We first evaluated the haplotypes containing SNPs rs563649 (C/T), rs2075572 (G/C) and rs533586 (C/T), which appear to be the minimal functional units. The sampling LD values between these SNPs can be determined directly from the haplotype frequencies, which were estimated with the expectation-maximization (EM) algorithm, and are given in Table 4. The three D′ values in this case are all very high (0.8, 1, −0.92) (Supplementary Material, Fig. S3). The haplotype T-C-T in this 3-loci set was significantly associated with pain sensitivity, as shown by a conservative P-value estimate calculated under different models (52) (Table 4). This haplotype was associated with significantly higher pain ratings (z = 4.83) and was observed in ∼6% of the subjects. We next examined whether SNPs within the OPRM1 gene locus, which have been previously reported to be associated with pain, analgesia or other pain-related phenotypes, are related to the pain-sensitivity haplotype established by our analysis. SNP rs1799971 (A118G) has been repeatedly shown to produce functional effects. Carriers of the minor 118G allele show decreased analgesic responses to morphine and M6G (22–25) and significantly higher
