MRI‐Based Genetic Studies Reveal Specific Genetic Variants and Disease Risks Associated With Fat Distribution Across Anatomical Sites

<b>Objective:</b> To investigate the genetic determinants of fat distribution across anatomical sites and their implications for health outcomes. <b>Methods:</b> We analyzed neck-to-knee MRI data from the UK Biobank (<i>n</i> = 37,589) to measure fat at various locations and used Mendelian randomization to assess effects on 26 obesity-related diseases and 94 biomarkers from FinnGen and other consortia. <b>Result:</b> We identified genetic loci associated with 10 fat depots: abdominal subcutaneous adipose tissue (<i>n</i> = 2 loci), thigh subcutaneous adipose tissue (25), thigh intermuscular adipose tissue (15), visceral adipose tissue (7), liver proton density fat fraction (PDFF) (8), pancreas PDFF (11), paraspinal adipose tissue (9), pelvic bone marrow fat (28), thigh bone marrow fat (27), and vertebrae bone marrow fat (5). Genetically higher abdominal subcutaneous adipose tissue was associated with an adverse metabolic profile and higher risks of Type 2 diabetes, and cardiovascular outcomes. Conversely, higher thigh subcutaneous adipose tissue was associated with a favorable profile and lower risks of Type 2 diabetes and cardiovascular outcomes. Higher visceral adipose tissue was associated with gallstones; higher liver PDFF was associated with elevated tyrosine levels, higher Type 2 diabetes risk, and fatty liver disease; pancreas PDFF was associated with thrombotic events; and thigh bone marrow fat was associated with osteoporosis. <b>Conclusion:</b> These results further suggest a unique contribution of fat deposition in different anatomical locations to disease risk, emphasizing the potential, beyond weight loss per se, for future research into depot-specific therapeutic strategies.