| Abstract | Objective To investigate the genetic determinants of fat distribution across anatomical sites and their implications for health outcomes. Research Design and Method We analyzed neck-to-knee MRI data from the UK Biobank (n=37,589) to measure fat deposition at various locations and used Mendelian randomization to assess their causal effects on 122 obesity-related diseases and biomarkers using data from FinnGen and other consortia. Result We identified genetic loci associated with fat depots: abdominal subcutaneous fat (n=2 loci), thigh subcutaneous fat (25), thigh intermuscular fat (15), visceral fat (7), liver fat (8), pancreas fat (11), paraspinal fat (9), pelvic bone marrow fat (28), thigh bone marrow fat (27) and vertebrae bone marrow fat (5). Genes such as RSPO3 and COBLL1, associated with thigh subcutaneous fat, emerged as promising candidates for therapeutic targeting. Genetically higher abdominal subcutaneous fat was independently associated with an adverse metabolic profile and higher risks of type 2 diabetes, and cardiovascular outcomes. Conversely, higher thigh subcutaneous fat was independently associated with a favourable profile and lower risks of type 2 diabetes and cardiovascular outcomes. Genetically higher visceral fat was associated with gallstones, liver fat with elevated tyrosine levels, type 2 diabetes risk and fatty liver disease, pancreas fat with thrombotic events, and thigh bone fat with osteoporosis. Conclusion These results highlight the unique contribution of fat deposition in different anatomical locations to disease risk, emphasizing the need for targeted interventions to address specific fat depots in mitigating obesity-related diseases. |
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