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; Niels Grarup; Christian T Have; Anna Jonsson; Marit Eika Jørgensen; Torben Jørgensen; Allan Linneberg; Petter Storm; Inger Njølstad; Torben Hansen; Oluf Pedersen; 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, 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, Niels Grarup, Christian T Have, Anna Jonsson, Marit Eika Jørgensen, Torben Jørgensen, Allan Linneberg, Petter Storm, Inger Njølstad, Torben Hansen, Oluf Pedersen, Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium

227 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	12
Sider (fra-til)	1415-25, 3 unpag. pages
Antal sider	14
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3437
Status	Udgivet - 1 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), 1415-25, 3 unpag. pages. https://doi.org/10.1038/ng.3437

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, Grarup, N, Have, CT, Jonsson, A, Jørgensen, ME, Jørgensen, T, Linneberg, A, Storm, P, Njølstad, I, Hansen, T , Pedersen, O & 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, bind 47, nr. 12, s. 1415-25, 3 unpag. pages. https://doi.org/10.1038/ng.3437

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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 Niels Grarup and Have, {Christian T} and Anna Jonsson and J{\o}rgensen, {Marit Eika} and Torben J{\o}rgensen and Allan Linneberg and Petter Storm and Inger Nj{\o}lstad and Torben Hansen and Oluf Pedersen and {Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium}",

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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 - Grarup, Niels

AU - Have, Christian T

AU - Jonsson, Anna

AU - Jørgensen, Marit Eika

AU - Jørgensen, Torben

AU - Linneberg, Allan

AU - Storm, Petter

AU - Njølstad, Inger

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium

PY - 2015/12/1

Y1 - 2015/12/1

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 - Journal article

C2 - 26551672

SN - 1061-4036

VL - 47

SP - 1415-25, 3 unpag. pages

JO - Nature: New biology

JF - Nature: New biology

IS - 12

ER -

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

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