A genome-wide association study (GWAS) and meta-analysis of body mass index (BMI) in up to 339,224 individuals identified 97 BMI-associated loci (P < 5 × 10⁻⁸), 56 of which are novel. These loci account for ~2.7% of BMI variation, with common genetic variation explaining >20% of BMI variation. Pathway analyses suggest a role of the central nervous system in obesity susceptibility, implicating genes and pathways related to synaptic function, glutamate signaling, insulin secretion, energy metabolism, lipid biology, and adipogenesis. The study highlights the biological processes underlying obesity and identifies new genes and pathways. The 97 loci were analyzed in European and non-European populations, with 41 previously associated with obesity measures. The study also examined the effects of these loci on other metabolic traits, finding some associations in the opposite direction of expected effects. The results suggest that common BMI-associated SNPs have comparable effects across ancestries and between sexes. The study also identified potential causal genes at associated loci, including those related to synaptic function, long-term potentiation, neurotransmitter signaling, and energy metabolism. The findings strengthen the connection between obesity and other metabolic diseases and enhance understanding of the tissues, physiological processes, and molecular pathways contributing to obesity. The study provides the strongest genetic evidence so far for a role of particular biological and CNS processes in the regulation of human body mass. The results underscore the heterogeneous aetiology of obesity and its links with several related metabolic diseases and processes. The study also highlights the importance of further research to identify genetic variants associated with BMI and to refine the biology of obesity.A genome-wide association study (GWAS) and meta-analysis of body mass index (BMI) in up to 339,224 individuals identified 97 BMI-associated loci (P < 5 × 10⁻⁸), 56 of which are novel. These loci account for ~2.7% of BMI variation, with common genetic variation explaining >20% of BMI variation. Pathway analyses suggest a role of the central nervous system in obesity susceptibility, implicating genes and pathways related to synaptic function, glutamate signaling, insulin secretion, energy metabolism, lipid biology, and adipogenesis. The study highlights the biological processes underlying obesity and identifies new genes and pathways. The 97 loci were analyzed in European and non-European populations, with 41 previously associated with obesity measures. The study also examined the effects of these loci on other metabolic traits, finding some associations in the opposite direction of expected effects. The results suggest that common BMI-associated SNPs have comparable effects across ancestries and between sexes. The study also identified potential causal genes at associated loci, including those related to synaptic function, long-term potentiation, neurotransmitter signaling, and energy metabolism. The findings strengthen the connection between obesity and other metabolic diseases and enhance understanding of the tissues, physiological processes, and molecular pathways contributing to obesity. The study provides the strongest genetic evidence so far for a role of particular biological and CNS processes in the regulation of human body mass. The results underscore the heterogeneous aetiology of obesity and its links with several related metabolic diseases and processes. The study also highlights the importance of further research to identify genetic variants associated with BMI and to refine the biology of obesity.