Further, we have identified a potentially functional haplotype associated with high pain sensitivity (Table 4), which is tagged by the minor allele T of rs563649. The frequency of this haplotype corresponded to the frequency of the minor T allele and the SNP rs563649 was the strongest individual contributor to the association, suggesting that the minor T allele of this newly identified SNP is a strong candidate for the functional site of the haplotype. This haplotype spans over the OPRM1 gene locus and consists of all the alleles that have previously been shown to be associated with lower pain thresholds (rs1799971, A allele) (26), negative mood (rs495491, G allele) (58) and increased substance dependency, including opioid dependence (rs609148, G allele and rs495491, G allele) (57), all of which are consistent with a low level of opioid receptor activity. On the other hand, whereas the T allele of rs563649 in our cohort is associated with a decreased analgesic response to opioids, again consistent with low levels of receptor activity (21), the A allele of rs1799971, which is situated on the haplotype tagged by the T allele of rs563649, is associated with an increased analgesic response to opioids (16).
