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

PLoS Genet
Authors
Keywords
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.

Year of Publication
2015
Journal
PLoS Genet
Volume
11
Issue
7
Pages
e1005230
Date Published
2015 Jul
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1005230
PubMed ID
26132169
PubMed Central ID
PMC4488845
Links
Grant list
K02AA018755 / AA / NIAAA NIH HHS / United States
G1001799 / Medical Research Council / United Kingdom
098017 / Wellcome Trust / United Kingdom
GR069224 / Wellcome Trust / United Kingdom
AA-09203 / AA / NIAAA NIH HHS / United States
1RL1MH083268-01 / MH / NIMH NIH HHS / United States
1RC2MH089951-01 / MH / NIMH NIH HHS / United States
AA-00145 / AA / NIAAA NIH HHS / United States
G0500539 / Medical Research Council / United Kingdom
AA15416 / AA / NIAAA NIH HHS / United States
MR/N01104X/1 / Medical Research Council / United Kingdom
5R01HL087679 / HL / NHLBI NIH HHS / United States
1RC2 MH089995-01 / MH / NIMH NIH HHS / United States
R01D0042157-01A / PHS HHS / United States
AA-12502 / AA / NIAAA NIH HHS / United States
G0902313 / Medical Research Council / United Kingdom
WT090532 / Wellcome Trust / United Kingdom
U24 MH068457-06 / MH / NIMH NIH HHS / United States
WT098017 / Wellcome Trust / United Kingdom
098381 / Wellcome Trust / United Kingdom
WT064890 / Wellcome Trust / United Kingdom
U01 DK062418 / DK / NIDDK NIH HHS / United States
G0600705 / Medical Research Council / United Kingdom
MH081802 / MH / NIMH NIH HHS / United States