Identification of rare loss of function genetic variation regulating body fat distribution

Abstract

Context: Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly non-coding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss-of-function (LoF) would be of most therapeutic benefit. Objective, Design and Setting: To identify genes/proteins involved in determining fat distribution, we combined the power of genome-wide analysis of array-based rare, non-synonymous variants in 450,562 individuals of UK Biobank with exome-sequence-based rare loss of function gene burden testing in 184,246 individuals. Results: The data indicates that loss-of-function of four genes (PLIN1 [LoF variants, p=5.86×10-7], INSR [LoF variants, p=6.21×10-7], ACVR1C [LoF + Moderate impact variants, p=1.68×10-7; Moderate impact variants, p=4.57×10-7] and PDE3B [LoF variants, p=1.41×10-6]) is associated with a beneficial impact on WHRadjBMI and increased gluteofemoral fat mass, whereas LoF of PLIN4 [LoF variants, p=5.86×10-7] adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B and ACVR1C favourably affects metabolic phenotypes (e.g. triglyceride [TG] and HDL cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes. Conclusion: This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counter-intuitive insight into the potential consequences of targeting these molecules therapeutically.