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,...
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Public Library of Science (PLoS)
2015-07-01
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Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC4488845?pdf=render |
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doaj-4951b009b4df434e8a71bfb9ab373a222020-11-24T21:19:12ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-07-01117e100523010.1371/journal.pgen.1005230Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.Momoko HorikoshiReedik MӓgiMartijn van de BuntIda SurakkaAntti-Pekka SarinAnubha MahajanLetizia MarulloGudmar ThorleifssonSara HӓggJouke-Jan HottengaClaes LadenvallJanina S RiedThomas W WinklerSara M WillemsNatalia PervjakovaTõnu EskoMarian BeekmanChristopher P NelsonChristina WillenborgSteven WiltshireTeresa FerreiraJuan FernandezKyle J GaultonValgerdur SteinthorsdottirAnders HamstenPatrik K E MagnussonGonneke WillemsenYuri MilaneschiNeil R RobertsonChristopher J GrovesAmanda J BennettTerho LehtimӓkiJorma S ViikariJohan RungValeriya LyssenkoMarkus PerolaIris M HeidChristian HerderHarald GrallertMartina Müller-NurasyidMichael RodenElina HypponenAaron IsaacsElisabeth M van LeeuwenLennart C KarssenEvelin MihailovJeanine J Houwing-DuistermaatAnton J M de CraenJoris DeelenAki S HavulinnaMatthew BladesChristian HengstenbergJeanette ErdmannHeribert SchunkertJaakko KaprioMartin D TobinNilesh J SamaniLars LindVeikko SalomaaCecilia M LindgrenP Eline SlagboomAndres MetspaluCornelia M van DuijnJohan G ErikssonAnnette PetersChristian GiegerAntti JulaLeif GroopOlli T RaitakariChris PowerBrenda W J H PenninxEco de GeusJohannes H SmitDorret I BoomsmaNancy L PedersenErik IngelssonUnnur ThorsteinsdottirKari StefanssonSamuli RipattiInga ProkopenkoMark I McCarthyAndrew P MorrisENGAGE ConsortiumReference 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.http://europepmc.org/articles/PMC4488845?pdf=render |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Momoko Horikoshi Reedik Mӓgi Martijn van de Bunt Ida Surakka Antti-Pekka Sarin Anubha Mahajan Letizia Marullo Gudmar Thorleifsson Sara Hӓgg Jouke-Jan Hottenga Claes Ladenvall Janina S Ried Thomas W Winkler Sara M Willems Natalia Pervjakova Tõnu Esko Marian Beekman Christopher P Nelson Christina Willenborg Steven Wiltshire Teresa Ferreira Juan Fernandez Kyle J Gaulton Valgerdur Steinthorsdottir Anders Hamsten Patrik K E Magnusson Gonneke Willemsen Yuri Milaneschi Neil R Robertson Christopher J Groves Amanda J Bennett Terho Lehtimӓki Jorma S Viikari Johan Rung Valeriya Lyssenko Markus Perola Iris M Heid Christian Herder Harald Grallert Martina Müller-Nurasyid Michael Roden Elina Hypponen Aaron Isaacs Elisabeth M van Leeuwen Lennart C Karssen Evelin Mihailov Jeanine J Houwing-Duistermaat Anton J M de Craen Joris Deelen Aki S Havulinna Matthew Blades Christian Hengstenberg Jeanette Erdmann Heribert Schunkert Jaakko Kaprio Martin D Tobin Nilesh J Samani Lars Lind Veikko Salomaa Cecilia M Lindgren P Eline Slagboom Andres Metspalu Cornelia M van Duijn Johan G Eriksson Annette Peters Christian Gieger Antti Jula Leif Groop Olli T Raitakari Chris Power Brenda W J H Penninx Eco de Geus Johannes H Smit Dorret I Boomsma Nancy L Pedersen Erik Ingelsson Unnur Thorsteinsdottir Kari Stefansson Samuli Ripatti Inga Prokopenko Mark I McCarthy Andrew P Morris ENGAGE Consortium |
spellingShingle |
Momoko Horikoshi Reedik Mӓgi Martijn van de Bunt Ida Surakka Antti-Pekka Sarin Anubha Mahajan Letizia Marullo Gudmar Thorleifsson Sara Hӓgg Jouke-Jan Hottenga Claes Ladenvall Janina S Ried Thomas W Winkler Sara M Willems Natalia Pervjakova Tõnu Esko Marian Beekman Christopher P Nelson Christina Willenborg Steven Wiltshire Teresa Ferreira Juan Fernandez Kyle J Gaulton Valgerdur Steinthorsdottir Anders Hamsten Patrik K E Magnusson Gonneke Willemsen Yuri Milaneschi Neil R Robertson Christopher J Groves Amanda J Bennett Terho Lehtimӓki Jorma S Viikari Johan Rung Valeriya Lyssenko Markus Perola Iris M Heid Christian Herder Harald Grallert Martina Müller-Nurasyid Michael Roden Elina Hypponen Aaron Isaacs Elisabeth M van Leeuwen Lennart C Karssen Evelin Mihailov Jeanine J Houwing-Duistermaat Anton J M de Craen Joris Deelen Aki S Havulinna Matthew Blades Christian Hengstenberg Jeanette Erdmann Heribert Schunkert Jaakko Kaprio Martin D Tobin Nilesh J Samani Lars Lind Veikko Salomaa Cecilia M Lindgren P Eline Slagboom Andres Metspalu Cornelia M van Duijn Johan G Eriksson Annette Peters Christian Gieger Antti Jula Leif Groop Olli T Raitakari Chris Power Brenda W J H Penninx Eco de Geus Johannes H Smit Dorret I Boomsma Nancy L Pedersen Erik Ingelsson Unnur Thorsteinsdottir Kari Stefansson Samuli Ripatti Inga Prokopenko Mark I McCarthy Andrew P Morris ENGAGE Consortium Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation. PLoS Genetics |
author_facet |
Momoko Horikoshi Reedik Mӓgi Martijn van de Bunt Ida Surakka Antti-Pekka Sarin Anubha Mahajan Letizia Marullo Gudmar Thorleifsson Sara Hӓgg Jouke-Jan Hottenga Claes Ladenvall Janina S Ried Thomas W Winkler Sara M Willems Natalia Pervjakova Tõnu Esko Marian Beekman Christopher P Nelson Christina Willenborg Steven Wiltshire Teresa Ferreira Juan Fernandez Kyle J Gaulton Valgerdur Steinthorsdottir Anders Hamsten Patrik K E Magnusson Gonneke Willemsen Yuri Milaneschi Neil R Robertson Christopher J Groves Amanda J Bennett Terho Lehtimӓki Jorma S Viikari Johan Rung Valeriya Lyssenko Markus Perola Iris M Heid Christian Herder Harald Grallert Martina Müller-Nurasyid Michael Roden Elina Hypponen Aaron Isaacs Elisabeth M van Leeuwen Lennart C Karssen Evelin Mihailov Jeanine J Houwing-Duistermaat Anton J M de Craen Joris Deelen Aki S Havulinna Matthew Blades Christian Hengstenberg Jeanette Erdmann Heribert Schunkert Jaakko Kaprio Martin D Tobin Nilesh J Samani Lars Lind Veikko Salomaa Cecilia M Lindgren P Eline Slagboom Andres Metspalu Cornelia M van Duijn Johan G Eriksson Annette Peters Christian Gieger Antti Jula Leif Groop Olli T Raitakari Chris Power Brenda W J H Penninx Eco de Geus Johannes H Smit Dorret I Boomsma Nancy L Pedersen Erik Ingelsson Unnur Thorsteinsdottir Kari Stefansson Samuli Ripatti Inga Prokopenko Mark I McCarthy Andrew P Morris ENGAGE Consortium |
author_sort |
Momoko Horikoshi |
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. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2015-07-01 |
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. |
url |
http://europepmc.org/articles/PMC4488845?pdf=render |
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