This study conducted a genome-wide association study (GWAS) and Metabochip meta-analysis of body mass index (BMI) in up to 339,224 individuals to better understand the genetic basis of obesity. The analysis identified 97 BMI-associated loci, 56 of which were novel. These loci account for approximately 2.7% of BMI variation, suggesting that common variation may account for over 20% of BMI variation. Pathway analyses highlighted the central nervous system's role in obesity susceptibility and implicated new genes and pathways related to synaptic function, glutamate signaling, insulin secretion/action, energy metabolism, lipid biology, and adipogenesis. The study also found that BMI-associated variants have comparable effects across ancestries and between sexes, and that some loci show significant associations with traits in the opposite direction of their expected effect based on their phenotypic correlation with BMI. These findings provide new insights into the genetic and biological mechanisms underlying obesity and suggest potential targets for therapeutic interventions.This study conducted a genome-wide association study (GWAS) and Metabochip meta-analysis of body mass index (BMI) in up to 339,224 individuals to better understand the genetic basis of obesity. The analysis identified 97 BMI-associated loci, 56 of which were novel. These loci account for approximately 2.7% of BMI variation, suggesting that common variation may account for over 20% of BMI variation. Pathway analyses highlighted the central nervous system's role in obesity susceptibility and implicated new genes and pathways related to synaptic function, glutamate signaling, insulin secretion/action, energy metabolism, lipid biology, and adipogenesis. The study also found that BMI-associated variants have comparable effects across ancestries and between sexes, and that some loci show significant associations with traits in the opposite direction of their expected effect based on their phenotypic correlation with BMI. These findings provide new insights into the genetic and biological mechanisms underlying obesity and suggest potential targets for therapeutic interventions.