Notably, our large-scale meta-analyses produced more than a dozen robust associations with FG and only two with FI/HOMA-IR (GCKR and IGF1). Although the somewhat smaller sample size for insulin may have contributed to this discrepancy, a comparison of the similarly-powered HOMA-B and HOMA-IR analyses reveals associations with HOMA-B several orders of magnitude more significant than those seen with HOMA-IR (Figure 2). Because insulin itself is a component of the numerator in both measures, one cannot attribute this discrepancy to technical differences in insulin measurements across cohorts. Similarly, because the QQ plots are very similar for FI and HOMA-IR, we do not believe that the use of a mathematical formula (HOMA-IR) rather than a direct measurement (FI) has affected our analyses substantially. HOMA-B and HOMA-IR have comparable heritability estimates (0.26 and 0.27 in Framingham respectively) and their correlation is significant (r=0.55 in Framingham). Thus, not only there may be a difference in the identity of specific genetic determinants for each trait46, but rather the genetic architecture may be distinct for each trait, with more modest effects, fewer loci, rarer variants or
