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

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dc.contributor.author Horikoshi, Momoko
dc.contributor.author Maegi, Reedik
dc.contributor.author van de Bunt, Martijn
dc.contributor.author Surakka, Ida
dc.contributor.author Sarin, Antti-Pekka
dc.contributor.author Mahajan, Anubha
dc.contributor.author Marullo, Letizia
dc.contributor.author Thorleifsson, Gudmar
dc.contributor.author Haegg, Sara
dc.contributor.author Hottenga, Jouke-Jan
dc.contributor.author Ladenvall, Claes
dc.contributor.author Ried, Janina S.
dc.contributor.author Winkler, Thomas W.
dc.contributor.author Willems, Sara M.
dc.contributor.author Tsernikova, Natalia
dc.contributor.author Esko, Tonu
dc.contributor.author Beekman, Marian
dc.contributor.author Nelson, Christopher P.
dc.contributor.author Willenborg, Christina
dc.contributor.author Wiltshire, Steven
dc.contributor.author Ferreira, Teresa
dc.contributor.author Fernandez, Juan
dc.contributor.author Gaulton, Kyle J.
dc.contributor.author Steinthorsdottir, Valgerdur
dc.contributor.author Hamsten, Anders
dc.contributor.author Magnusson, Patrik K. E.
dc.contributor.author Willemsen, Gonneke
dc.contributor.author Milaneschi, Yuri
dc.contributor.author Robertson, Neil R.
dc.contributor.author Groves, Christopher J.
dc.contributor.author Bennett, Amanda J.
dc.contributor.author Lehtimaeki, Terho
dc.contributor.author Viikari, Jorma S.
dc.contributor.author Rung, Johan
dc.contributor.author Lyssenko, Valeriya
dc.contributor.author Perola, Markus
dc.contributor.author Heid, Iris M.
dc.contributor.author Herder, Christian
dc.contributor.author Grallert, Harald
dc.contributor.author Mueller-Nurasyid, Martina
dc.contributor.author Roden, Michael
dc.contributor.author Hypponen, Elina
dc.contributor.author Isaacs, Aaron
dc.contributor.author van Leeuwen, Elisabeth M.
dc.contributor.author Karssen, Lennart C.
dc.contributor.author Mihailov, Evelin
dc.contributor.author Kaprio, Jaakko
dc.contributor.author Eriksson, Johan G.
dc.contributor.author Groop, Leif
dc.contributor.author Ripatti, Samuli
dc.contributor.author ENGAGE Consortium
dc.date.accessioned 2016-05-13T14:22:02Z
dc.date.available 2016-05-13T14:22:02Z
dc.date.issued 2015-07
dc.identifier.citation Horikoshi , M , Maegi , R , van de Bunt , M , Surakka , I , Sarin , A-P , Mahajan , A , Marullo , L , Thorleifsson , G , Haegg , S , Hottenga , J-J , Ladenvall , C , Ried , J S , Winkler , T W , Willems , S M , Tsernikova , N , Esko , T , Beekman , M , Nelson , C P , Willenborg , C , Wiltshire , S , Ferreira , T , Fernandez , J , Gaulton , K J , Steinthorsdottir , V , Hamsten , A , Magnusson , P K E , Willemsen , G , Milaneschi , Y , Robertson , N R , Groves , C J , Bennett , A J , Lehtimaeki , T , Viikari , J S , Rung , J , Lyssenko , V , Perola , M , Heid , I M , Herder , C , Grallert , H , Mueller-Nurasyid , M , Roden , M , Hypponen , E , Isaacs , A , van Leeuwen , E M , Karssen , L C , Mihailov , E , Kaprio , J , Eriksson , J G , Groop , L , Ripatti , S & ENGAGE Consortium 2015 , ' Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation ' , PLoS Genetics , vol. 11 , no. 7 , 1005230 . https://doi.org/10.1371/journal.pgen.1005230
dc.identifier.other PURE: 53821125
dc.identifier.other PURE UUID: 96c60c00-f6a7-48b6-afb8-84c5ec735d63
dc.identifier.other WOS: 000360622200002
dc.identifier.other Scopus: 84938765668
dc.identifier.uri http://hdl.handle.net/10138/162070
dc.description.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. en
dc.format.extent 24
dc.language.iso eng
dc.relation.ispartof PLoS Genetics
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject GENOME-WIDE ASSOCIATION
dc.subject BODY-MASS INDEX
dc.subject RARE GENETIC-VARIATION
dc.subject TYPE-2 DIABETES RISK
dc.subject WAIST-HIP RATIO
dc.subject LOW-FREQUENCY
dc.subject INSULIN-RESISTANCE
dc.subject FASTING GLUCOSE
dc.subject GENOTYPE IMPUTATION
dc.subject ASIAN POPULATIONS
dc.subject 3111 Biomedicine
dc.title Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation en
dc.type Article
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Clinicum
dc.contributor.organization Jaakko Kaprio / Principal Investigator
dc.contributor.organization Department of Public Health
dc.contributor.organization Johan Eriksson / Principal Investigator
dc.contributor.organization Department of General Practice and Primary Health Care
dc.contributor.organization Leif Groop Research Group
dc.contributor.organization Samuli Olli Ripatti / Principal Investigator
dc.contributor.organization Biostatistics Helsinki
dc.contributor.organization Quantitative Genetics
dc.contributor.organization Complex Disease Genetics
dc.contributor.organization Genetic Epidemiology
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1371/journal.pgen.1005230
dc.relation.issn 1553-7390
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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