Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ​ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings ​across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women’s Health Initiative (WHI).

We identified a genome-wide significant association in MESA Hispanics—rs12253976 in KLF6 (beta = 5.792 kg/m² per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10⁻⁹)—and suggestive SNPs with p < 5 × 10⁻⁶ in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = −1.111 kg/m², 95 % CI: −1.578, −0.645; p = 3.33 × 10⁻⁶) and WHI Hispanics (beta = −0.304 kg/m², 95 % CI: −0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10⁻³) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m², 95 % CI: 0.643, 1.564; p = 2.85 × 10⁻⁶) and WHI African Americans (beta = 0.219 kg/m², 95 % CI: −0.021, 0.460; p = 0.074).

Two BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.