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

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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 .

Title: Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
Author: Horikoshi, Momoko; Maegi, Reedik; van de Bunt, Martijn; Surakka, Ida; Sarin, Antti-Pekka; Mahajan, Anubha; Marullo, Letizia; Thorleifsson, Gudmar; Haegg, Sara; Hottenga, Jouke-Jan; Ladenvall, Claes; Ried, Janina S.; Winkler, Thomas W.; Willems, Sara M.; Tsernikova, Natalia; Esko, Tonu; 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.; Lehtimaeki, Terho; Viikari, Jorma S.; Rung, Johan; Lyssenko, Valeriya; Perola, Markus; Heid, Iris M.; Herder, Christian; Grallert, Harald; Mueller-Nurasyid, Martina; Roden, Michael; Hypponen, Elina; Isaacs, Aaron; van Leeuwen, Elisabeth M.; Karssen, Lennart C.; Mihailov, Evelin; Kaprio, Jaakko; Eriksson, Johan G.; Groop, Leif; Ripatti, Samuli; ENGAGE Consortium
Contributor organization: Institute for Molecular Medicine Finland
Jaakko Kaprio / Principal Investigator
Department of Public Health
Johan Eriksson / Principal Investigator
Department of General Practice and Primary Health Care
Leif Groop Research Group
Samuli Olli Ripatti / Principal Investigator
Biostatistics Helsinki
Quantitative Genetics
Complex Disease Genetics
Genetic Epidemiology
Date: 2015-07
Language: eng
Number of pages: 24
Belongs to series: PLoS Genetics
ISSN: 1553-7390
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.
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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