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

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,...

Full description

Bibliographic Details
Main Authors:	Horikoshi, Momoko, Mӓgi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Hӓgg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S., Winkler, Thomas W., Willems, Sara M., Pervjakova, Natalia, Esko, Tõnu, Beekman, Marian, Nelson, Christopher P., Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J., Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K. E., Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R., Groves, Christopher J., Bennett, Amanda J., Lehtimӓki, Terho, Viikari, Jorma S., Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M., Herder, Christian, Grallert, Harald, Müller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M., Karssen, Lennart C., Mihailov, Evelin, Houwing-Duistermaat, Jeanine J., de Craen, Anton J. M., Deelen, Joris, Havulinna, Aki S., Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D., Samani, Nilesh J., Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M., Slagboom, P. Eline, Metspalu, Andres, van Duijn, Cornelia M., Eriksson, Johan G., Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T., Power, Chris, Penninx, Brenda W. J. H., de Geus, Eco, Smit, Johannes H., Boomsma, Dorret I., Pedersen, Nancy L., Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I., Morris, Andrew P.
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488845/

id	pubmed-4488845
recordtype	oai_dc
spelling	pubmed-44888452015-07-14 Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation Horikoshi, Momoko Mӓgi, Reedik van de Bunt, Martijn Surakka, Ida Sarin, Antti-Pekka Mahajan, Anubha Marullo, Letizia Thorleifsson, Gudmar Hӓgg, Sara Hottenga, Jouke-Jan Ladenvall, Claes Ried, Janina S. Winkler, Thomas W. Willems, Sara M. Pervjakova, Natalia Esko, Tõnu Beekman, Marian Nelson, Christopher P. Willenborg, Christina Wiltshire, Steven Ferreira, Teresa Fernandez, Juan Gaulton, Kyle J. Steinthorsdottir, Valgerdur Hamsten, Anders Magnusson, Patrik K. E. Willemsen, Gonneke Milaneschi, Yuri Robertson, Neil R. Groves, Christopher J. Bennett, Amanda J. Lehtimӓki, Terho Viikari, Jorma S. Rung, Johan Lyssenko, Valeriya Perola, Markus Heid, Iris M. Herder, Christian Grallert, Harald Müller-Nurasyid, Martina Roden, Michael Hypponen, Elina Isaacs, Aaron van Leeuwen, Elisabeth M. Karssen, Lennart C. Mihailov, Evelin Houwing-Duistermaat, Jeanine J. de Craen, Anton J. M. Deelen, Joris Havulinna, Aki S. Blades, Matthew Hengstenberg, Christian Erdmann, Jeanette Schunkert, Heribert Kaprio, Jaakko Tobin, Martin D. Samani, Nilesh J. Lind, Lars Salomaa, Veikko Lindgren, Cecilia M. Slagboom, P. Eline Metspalu, Andres van Duijn, Cornelia M. Eriksson, Johan G. Peters, Annette Gieger, Christian Jula, Antti Groop, Leif Raitakari, Olli T. Power, Chris Penninx, Brenda W. J. H. de Geus, Eco Smit, Johannes H. Boomsma, Dorret I. Pedersen, Nancy L. Ingelsson, Erik Thorsteinsdottir, Unnur Stefansson, Kari Ripatti, Samuli Prokopenko, Inga McCarthy, Mark I. Morris, Andrew P. Research Article 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. Public Library of Science 2015-07-01 /pmc/articles/PMC4488845/ /pubmed/26132169 http://dx.doi.org/10.1371/journal.pgen.1005230 Text en © 2015 Horikoshi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Horikoshi, Momoko Mӓgi, Reedik van de Bunt, Martijn Surakka, Ida Sarin, Antti-Pekka Mahajan, Anubha Marullo, Letizia Thorleifsson, Gudmar Hӓgg, Sara Hottenga, Jouke-Jan Ladenvall, Claes Ried, Janina S. Winkler, Thomas W. Willems, Sara M. Pervjakova, Natalia Esko, Tõnu Beekman, Marian Nelson, Christopher P. Willenborg, Christina Wiltshire, Steven Ferreira, Teresa Fernandez, Juan Gaulton, Kyle J. Steinthorsdottir, Valgerdur Hamsten, Anders Magnusson, Patrik K. E. Willemsen, Gonneke Milaneschi, Yuri Robertson, Neil R. Groves, Christopher J. Bennett, Amanda J. Lehtimӓki, Terho Viikari, Jorma S. Rung, Johan Lyssenko, Valeriya Perola, Markus Heid, Iris M. Herder, Christian Grallert, Harald Müller-Nurasyid, Martina Roden, Michael Hypponen, Elina Isaacs, Aaron van Leeuwen, Elisabeth M. Karssen, Lennart C. Mihailov, Evelin Houwing-Duistermaat, Jeanine J. de Craen, Anton J. M. Deelen, Joris Havulinna, Aki S. Blades, Matthew Hengstenberg, Christian Erdmann, Jeanette Schunkert, Heribert Kaprio, Jaakko Tobin, Martin D. Samani, Nilesh J. Lind, Lars Salomaa, Veikko Lindgren, Cecilia M. Slagboom, P. Eline Metspalu, Andres van Duijn, Cornelia M. Eriksson, Johan G. Peters, Annette Gieger, Christian Jula, Antti Groop, Leif Raitakari, Olli T. Power, Chris Penninx, Brenda W. J. H. de Geus, Eco Smit, Johannes H. Boomsma, Dorret I. Pedersen, Nancy L. Ingelsson, Erik Thorsteinsdottir, Unnur Stefansson, Kari Ripatti, Samuli Prokopenko, Inga McCarthy, Mark I. Morris, Andrew P.
spellingShingle	Horikoshi, Momoko Mӓgi, Reedik van de Bunt, Martijn Surakka, Ida Sarin, Antti-Pekka Mahajan, Anubha Marullo, Letizia Thorleifsson, Gudmar Hӓgg, Sara Hottenga, Jouke-Jan Ladenvall, Claes Ried, Janina S. Winkler, Thomas W. Willems, Sara M. Pervjakova, Natalia Esko, Tõnu Beekman, Marian Nelson, Christopher P. Willenborg, Christina Wiltshire, Steven Ferreira, Teresa Fernandez, Juan Gaulton, Kyle J. Steinthorsdottir, Valgerdur Hamsten, Anders Magnusson, Patrik K. E. Willemsen, Gonneke Milaneschi, Yuri Robertson, Neil R. Groves, Christopher J. Bennett, Amanda J. Lehtimӓki, Terho Viikari, Jorma S. Rung, Johan Lyssenko, Valeriya Perola, Markus Heid, Iris M. Herder, Christian Grallert, Harald Müller-Nurasyid, Martina Roden, Michael Hypponen, Elina Isaacs, Aaron van Leeuwen, Elisabeth M. Karssen, Lennart C. Mihailov, Evelin Houwing-Duistermaat, Jeanine J. de Craen, Anton J. M. Deelen, Joris Havulinna, Aki S. Blades, Matthew Hengstenberg, Christian Erdmann, Jeanette Schunkert, Heribert Kaprio, Jaakko Tobin, Martin D. Samani, Nilesh J. Lind, Lars Salomaa, Veikko Lindgren, Cecilia M. Slagboom, P. Eline Metspalu, Andres van Duijn, Cornelia M. Eriksson, Johan G. Peters, Annette Gieger, Christian Jula, Antti Groop, Leif Raitakari, Olli T. Power, Chris Penninx, Brenda W. J. H. de Geus, Eco Smit, Johannes H. Boomsma, Dorret I. Pedersen, Nancy L. Ingelsson, Erik Thorsteinsdottir, Unnur Stefansson, Kari Ripatti, Samuli Prokopenko, Inga McCarthy, Mark I. Morris, Andrew P. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
author_facet	Horikoshi, Momoko Mӓgi, Reedik van de Bunt, Martijn Surakka, Ida Sarin, Antti-Pekka Mahajan, Anubha Marullo, Letizia Thorleifsson, Gudmar Hӓgg, Sara Hottenga, Jouke-Jan Ladenvall, Claes Ried, Janina S. Winkler, Thomas W. Willems, Sara M. Pervjakova, Natalia Esko, Tõnu Beekman, Marian Nelson, Christopher P. Willenborg, Christina Wiltshire, Steven Ferreira, Teresa Fernandez, Juan Gaulton, Kyle J. Steinthorsdottir, Valgerdur Hamsten, Anders Magnusson, Patrik K. E. Willemsen, Gonneke Milaneschi, Yuri Robertson, Neil R. Groves, Christopher J. Bennett, Amanda J. Lehtimӓki, Terho Viikari, Jorma S. Rung, Johan Lyssenko, Valeriya Perola, Markus Heid, Iris M. Herder, Christian Grallert, Harald Müller-Nurasyid, Martina Roden, Michael Hypponen, Elina Isaacs, Aaron van Leeuwen, Elisabeth M. Karssen, Lennart C. Mihailov, Evelin Houwing-Duistermaat, Jeanine J. de Craen, Anton J. M. Deelen, Joris Havulinna, Aki S. Blades, Matthew Hengstenberg, Christian Erdmann, Jeanette Schunkert, Heribert Kaprio, Jaakko Tobin, Martin D. Samani, Nilesh J. Lind, Lars Salomaa, Veikko Lindgren, Cecilia M. Slagboom, P. Eline Metspalu, Andres van Duijn, Cornelia M. Eriksson, Johan G. Peters, Annette Gieger, Christian Jula, Antti Groop, Leif Raitakari, Olli T. Power, Chris Penninx, Brenda W. J. H. de Geus, Eco Smit, Johannes H. Boomsma, Dorret I. Pedersen, Nancy L. Ingelsson, Erik Thorsteinsdottir, Unnur Stefansson, Kari Ripatti, Samuli Prokopenko, Inga McCarthy, Mark I. Morris, Andrew P.
author_sort	Horikoshi, Momoko
title	Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
title_short	Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
title_full	Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
title_fullStr	Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
title_full_unstemmed	Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
title_sort	discovery and fine-mapping of glycaemic and obesity-related trait loci using high-density imputation
description	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.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488845/
_version_	1613242882252079104

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

Similar Items