Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension
Recent genetic studies have identified alleles associated with opposite effects on
adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and
test the hypothesis that such “favourable adiposity” alleles are associated with higher
subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging
(MRI) data with genome-wide association studies (GWAS) of body fat % and
metabolic traits. We report 14 alleles, including 7 newly characterized alleles,
associated with higher adiposity, but a favourable metabolic profile. Consistent with
previous studies, individuals carrying more “favourable adiposity” alleles had higher
body fat % and higher BMI, but lower risk of type 2 diabetes, heart disease and
hypertension. These individuals also had higher subcutaneous fat, but lower liver fat
and lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated
with higher body fat % but lower liver fat and lower risk of type 2 diabetes included
those in PPARG, GRB14 and IRS1, whilst the allele in ANKRD55 was paradoxically
associated with higher visceral fat but lower risk of type 2 diabetes. Most identified
“favourable adiposity” alleles are associated with higher subcutaneous and lower liver
fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in
metabolically low risk depots.Diabetes UK RD Lawrence fellowship, European Research Council, Wellcome Trust and Royal Society grant, European Regional Development Fund, Medical Research Council, German Federal Ministry of Education and Research, German Research Foundation, Innovative Medicines Initiative Joint Undertaking, European Union's
Seventh Framework Programme, Dutch Science Organisation, Scottish Government Health Directorates, Scottish Funding Council and Medical Research Council UK and the Wellcome Trust