SummaryThe growth hormone/insulinâlike growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGFârelated proteins including IGFâI and IGFâbinding proteinâ3 (IGFBPâ3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30Â 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGFâI and IGFBPâ3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotypeâphenotype associations between men and women, were found only for associations of IGFBPâ3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGFâI and IGFBPâ3 concentrations. The IGFâIâdecreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90Â years. The known longevityâassociated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGFâI concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGFâIâ and IGFBPâ3âassociated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGFâI and IGFBPâ3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevityâassociated loci.