have encountered concerns the genomewide association analysis of G6PD activity levels in a sample of Sardinian individuals (77, 94). There, analysis of directly genotyped SNPs revealed two sets of SNPs strongly associated (p < 5×10−8) with G6PD activity levels, one near the G6PD gene locus on chromosome X and another near the HBB locus on chromosome 11. Genotype imputation revealed a strong additional signal (also with p < 5×10−8) upstream of the 6PGD locus on chromosome 1 (Manuela Uda, Serena Sanna, David Schlessinger, personal communication; Figure 4). The three signals (near G6PD, HBB and 6PGD) all fit with our understanding of the biological basis of measurements of G6PD activity: the role of variants near G6PD in the regulation of G6PD activity in Sardinia and elsewhere is well established (25), variants in the HBB locus can influence the lifespan and rate of turnover of red blood cells and it is well established that G6PD activity is higher in younger cells (70) and, finally, it is well known than 6PGD activity levels impact commonly used assays for G6PD activity (13, 31).
