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OBJECTIVE Meta-analyses of genome-wide association studies in Europeans have identified > 98 loci for BMI. Transferability of these established associations in Pima Indians was analyzed. METHODS Among 98 lead single nucleotide polymorphisms (SNPs), 82 had minor allele frequency ≥ 0.01 in Pima Indians and were analyzed for association with the maximum BMI in adulthood (n = 3,491) and BMI z score in childhood (n = 1,958). 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) were 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 (beta = 0.48% per risk allele; P = 1.6 × 10-9 ) and BMI z score in childhood (beta = 0.024 SD; P = 1.7 × 10-7 ). GRS was 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.

Aims Insulin-like growth factor 1 receptor (IGF1R) is involved in cell growth and glucose homeostasis. In the current study, the IGF1R locus was analysed as a candidate gene for type 2 diabetes (T2D) in American Indians. Materials and methods Whole genome sequence data from 335 American Indians identified 3 novel missense variants in IGF1R. The associations of IGF1R variants with T2D, age of T2D onset and birth weight were analysed in a population-based sample of 7701 American Indians. Results A novel glycine-to-aspartic acid substitution (G310D) in IGF1R was identified, which associated with T2D in a sex-specific manner (Psex interaction = 0.02). In women, the aspartic acid (D) allele (frequency = 0.034) was associated with increased risk for T2D (n = 4292, P = 2.0 × 10-5 adjusted for age, birth year, and the first 5 genetic principal components; odds ratio [OR] = 2.23 [1.54-3.23] per risk allele) and an earlier age of T2D onset (n = 4292, P = 2 × 10-4 , hazard rate ratio = 1.45 [1.20-1.75], Psex interaction = 0.05). Female carriers of the D-allele also had lower birth weight (n = 1313, β = -163 g, P = .006, Psex interaction = 0.008). Among 85 siblings discordant for G310D, carriers of the D-allele had shorter stature as compared with carriers of the G-allele (β = -1.6 cm, P = .001, within family model). The G310D variant was functionally studied in vitro, where the D-allele had a 22% increase (P = .0005) in FOXO1-induced transcriptional activity, due to decreased activation of the PI3K/AKT pathway mediated through reduced IGF1R activity. Conclusion A unique G310D variant in IGF1R, which occurs in 6% American Indians, may impair IGF1R signalling pathways, thereby increasing the risk of T2D.