Genome-Wide and Abdominal Imaging Data Characterizes Common Alleles Associated with Higher BMI and Subcutaneous Fat but Less Liver Fat and Lower Risk of Type 2 Diabetes

Genetic studies have identified “favourable adiposity” variants - where the allele associated with higher adiposity is associated with lower risk of type 2 diabetes. We took a novel approach to find more of these alleles and find the underlying mechanisms.

We first performed a genome wide association study (GWAS) of body fat percentage using 451000 individuals from UK Biobank. Second, we used published genetic data in a multivariate test to find alleles associated with higher adiposity but a “favourable” metabolic phenotype: higher HDL-C, adiponectin, sex hormone binding globulin, but lower triglycerides, fasting insulin and alanine transaminase. Third, we used abdominal imaging data from 4 studies to define the adiposity phenotype in more detail.

We identified 620 variants associated with body fat percentage (p<5x10^-8). Fourteen alleles had a “favourable adiposity” phenotype, including 7 previously known variants (in/near PPARG, LYPLAL1, GRB14, IRS1, PEPD, FAM13A and ANKRD55), 5 known to be associated with a relevant trait (TRIB1, KLF14/MKLN1, DNAH10, VEGFA/C6orf223 and AEBP2/PDE3A) and 2 novel variants (MAFF and CITED2). Carrying 10 additional "favourable adiposity" allele was associated with higher BMI (0.63 kg/m², p = 4x10^-45) but lower risk of type 2 diabetes (odds ratio: 0.60, p = 4x10^-44, 14371 cases), lower risk of heart disease (0.82, p = 3x10^-14, 37741 cases) and lower risk of hypertension (0.82, p = 1x10^-33, 241691 cases). Using MRI/CT scans of abdominal fat from UK Biobank (N = 5000), NEO (2236), TÜF (900), and a published GWAS (10557), carrying more “favourable adiposity” alleles was associated with higher subcutaneous fat (p = 1x10^-12) but lower liver fat (p = 1x10^-7). These effects were similar when we removed the 7 known “favourable adiposity” variants.

“Favourable adiposity” alleles associated with higher BMI but lower risk of type 2 diabetes are characterized by higher subcutaneous but lower liver fat.