Genetic Determinants of Fatty Acid Composition in Subcutaneous and Visceral Adipose Tissue.

Objective: Fatty acids in adipose tissue are key structural and metabolic regulators of cardiometabolic health, but the genetic architecture governing depot-specific composition in subcutaneous (SAT) and visceral adipose tissue (VAT) is not well defined.

Methods: We used MRI-derived estimates of fatty acid composition in SAT and VAT from 33,583 UK Biobank participants to perform genome-wide association studies. Functional annotation, fine mapping, colocalization, and expression QTL analyses were conducted to prioritize likely causal variants and explore mechanisms.

Results: We identified six loci associated with adipose tissue fatty acid composition, including both shared (PKD2L1, INSIG1) and depot-specific associations (LEKR1 and KLF14 for SAT; CDCA2 for VAT). The strongest association, rs603424-G (near PKD2L1), was linked to higher monounsaturated and polyunsaturated fatty acids, lower saturated fatty acids, and increased SCD1 expression in SAT and VAT, suggesting a role in desaturation and lipid remodeling. Several loci were linked to cardiometabolic outcomes including type 2 diabetes, hypertension, and cholelithiasis, with functional evidence supporting gene-diet interactions at the PKD2L1 locus.

Conclusions: Our findings uncover genetic determinants of human adipose tissue fatty acid composition, highlight depot-specific regulation, and point to SCD1 as a potential metabolic regulator. These results deepen understanding of lipid metabolism and its links to cardiometabolic risk.