For any given level of overall adiposity – as quantified in clinical practice by body mass index (BMI)– individuals vary considerably in fat distribution. Increased visceral adipose tissue (VAT) is associated with increased cardiometabolic risk, while gluteofemoral adipose tissue (GFAT) may be protective. Monogenic familial partial lipodystrophy (FPLD) – often caused by rare variants in LMNA – is an extreme example of this paradigm, often characterized by reduced GFAT with maintained or increased VAT in association with insulin resistance and an adverse metabolic profile. In contrast, the inherited basis of fat distribution in the broader population is not fully understood. To build on prior genetic studies with anthropometric surrogates, we studied up to 38,965 UK Biobank participants with VAT, abdominal subcutaneous (ASAT), and GFAT volumes precisely quantified using MRI imaging. Because genetic associations with these raw fat depot volumes were largely driven by variants known to affect BMI, we next studied six measures of local adiposity: VAT adjusted for BMI and height (VATadj), ASATadj, GFATadj, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 250 loci associated with at least one adiposity trait, including 39 newly-identified loci. Rare variant association studies extend prior evidence for PDE3B as an important modulator of fat distribution. Sex-specific analyses of local adiposity measures noted overall higher estimated heritability in female participants, increased effect sizes for identified loci, and 26 female-specific associations. Individuals in the extreme tails of VATadj, ASATadj, and GFATadj were highly enriched for predisposing common variants, as quantified using polygenic scores. Taking GFATadj as an example, individuals with GFATadj in the top 5% were 3.8-fold (95%CI 2.8 to 5.2) more likely to have a polygenic score within the top 5% of the distribution. A VATadj polygenic score was associated with a metabolically unhealthy profile, while a GFATadj score was associated with a metabolically healthy profile. These results – using MRI-derived, BMI-independent measures of local adiposity – confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.

Fat Depots,GWAS,Rare Variant Association Study,Polygenic Score