Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation

M. Horikoshi; R. Mägi; M. van de Bunt; I. Surakka; A.-P. Sarin; A. Mahajan; L. Marullo; G. Thorleifsson; S. Hägg; J.J. Hottenga; C. Ladenvall; J.S. Ried; T.W. Winkler; S.M. Willems; N. Pervjakova; T. Esko; M. Beekman; C.P. Nelson; C. Willenborg; S. Wiltshire; T. Ferreira; J. Fernandez; K.J. Gaulton; V. Steinthorsdottir; A. Hamsten; P.K.E. Magnusson; G. Willemsen; Y. Milaneschi; N.R. Robertson; C.J. Groves; A.J. Bennett; T. Lehtimäki; J.S. Viikari; J. Rung; V. Lyssenko; M. Perola; I.M. Heid; C. Herder; H. Grallert; M. Müller-Nurasyid; M. Roden; E. Hypponen; A. Isaacs; E.M. van Leeuwen; L.C. Karssen; E. Mihailov; J.J. Houwing-Duistermaat; A.J. de Craen; J. Deelen; A.S. Havulinna; M. Blades; C. Hengstenberg; J. Erdmann; H. Schunkert; J. Kaprio; M.D. Tobin; N.J. Samani; L. Lind; V. Salomaa; C.M. Lindgren; P.E. Slagboom; A. Metspalu; C.M. van Duijn; J.G. Eriksson; A. Peters; C. Gieger; A. Jula; L. Groop; O.T. Raitakari; C. Power; B.W.J.H. Penninx; E.J.C. de Geus; J.H. Smit; D.I. Boomsma; N.L. Pedersen; E. Ingelsson; U. Thorsteinsdottir; K. Stefansson; S. Ripatti; I. Prokopenko; M.I. McCarthy; A.P. Morris

doi:10.1371/journal.pgen.1005230

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation

M. Horikoshi, R. Mägi, M. van de Bunt, I. Surakka, A.-P. Sarin, A. Mahajan, L. Marullo, G. Thorleifsson, S. Hägg, J.J. Hottenga, C. Ladenvall, J.S. Ried, T.W. Winkler, S.M. Willems, N. Pervjakova, T. Esko, M. Beekman, C.P. Nelson, C. Willenborg, S. WiltshireT. Ferreira, J. Fernandez, K.J. Gaulton, V. Steinthorsdottir, A. Hamsten, P.K.E. Magnusson, G. Willemsen, Y. Milaneschi, N.R. Robertson, C.J. Groves, A.J. Bennett, T. Lehtimäki, J.S. Viikari, J. Rung, V. Lyssenko, M. Perola, I.M. Heid, C. Herder, H. Grallert, M. Müller-Nurasyid, M. Roden, E. Hypponen, A. Isaacs, E.M. van Leeuwen, L.C. Karssen, E. Mihailov, J.J. Houwing-Duistermaat, A.J. de Craen, J. Deelen, A.S. Havulinna, M. Blades, C. Hengstenberg, J. Erdmann, H. Schunkert, J. Kaprio, M.D. Tobin, N.J. Samani, L. Lind, V. Salomaa, C.M. Lindgren, P.E. Slagboom, A. Metspalu, C.M. van Duijn, J.G. Eriksson, A. Peters, C. Gieger, A. Jula, L. Groop, O.T. Raitakari, C. Power, B.W.J.H. Penninx, E.J.C. de Geus, J.H. Smit, D.I. Boomsma, N.L. Pedersen, E. Ingelsson, U. Thorsteinsdottir, K. Stefansson, S. Ripatti, I. Prokopenko, M.I. McCarthy, A.P. Morris

Biological Psychology

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Original language	English
Article number	e1005230
Number of pages	24
Journal	PLoS Genetics
Volume	11
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1005230
Publication status	Published - 2015

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Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1005230

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Horikoshi, M., Mägi, R., van de Bunt, M., Surakka, I., Sarin, A.-P., Mahajan, A., Marullo, L., Thorleifsson, G., Hägg, S., Hottenga, J. J., Ladenvall, C., Ried, J. S., Winkler, T. W., Willems, S. M., Pervjakova, N., Esko, T., Beekman, M., Nelson, C. P., Willenborg, C., ... Morris, A. P. (2015). Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation. PLoS Genetics, 11(7), Article e1005230. https://doi.org/10.1371/journal.pgen.1005230

@article{77843de738074452abca2ad385c4343b,

title = "Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation",

abstract = "Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5\% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.",

author = "M. Horikoshi and R. M{\"a}gi and \{van de Bunt\}, M. and I. Surakka and A.-P. Sarin and A. Mahajan and L. Marullo and G. Thorleifsson and S. H{\"a}gg and J.J. Hottenga and C. Ladenvall and J.S. Ried and T.W. Winkler and S.M. Willems and N. Pervjakova and T. Esko and M. Beekman and C.P. Nelson and C. Willenborg and S. Wiltshire and T. Ferreira and J. Fernandez and K.J. Gaulton and V. Steinthorsdottir and A. Hamsten and P.K.E. Magnusson and G. Willemsen and Y. Milaneschi and N.R. Robertson and C.J. Groves and A.J. Bennett and T. Lehtim{\"a}ki and J.S. Viikari and J. Rung and V. Lyssenko and M. Perola and I.M. Heid and C. Herder and H. Grallert and M. M{\"u}ller-Nurasyid and M. Roden and E. Hypponen and A. Isaacs and \{van Leeuwen\}, E.M. and L.C. Karssen and E. Mihailov and J.J. Houwing-Duistermaat and \{de Craen\}, A.J. and J. Deelen and A.S. Havulinna and M. Blades and C. Hengstenberg and J. Erdmann and H. Schunkert and J. Kaprio and M.D. Tobin and N.J. Samani and L. Lind and V. Salomaa and C.M. Lindgren and P.E. Slagboom and A. Metspalu and \{van Duijn\}, C.M. and J.G. Eriksson and A. Peters and C. Gieger and A. Jula and L. Groop and O.T. Raitakari and C. Power and B.W.J.H. Penninx and \{de Geus\}, E.J.C. and J.H. Smit and D.I. Boomsma and N.L. Pedersen and E. Ingelsson and U. Thorsteinsdottir and K. Stefansson and S. Ripatti and I. Prokopenko and M.I. McCarthy and A.P. Morris",

year = "2015",

doi = "10.1371/journal.pgen.1005230",

language = "English",

volume = "11",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "7",

}

Horikoshi, M, Mägi, R, van de Bunt, M, Surakka, I, Sarin, A-P, Mahajan, A, Marullo, L, Thorleifsson, G, Hägg, S, Hottenga, JJ, Ladenvall, C, Ried, JS, Winkler, TW, Willems, SM, Pervjakova, N, Esko, T, Beekman, M, Nelson, CP, Willenborg, C, Wiltshire, S, Ferreira, T, Fernandez, J, Gaulton, KJ, Steinthorsdottir, V, Hamsten, A, Magnusson, PKE, Willemsen, G, Milaneschi, Y, Robertson, NR, Groves, CJ, Bennett, AJ, Lehtimäki, T, Viikari, JS, Rung, J, Lyssenko, V, Perola, M, Heid, IM, Herder, C, Grallert, H, Müller-Nurasyid, M, Roden, M, Hypponen, E, Isaacs, A, van Leeuwen, EM, Karssen, LC, Mihailov, E, Houwing-Duistermaat, JJ, de Craen, AJ, Deelen, J, Havulinna, AS, Blades, M, Hengstenberg, C, Erdmann, J, Schunkert, H, Kaprio, J, Tobin, MD, Samani, NJ, Lind, L, Salomaa, V, Lindgren, CM, Slagboom, PE, Metspalu, A, van Duijn, CM, Eriksson, JG, Peters, A, Gieger, C, Jula, A, Groop, L, Raitakari, OT, Power, C, Penninx, BWJH, de Geus, EJC, Smit, JH, Boomsma, DI, Pedersen, NL, Ingelsson, E, Thorsteinsdottir, U, Stefansson, K, Ripatti, S, Prokopenko, I, McCarthy, MI & Morris, AP 2015, 'Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation', PLoS Genetics, vol. 11, no. 7, e1005230. https://doi.org/10.1371/journal.pgen.1005230

TY - JOUR

T1 - Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation

AU - Horikoshi, M.

AU - Mägi, R.

AU - van de Bunt, M.

AU - Surakka, I.

AU - Sarin, A.-P.

AU - Mahajan, A.

AU - Marullo, L.

AU - Thorleifsson, G.

AU - Hägg, S.

AU - Hottenga, J.J.

AU - Ladenvall, C.

AU - Ried, J.S.

AU - Winkler, T.W.

AU - Willems, S.M.

AU - Pervjakova, N.

AU - Esko, T.

AU - Beekman, M.

AU - Nelson, C.P.

AU - Willenborg, C.

AU - Wiltshire, S.

AU - Ferreira, T.

AU - Fernandez, J.

AU - Gaulton, K.J.

AU - Steinthorsdottir, V.

AU - Hamsten, A.

AU - Magnusson, P.K.E.

AU - Willemsen, G.

AU - Milaneschi, Y.

AU - Robertson, N.R.

AU - Groves, C.J.

AU - Bennett, A.J.

AU - Lehtimäki, T.

AU - Viikari, J.S.

AU - Rung, J.

AU - Lyssenko, V.

AU - Perola, M.

AU - Heid, I.M.

AU - Herder, C.

AU - Grallert, H.

AU - Müller-Nurasyid, M.

AU - Roden, M.

AU - Hypponen, E.

AU - Isaacs, A.

AU - van Leeuwen, E.M.

AU - Karssen, L.C.

AU - Mihailov, E.

AU - Houwing-Duistermaat, J.J.

AU - de Craen, A.J.

AU - Deelen, J.

AU - Havulinna, A.S.

AU - Blades, M.

AU - Hengstenberg, C.

AU - Erdmann, J.

AU - Schunkert, H.

AU - Kaprio, J.

AU - Tobin, M.D.

AU - Samani, N.J.

AU - Lind, L.

AU - Salomaa, V.

AU - Lindgren, C.M.

AU - Slagboom, P.E.

AU - Metspalu, A.

AU - van Duijn, C.M.

AU - Eriksson, J.G.

AU - Peters, A.

AU - Gieger, C.

AU - Jula, A.

AU - Groop, L.

AU - Raitakari, O.T.

AU - Power, C.

AU - Penninx, B.W.J.H.

AU - de Geus, E.J.C.

AU - Smit, J.H.

AU - Boomsma, D.I.

AU - Pedersen, N.L.

AU - Ingelsson, E.

AU - Thorsteinsdottir, U.

AU - Stefansson, K.

AU - Ripatti, S.

AU - Prokopenko, I.

AU - McCarthy, M.I.

AU - Morris, A.P.

PY - 2015

Y1 - 2015

N2 - Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

AB - Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

UR - https://www.scopus.com/pages/publications/84938765668

UR - https://www.scopus.com/inward/citedby.url?scp=84938765668&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1005230

DO - 10.1371/journal.pgen.1005230

M3 - Article

SN - 1553-7390

VL - 11

JO - PLoS Genetics

JF - PLoS Genetics

IS - 7

M1 - e1005230

ER -

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation

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UN SDGs

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