The high SNP density of the HapMap makes it possible that some of the SNPs interrogated are actually the causal variants (it is estimated that 30-50% of SNPs with MAF > 5% are represented in the HapMap 22,23), which means that evaluation of the genomic annotation where associated SNPs are found may be informative. For each of the 4 populations, we mapped the most significant SNP for each of the genes with significant cis- associations from the single population analysis relative to the transcription start site (TSS) of genes with annotated 5′UTRs. We found a strong signal for the SNPs to be located very close to the TSS (Figure 4), with no discernable trend toward 3′ or 5′. This symmetrical trend was also evident in the recent analysis of the ENCODE consortium 31. When we considered the most significant SNP of the 341 additional genes detected in the 4-population multi-population analysis, the signal was even tighter around the TSS. Three of the associated SNPs (rs10998076, rs869736, rs1010167) have been previously shown in promoter transfection assays to have a direct effect on transcriptional activation 32 in kidney and brain cell lines.
