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.
Highlights
Quantitative human glycaemic and obesity-related traits, including fasting plasma glucose and insulin (FG and FI), body mass index (BMI), and waist-hip ratio (WHR) are highly heritable [1,2,3,4,5], and are well established risk factors for type 2 diabetes (T2D) and cardiovascular disease [6,7,8,9,10]
We considered the quality of imputation of variants from the 1000 Genomes (1000G) reference panel in two contributing studies (S4 Table): the 1958 British Birth Cohort from the Wellcome Trust Case Control Consortium
Amongst rarer variants, the quality of imputation was noticeably poorer in NFBC1966 (62.8%) than 58BC-WTCCC, presumably reflecting less representation of low-frequency haplotypes from the isolated Northern Finnish population in the 1000G reference panel
Summary
Quantitative human glycaemic and obesity-related traits, including fasting plasma glucose and insulin (FG and FI), body mass index (BMI), and waist-hip ratio (WHR) are highly heritable [1,2,3,4,5], and are well established risk factors for type 2 diabetes (T2D) and cardiovascular disease [6,7,8,9,10]. Large-scale genome-wide association studies (GWAS) have proved to be extremely successful in the identification of loci harbouring genetic variants contributing to these traits in multiple ethnic groups [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. The detected loci are typically characterised by common variant association signals, defined by lead SNPs with minor allele frequency (MAF) of at least 5%, which extend over large genomic intervals because of linkage disequilibrium (LD). They often map to non-coding sequence, making direct biological interpretation of their effect more difficult than agreement number 259679. There has been limited progress in identifying the genes through which GWAS association signals are mediated, and characterisation of the downstream molecular mechanisms influencing glycaemic and obesity-related traits remains a considerable challenge
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