By conducting a multistage GWAS for the first time in healthy subjects who were treated with opioid analgesics, we identified a potent locus for opioid sensitivity that encompasses an LD block that includes the most significant SNP, rs2952768. The C allele of this SNP, especially homozygotes of the C allele, was associated with more analgesic requirements, suggesting the possibility to classify the patients into groups of high responders and low responders or non-responders to the given opioid, which would presumably correspond to the T/T or T/C and C/C genotype groups, respectively. Surprisingly, this SNP was also found to be significantly associated with postoperative analgesic requirements in subjects who also received opioids but underwent different surgical procedures. Moreover, the C allele with likely less opioid sensitivity in this SNP was associated with a lower risk for serious symptoms of substance dependence and a lower RD score on the TCI in healthy subjects. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence.
