A genome-wide association study (GWAS) identified 49 loci associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and 19 additional loci linked to related waist and hip circumference measures in up to 224,459 individuals. These loci were enriched for genes expressed in adipose tissue and regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance in fat distribution. The study also found sexual dimorphism in the genetic effects, with 19 of the 49 WHRadjBMI loci showing stronger effects in women. Additional analyses identified 19 loci associated with five other traits, including unadjusted WHR, BMI-adjusted and unadjusted waist and hip circumferences. These loci were enriched for genes involved in adipogenesis, angiogenesis, and transcriptional regulation. The study also identified potential functional variants, including those in regulatory elements and eQTLs, and highlighted biological mechanisms such as VEGF signaling and PTEN signaling. The results suggest that genetic variants associated with WHRadjBMI may influence cardiometabolic traits and that these loci may be involved in processes related to insulin resistance and adipose biology. The study also found that some loci were more strongly associated with WCadjBMI or HIPadjBMI than with WHRadjBMI or BMI, indicating that these traits may capture aspects of central obesity not fully reflected by WHRadjBMI or BMI. The study provides insights into the genetic architecture of body fat distribution and its molecular links to cardiometabolic traits, highlighting the importance of adipose tissue and mesenchymal-derived tissues in fat distribution and central obesity. The findings may have implications for understanding the genetic basis of metabolic and cardiovascular diseases.A genome-wide association study (GWAS) identified 49 loci associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and 19 additional loci linked to related waist and hip circumference measures in up to 224,459 individuals. These loci were enriched for genes expressed in adipose tissue and regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance in fat distribution. The study also found sexual dimorphism in the genetic effects, with 19 of the 49 WHRadjBMI loci showing stronger effects in women. Additional analyses identified 19 loci associated with five other traits, including unadjusted WHR, BMI-adjusted and unadjusted waist and hip circumferences. These loci were enriched for genes involved in adipogenesis, angiogenesis, and transcriptional regulation. The study also identified potential functional variants, including those in regulatory elements and eQTLs, and highlighted biological mechanisms such as VEGF signaling and PTEN signaling. The results suggest that genetic variants associated with WHRadjBMI may influence cardiometabolic traits and that these loci may be involved in processes related to insulin resistance and adipose biology. The study also found that some loci were more strongly associated with WCadjBMI or HIPadjBMI than with WHRadjBMI or BMI, indicating that these traits may capture aspects of central obesity not fully reflected by WHRadjBMI or BMI. The study provides insights into the genetic architecture of body fat distribution and its molecular links to cardiometabolic traits, highlighting the importance of adipose tissue and mesenchymal-derived tissues in fat distribution and central obesity. The findings may have implications for understanding the genetic basis of metabolic and cardiovascular diseases.