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Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
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2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 7, e1005230Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 11, no 7, e1005230
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-263537DOI: 10.1371/journal.pgen.1005230ISI: 000360622200002PubMedID: 26132169OAI: oai:DiVA.org:uu-263537DiVA: diva2:858849
Wellcome trust, 068545/Z/02 076113Swedish Research Council, 31475113580 M-2005-1112 2009-2298EU, FP7, Seventh Framework ProgrammeSwedish Foundation for Strategic Research , ICA08-0047NIH (National Institute of Health), DK U01-066134Swedish Heart Lung Foundation
Available from: 2015-10-05 Created: 2015-10-02 Last updated: 2016-01-25Bibliographically approved

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Lind, LarsIngelsson, Erik
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