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

M Horikoshi; R Magi; M van de Bunt; I Surakka; AP Sarin; A Mahajan; L Marullo; G Thorleifsson; S Hagg; JJ (Jouke Jan) Hottenga; C Ladenvall; JS Ried; TW Winkler; SM Willems; N Pervjakova; T Esko; M Beekman; CP Nelson; C Willenborg; S Wiltshire; T Ferreira; J Fernandez; KJ Gaulton; V Steinthorsdottir; A Hamsten; PKE Magnusson; G Willemsen; Y Milaneschi; NR Robertson; CJ Groves; AJ Bennett; T Lehtimaki; JS Viikari; J Rung; V Lyssenko; M Perola; IM Heid; Cindy Herder; H Grallert; M Muller-Nurasyid; M Roden; E Hypponen; Aaron Isaacs; Elisa Leeuwen; Lennart Karssen; E Mihailov; JJ Houwing-Duistermaat; AJM de Craen; J Deelen; AS Havulinna; M Blades; C Hengstenberg; J Erdmann; H Schunkert; J Kaprio; MD Tobin; NJ Samani; L Lind; V Salomaa; CM Lindgren; PE (Eline) Slagboom; A Metspalu; Cornelia Duijn; JG Eriksson; A Peters; C Gieger; A Jula; L Groop; OT Raitakari; C Power; BWJH Penninx; ED de Geus; JH Smit; DI Boomsma; NL Pedersen; E Ingelsson; U Thorsteinsdottir; K Stefansson; S Ripatti; I Prokopenko; MI McCarthy; AP 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 Magi, M van de Bunt, I Surakka, AP Sarin, A Mahajan, L Marullo, G Thorleifsson, S Hagg, JJ (Jouke Jan) Hottenga, C Ladenvall, JS Ried, TW Winkler, SM Willems, N Pervjakova, T Esko, M Beekman, CP Nelson, C Willenborg, S WiltshireT Ferreira, J Fernandez, KJ Gaulton, V Steinthorsdottir, A Hamsten, PKE Magnusson, G Willemsen, Y Milaneschi, NR Robertson, CJ Groves, AJ Bennett, T Lehtimaki, JS Viikari, J Rung, V Lyssenko, M Perola, IM Heid, Cindy Herder, H Grallert, M Muller-Nurasyid, M Roden, E Hypponen, Aaron Isaacs, Elisa Leeuwen, Lennart Karssen, E Mihailov, JJ Houwing-Duistermaat, AJM de Craen, J Deelen, AS Havulinna, M Blades, C Hengstenberg, J Erdmann, H Schunkert, J Kaprio, MD Tobin, NJ Samani, L Lind, V Salomaa, CM Lindgren, PE (Eline) Slagboom, A Metspalu, Cornelia Duijn, JG Eriksson, A Peters, C Gieger, A Jula, L Groop, OT Raitakari, C Power, BWJH Penninx, ED de Geus, JH Smit, DI Boomsma, NL Pedersen, E Ingelsson, U Thorsteinsdottir, K Stefansson, S Ripatti, I Prokopenko, MI McCarthy, AP Morris

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

68 Citations (Scopus)

21 Downloads (Pure)

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	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	11
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1005230
Publication status	Published - 2015

Research programs

EMC NIHES-01-64-01

UN SDGs

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

Access to Document

10.1371/journal.pgen.1005230

REPUB_82310-OA.pdfFinal published version, 2.18 MB

http://hdl.handle.net/1765/82310

Cite this

Horikoshi, M., Magi, R., van de Bunt, M., Surakka, I., Sarin, AP., Mahajan, A., Marullo, L., Thorleifsson, G., Hagg, S., Hottenga, JJ., Ladenvall, C., Ried, JS., Winkler, TW., Willems, SM., Pervjakova, N., Esko, T., Beekman, M., Nelson, CP., Willenborg, C., ... Morris, AP. (2015). Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation. PLoS Genetics (print), 11(7). https://doi.org/10.1371/journal.pgen.1005230

@article{8083a54d0e1340edbfec4a51fd142beb,

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 Magi and {van de Bunt}, M and I Surakka and AP Sarin and A Mahajan and L Marullo and G Thorleifsson and S Hagg and Hottenga, {JJ (Jouke Jan)} and C Ladenvall and JS Ried and TW Winkler and SM Willems and N Pervjakova and T Esko and M Beekman and CP Nelson and C Willenborg and S Wiltshire and T Ferreira and J Fernandez and KJ Gaulton and V Steinthorsdottir and A Hamsten and PKE Magnusson and G Willemsen and Y Milaneschi and NR Robertson and CJ Groves and AJ Bennett and T Lehtimaki and JS Viikari and J Rung and V Lyssenko and M Perola and IM Heid and Cindy Herder and H Grallert and M Muller-Nurasyid and M Roden and E Hypponen and Aaron Isaacs and Elisa Leeuwen and Lennart Karssen and E Mihailov and JJ Houwing-Duistermaat and {de Craen}, AJM and J Deelen and AS Havulinna and M Blades and C Hengstenberg and J Erdmann and H Schunkert and J Kaprio and MD Tobin and NJ Samani and L Lind and V Salomaa and CM Lindgren and Slagboom, {PE (Eline)} and A Metspalu and Cornelia Duijn and JG Eriksson and A Peters and C Gieger and A Jula and L Groop and OT Raitakari and C Power and BWJH Penninx and {de Geus}, ED and JH Smit and DI Boomsma and NL Pedersen and E Ingelsson and U Thorsteinsdottir and K Stefansson and S Ripatti and I Prokopenko and MI McCarthy and AP Morris",

year = "2015",

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

language = "Undefined/Unknown",

volume = "11",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "7",

}

Horikoshi, M, Magi, R, van de Bunt, M, Surakka, I, Sarin, AP, Mahajan, A, Marullo, L, Thorleifsson, G, Hagg, 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, Lehtimaki, T, Viikari, JS, Rung, J, Lyssenko, V, Perola, M, Heid, IM, Herder, C, Grallert, H, Muller-Nurasyid, M, Roden, M, Hypponen, E, Isaacs, A, Leeuwen, E, Karssen, L, Mihailov, E, Houwing-Duistermaat, JJ, de Craen, AJM, 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, Duijn, C, Eriksson, JG, Peters, A, Gieger, C, Jula, A, Groop, L, Raitakari, OT, Power, C, Penninx, BWJH, de Geus, ED, 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 (print), vol. 11, no. 7. 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 - Magi, R

AU - van de Bunt, M

AU - Surakka, I

AU - Sarin, AP

AU - Mahajan, A

AU - Marullo, L

AU - Thorleifsson, G

AU - Hagg, S

AU - Hottenga, JJ (Jouke Jan)

AU - Ladenvall, C

AU - Ried, JS

AU - Winkler, TW

AU - Willems, SM

AU - Pervjakova, N

AU - Esko, T

AU - Beekman, M

AU - Nelson, CP

AU - Willenborg, C

AU - Wiltshire, S

AU - Ferreira, T

AU - Fernandez, J

AU - Gaulton, KJ

AU - Steinthorsdottir, V

AU - Hamsten, A

AU - Magnusson, PKE

AU - Willemsen, G

AU - Milaneschi, Y

AU - Robertson, NR

AU - Groves, CJ

AU - Bennett, AJ

AU - Lehtimaki, T

AU - Viikari, JS

AU - Rung, J

AU - Lyssenko, V

AU - Perola, M

AU - Heid, IM

AU - Herder, Cindy

AU - Grallert, H

AU - Muller-Nurasyid, M

AU - Roden, M

AU - Hypponen, E

AU - Isaacs, Aaron

AU - Leeuwen, Elisa

AU - Karssen, Lennart

AU - Mihailov, E

AU - Houwing-Duistermaat, JJ

AU - de Craen, AJM

AU - Deelen, J

AU - Havulinna, AS

AU - Blades, M

AU - Hengstenberg, C

AU - Erdmann, J

AU - Schunkert, H

AU - Kaprio, J

AU - Tobin, MD

AU - Samani, NJ

AU - Lind, L

AU - Salomaa, V

AU - Lindgren, CM

AU - Slagboom, PE (Eline)

AU - Metspalu, A

AU - Duijn, Cornelia

AU - Eriksson, JG

AU - Peters, A

AU - Gieger, C

AU - Jula, A

AU - Groop, L

AU - Raitakari, OT

AU - Power, C

AU - Penninx, BWJH

AU - de Geus, ED

AU - Smit, JH

AU - Boomsma, DI

AU - Pedersen, NL

AU - Ingelsson, E

AU - Thorsteinsdottir, U

AU - Stefansson, K

AU - Ripatti, S

AU - Prokopenko, I

AU - McCarthy, MI

AU - Morris, AP

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.

U2 - 10.1371/journal.pgen.1005230

DO - 10.1371/journal.pgen.1005230

M3 - Article

SN - 1553-7390

VL - 11

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 7

ER -