M. E., Mahajan, A., Locke, A., William Rayner, N., Robertson, N., Scott, R. A., Prokopenko, I., Scott, L. J., Green, T., Sparso, T., Thuillier, D., Yengo, L., Grallert, H., Wahl, S., ... 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

@article{314f1572d6c14592b14af2fe46ab2b7b,

title = "Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci",

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.",

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

year = "2015",

month = dec,

doi = "10.1038/ng.3437",

language = "English",

volume = "47",

pages = "1415--1425",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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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

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

C2 - 26551672

SN - 1061-4036

VL - 47

SP - 1415

EP - 1425

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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