biostudies-literatureZhang XBLRD VANCATS NIH HHSNIBIB NIH HHSNCRR NIH HHSNIA NIH HHSNIAID NIH HHSNHLBI NIH HHSU.S. Department of Health &amp; Human Services | NIH | Office of Extramural Research, National Institutes of HealthNIDDK NIH HHSNHGRI NIH HHSU.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)NCI NIH HHSNINDS NIH HHSNIAMS NIH HHSNIGMS NIH HHS3470https://www.ebi.ac.uk/biostudies/studies/S-EPMC11992084biostudies-literatureUnknown16(1)Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10^-⁹), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpoNature communicationsWhole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.PMC11992084P20 GM109036F32 HL085989R01 AG058921R01 HL104135R01 HL153460U01 HG007416R01 DK122503U01 HL054509R01 HL092301R01 HL055673I01 BX004821U01 HL089897R01 HL068959U01 HL089856R01 HL067348T32 HL007055R01 AI132476R01 HL120393R01 EB015611R01 DK075787P01 HL132825U01 HG009088R01 DK124097R01 DK135938I01 BX003362U01 HL072524R01 HL104608KL2 TR002490U01 HL054472U01 HL054473P30 CA008748R01 HL093093R01 HG010297R01 DK 122503P30 CA071789R01 AR048797U01 HL120393R01 DK071891R01 HL119443M01 RR007122P01 CA134294K08 HL136928R35 CA197449R01 NS058700T32 HL129982R01 HL113338R01 HL172803U01 HL072507R01 DK107786R01 HL142302I01 BX003340R01 AI114555R01 HL142825R01 DK110113R01 HL133040U01 HL054495R01 HL105756U19 CA203654Cupples LAPsaty BMBowden DWKardia SLRBurchard EGChami NGuo XLin XBielak LFMorrison ACHighland HMLe Marchand LChasman DIYoneda ZTWiggins KLRodriguez-Santana JChang KMTiwari HKHui QBroome JGHe JGarrett MEXu HJustice AEJain DChavan SHu DShoemaker MBPankow JSRegan EAHwu CMJackson RDKalyani RRYanek LRIrvin MRChittoor GRoden DMLeNoir MChuang LMZhao WBlangero JGraff MNaseri TLoos RJFConomos MPMinster RLBenjamin Shoemaker MHeard-Costa NSmith JATaylor KDGupta SReiner APMcHugh CPHaiman CNouraie MWilson PWFHeckbert SRPalmer NDBecker DMWilkens LRBis JCFohner AEKooperberg CCarson APMitchell BDRotter JIHo YLBoerwinkle ERich SSIda Chen YDPeters UCurran JEAllison MATelen MJWang ZEng CLi CVasan RSRaffield LMFreedman BIMeyer MButh EJChiu YFWeeks DELi XLi ZLiu CTBrody JAO'Connell JKelly TNLange LADuggirala RFornage MDeMeo DLDu MFerrier KRAshley-Koch AEGordeuk VRWessel JZollner SHobbs BDHixson JESitlani CMSmith NLSun YVBoorgula MPWeiss STArnett DKJosyula NSMcDonald MNO'Donnell CJPreuss MHHeavner BDRao DCHidalgo BPerry JAReupena SMCarlson CSHou LLange EMZhang YZhang XNHLBI Trans-Omics for Precision Medicine (TOPMed) ConsortiumBarnes KCChen YINorth KEfalseWhole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10^-⁹), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpo2025-01-01T00:00:00Z2025 Apr2026-06-01T17:58:04.376Z2025-06-26T03:06:09.698ZS-EPMC119920844021675910.1038/s41467-025-58420-2