BackgroundGenome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians. Here, we identify and characterize a new locus for BMI that was detected by analyzing moderate associations with BMI obtained in a population-based sample of southwestern American Indians together with the well-powered GIANT dataset.MethodsGenotypes for 10.5 million variants were tested for association with BMI in 5870 American Indians and 2600 variants that showed an associationP< 10−3in the American Indian sample were combined in a meta-analysis with the BMI data reported in GIANT (N= 240,608). The newly identified gene,NFIA-AS2was functionally characterized, and the impact of its lead associated variant rs1777538 was studied both in-silico and in-vitro.ResultsRs1777538 (T/C; C allele frequency = 0.16 in American Indians and 0.04 in GIANT, meta-analysisP= 5.0 × 10−7) exhibited a large effect in American Indians (1 kg/m2decrease in BMI per copy of C allele). NFIA-AS2 was found to be a nuclear localized long non-coding RNA expressed in tissues pertinent to human obesity. Analysis of this variant in human brown preadipocytes showed that NFIA-AS2 transcripts carrying the C allele had increased RNA degradation compared to the T allele transcripts (half-lives = 9 h, 13 h respectively). During brown adipogenesis,NFIA-AS2featured a stage-specific regulation of nearby gene expression where rs1777538 demonstrated an allelic difference in regulation in the mature adipocytes (the strongest difference was observed forL1TD1,P= 0.007).ConclusionOur findings support a role forNFIA-AS2in regulating pathways that impact BMI.