biostudies-literatureUnknown16(1)Jonsdottir ABObesity is associated with adverse effects on health and quality of life. Improved understanding of its underlying pathophysiology is essential for developing counteractive measures. To search for sequence variants with large effects on BMI, we perform a multi-ancestry meta-analysis of 13 genome-wide association studies on BMI, including data derived from 1,534,555 individuals of European ancestry, 339,657 of Asian ancestry, and 130,968 of African ancestry. We identify an intergenic 262,760 base pair deletion at the MC4R locus that associates with 4.11 kg/m² higher BMI per allele, likely through downregulation of MC4R. Moreover, a rare FRS3 missense variant, p.Glu115Lys, only found in individuals from Finland, associates with 1.09 kg/m² lower BMI per allele. We also dNature communications2694https://www.ebi.ac.uk/biostudies/studies/S-EPMC11937519biostudies-literatureMissense variants in FRS3 affect body mass index in populations of diverse ancestries.PMC11937519Magnusson OTBundgaard HSigurdsson AThorleifsson GStefansson KIversen KKSigurdsson ELTragante VEinarsson GStefansson HBrunak SThorisson GASorensen ENadauld LDHelgason ABeyter DJonsdottir ABNorddahl GLEggertsson HPTamlander MOddsson AGhouse JFridriksdottir RLarusdottir AEOlason PIIvarsdottir EVUllum HGretarsdottir SThorolfsdottir RBKristmundsdottir SHolm HJensen BAThorsteinsdottir UBjornsdottir GErikstrup CUlfarsson MOTopholm Bruun MHalldorsson BVRipatti SSteinthorsdottir VRognvaldsson SArnar DOKnight SWalters GBStyrkarsdottir UJonsdottir ISveinbjornsson GBjarnason RGHalldorsson GHMikkelsen CBanasik KOlafsdottir TAegisdottir HMMoore KHSHolm PCThorgeirsson TEMasson GSturluson ADBDS Genomic ConsortiumHelgadottir ASteingrimsdottir TVikingsson ASchwinn MSulem PDowsett JKnowlton KUOstrowski SRHansen TEinarsson ESkaftason ATeitsdottir UDMelsted PGudbjartsson DFPedersen OBPalsson FStefansdottir LfalseMissense variants in FRS3 affect body mass index in populations of diverse ancestries.Obesity is associated with adverse effects on health and quality of life. Improved understanding of its underlying pathophysiology is essential for developing counteractive measures. To search for sequence variants with large effects on BMI, we perform a multi-ancestry meta-analysis of 13 genome-wide association studies on BMI, including data derived from 1,534,555 individuals of European ancestry, 339,657 of Asian ancestry, and 130,968 of African ancestry. We identify an intergenic 262,760 base pair deletion at the MC4R locus that associates with 4.11 kg/m² higher BMI per allele, likely through downregulation of MC4R. Moreover, a rare FRS3 missense variant, p.Glu115Lys, only found in individuals from Finland, associates with 1.09 kg/m² lower BMI per allele. We also d2025-01-01T00:00:00Z2025 Mar2026-06-01T10:14:48.799Z2025-07-13T03:04:46.132ZS-EPMC119375194013325710.1038/s41467-025-57753-2