TY  - JOUR
JF  - PLOS Genetics
UR  - https://epub.ub.uni-muenchen.de/34200/
SN  - 1553-7390
Y1  - 2015///
N2  - 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.
IS  - 7
AV  - public
ID  - epub34200
TI  - Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation
PB  - PLOS
A1  - Horikoshi, Momoko
A1  - Maegi, Reedik
A1  - Bunt, Martijn van de
A1  - Surakka, Ida
A1  - Sarin, Antti-Pekka
A1  - Mahajan, Anubha
A1  - Marullo, Letizia
A1  - Thorleifsson, Gudmar
A1  - Haegg, Sara
A1  - Hottenga, Jouke-Jan
A1  - Ladenvall, Claes
A1  - Ried, Janina S.
A1  - Winkler, Thomas W.
A1  - Willems, Sara M.
A1  - Pervjakova, Natalia
A1  - Esko, Tonu
A1  - Beekman, Marian
A1  - Nelson, Christopher P.
A1  - Willenborg, Christina
A1  - Wiltshire, Steven
A1  - Ferreira, Teresa
A1  - Fernandez, Juan
A1  - Gaulton, Kyle J.
A1  - Steinthorsdottir, Valgerdur
A1  - Hamsten, Anders
A1  - Magnusson, Patrik K. E.
A1  - Willemsen, Gonneke
A1  - Milaneschi, Yuri
A1  - Robertson, Neil R.
A1  - Groves, Christopher J.
A1  - Bennett, Amanda J.
A1  - Lehtimaeki, Terho
A1  - Viikari, Jorma S.
A1  - Rung, Johan
A1  - Lyssenko, Valeriya
A1  - Perola, Markus
A1  - Heid, Iris M.
A1  - Herder, Christian
A1  - Grallert, Harald
A1  - Mueller-Nurasyid, Martina
A1  - Roden, Michael
A1  - Hypponen, Elina
A1  - Isaacs, Aaron
A1  - Leeuwen, Elisabeth M. van
A1  - Karssen, Lennart C.
A1  - Mihailov, Evelin
A1  - Houwing-Duistermaat, Jeanine J.
A1  - de Craen, Anton J. M.
A1  - Deelen, Joris
A1  - Havulinna, Aki S.
A1  - Blades, Matthew
A1  - Hengstenberg, Christian
A1  - Erdmann, Jeanette
A1  - Schunkert, Heribert
A1  - Kaprio, Jaakko
A1  - Tobin, Martin D.
A1  - Samani, Nilesh J.
A1  - Lind, Lars
A1  - Salomaa, Veikko
A1  - Lindgren, Cecilia M.
A1  - Slagboom, P. Eline
A1  - Metspalu, Andres
A1  - Duijn, Cornelia M. van
A1  - Eriksson, Johan G.
A1  - Peters, Annette
A1  - Gieger, Christian
A1  - Jula, Antti
A1  - Groop, Leif
A1  - Raitakari, Olli T.
A1  - Power, Chris
A1  - Penninx, Brenda W. J. H.
A1  - de Geus, Eco
A1  - Smit, Johannes H.
A1  - Boomsma, Dorret I.
A1  - Pedersen, Nancy L.
A1  - Ingelsson, Erik
A1  - Thorsteinsdottir, Unnur
A1  - Stefansson, Kari
A1  - Ripatti, Samuli
A1  - Prokopenko, Inga
A1  - McCarthy, Mark I.
A1  - Morris, Andrew P.
ER  -