Our results interrogate only a fraction of the common variants in any given genomic region; we therefore expect that for the majority of the loci here described the underlying causal variant has yet to be identified. Nevertheless for some there are intriguing possible SNP candidates: in SLC2A2 the lead SNP (rs11920090) is in perfect LD (r2 = 1.0) with rs5400 (Stage 1 discovery association P=5.9×10−6), which codes for the amino acid substitution T110I, predicted to be “possibly damaging” by PolyPhen35 and PANTHER (Pdel= 0.92)36. In GCKR the lead SNP is in strong LD (r2=0.93) with rs1260326, encoding P446L, a non-synomymous variant previously associated with the same traits30 and predicted by PolyPhen to be “probably damaging”. A recent functional study has demonstrated that this variant indirectly leads to increased GCK activity, resulting in the observed effects on FG and triglyceride levels37. Both SLC2A2 T110I and GCKR P446L were predicted “tolerated” by SIFT38, highlighting the difficulties in obtaining consensus functional predictions from different informatic approaches.
