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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 and Hottenga, Jouke-Jan, et al. (2015) In PLoS Genetics 11(7).
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... (More)
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. (Less)
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PLoS Genetics
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11
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7
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Public Library of Science
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  • pmid:26132169
  • wos:000360622200002
  • scopus:84938765668
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1553-7404
DOI
10.1371/journal.pgen.1005230
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English
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9376a6a0-6b9b-4b1e-8f75-e4c9f79f087d (old id 7751176)
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@article{9376a6a0-6b9b-4b1e-8f75-e4c9f79f087d,
  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.},
  articleno    = {e1005230},
  author       = {Horikoshi, Momoko and Mӓgi, Reedik and van de Bunt, Martijn and Surakka, Ida and Sarin, Antti-Pekka and Mahajan, Anubha and Marullo, Letizia and Thorleifsson, Gudmar and Hӓgg, Sara and Hottenga, Jouke-Jan and Ladenvall, Claes and Ried, Janina S and Winkler, Thomas W and Willems, Sara M and Pervjakova, Natalia and Esko, Tõnu and Beekman, Marian and Nelson, Christopher P and Willenborg, Christina and Wiltshire, Steven and Ferreira, Teresa and Fernandez, Juan and Gaulton, Kyle J and Steinthorsdottir, Valgerdur and Hamsten, Anders and Magnusson, Patrik K E and Willemsen, Gonneke and Milaneschi, Yuri and Robertson, Neil R and Groves, Christopher J and Bennett, Amanda J and Lehtimӓki, Terho and Viikari, Jorma S and Rung, Johan and Lyssenko, Valeriya and Perola, Markus and Heid, Iris M and Herder, Christian and Grallert, Harald and Müller-Nurasyid, Martina and Roden, Michael and Hypponen, Elina and Isaacs, Aaron and van Leeuwen, Elisabeth M and Karssen, Lennart C and Mihailov, Evelin and Houwing-Duistermaat, Jeanine J and de Craen, Anton J M and Deelen, Joris and Havulinna, Aki S and Blades, Matthew and Hengstenberg, Christian and Erdmann, Jeanette and Schunkert, Heribert and Kaprio, Jaakko and Tobin, Martin D and Samani, Nilesh J and Lind, Lars and Salomaa, Veikko and Lindgren, Cecilia M and Slagboom, P Eline and Metspalu, Andres and van Duijn, Cornelia M and Eriksson, Johan G and Peters, Annette and Gieger, Christian and Jula, Antti and Groop, Leif and Raitakari, Olli T and Power, Chris and Penninx, Brenda W J H and de Geus, Eco and Smit, Johannes H and Boomsma, Dorret I and Pedersen, Nancy L and Ingelsson, Erik and Thorsteinsdottir, Unnur and Stefansson, Kari and Ripatti, Samuli and Prokopenko, Inga and McCarthy, Mark I and Morris, Andrew P},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1005230},
  volume       = {11},
  year         = {2015},
}