Assessing the Role of 98 Established Loci for BMI in American Indians.

Abstract

Objective:Meta-analyses of genome-wide association studies (GWAS) in Europeans have identified >98 loci for Body Mass Index (BMI). We analyze transferability of these established associations in Pima Indians.Methods:Among 98 lead SNPs, 82 had minor allele frequency≥0.01 in Pima Indians, and were analyzed for association with the maximum BMI in adulthood (n=3491) and BMI z-score in childhood (n=1958). Common tag SNPs across 98 loci were also analyzed for additional signals.Results:Among the lead SNPs, 13 (TMEM18, TCF7L2, MRPS33P4, PRKD1, ZFP64, FTO, TAL1, CALCR, GNPDA2, CREB1, LMX1B, ADCY9, NLRC3) associated with BMI (p≤0.05) in Pima adults. A multi-allelic genetic risk score (GRS), which summed the risk alleles for 82 lead SNPs, showed a significant trend for a positive relationship between GRS and BMI in adulthood (β=0.48% per risk allele, p=1.6×10−9) and BMI z-score in childhood (β=0.024SD, p=1.7×10−7). GRS significantly associated with BMI across all age groups ≥5 years, except for those ≥50 years. The strongest association was seen in adolescence (age 14–16 years, p=1.84×10−9).Conclusions:In aggregate, European-derived lead SNPs had a notable effect on BMI in Pima Indians. Polygenic obesity in this population manifests strongly in childhood and adolescence, and persists throughout much of adult life.