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Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the  IGFBP3  gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of  P  &lt; 5 × 10 −8  ( P  = 3.3 × 10 −101 ). Furthermore, the same  IGFBP3  gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration ( P  = 1.9 × 10 −26 ). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 ( P  = 4.4 × 10 −21 ) and higher IGF-I ( P  = 4.9 × 10 −9 ) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3,  P  = 1.2 × 10 −11 ,  IGFALS , a confirmatory finding; and rs4234798, chromosome 4p16.1,  P  = 4.5 × 10 −10 ,  SORCS2 , a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and  FOXO3  (rs2153960, chromosome 6q21,  P  = 5.1 × 10 −7 ), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3