With regard to insulin resistance, our analyses resulted in only one novel genome-wide significant locus associated with FI and HOMA-IR. The associated SNP rs35767 is 1.2 kb upstream of IGF1, raising the possibility that it may influence IGF1 expression levels (we have found no direct support for this notion in the limited eQTL data available). Although not reaching genome-wide-significance, we note that SNP rs4675095 in the insulin receptor substrate-1 gene (IRS1) was also associated with HOMA-IR (P=4.6×10−3), which given IRS1’s excellent biological credentials will warrant further investigation. This SNP is not in LD with the widely studied missense SNP G972R (rs1801278) nor with the newly discovered T2D SNP rs294364145, whose C risk allele was only nominally associated with increased FI (P=0.02) and HOMA-IR (P=0.04) in our discovery dataset. The previously reported associations of SNPs in PANK1 with fasting insulin24 did not receive strong support in our discovery cohorts (P=0.04 and 0.17 for rs11185790 and rs1075374, respectively).
