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In a whole blood TWAS using different approaches (eWASs) that chose significant two-sided genes based on the Bayes factor, we identified the general anaesthetics and analgesics shown in Table 2 as the most significant in the association with pain sensitivity. The suggested PPIN genes likely indicate the sources of the molecular mechanisms of anaesthesia. For example, among the four genes, the down regulation of GRIN1 and GNAO1 genes in the central nervous system has been reported to be associated with anaesthetised or stressed states/disorders in the literature56. The ESR1 gene, known to be activated by the general anesthetics, is associated with the acute stress disorder, which can be caused by administration of the general anaesthetics57. The anthracenyl nucleus is a structure of interest for anaesthetic agents. The CYP family enzymes metabolise this structure to form an amine58, and one of these CYP enzymes, CYP3A4, has been reported to be the primary drug-metabolising enzyme for some anaesthetics59. The OPRM1 gene, which has been shown previously to be involved in the regulation of the general anaesthesia, has been found to participate in the process of pain that leads to an analgesic effect of morphine60. Importantly, the OPRM1 gene affects the activity of opioid receptors61. In the nasal-sensitive network, the TBL1XR1 gene was significantly associated with the general anaesthetics and the GNAO1 gene was found to be the most representative, but these genes were not significant in the whole blood eWAS, suggesting that nasal-sensitive mechanisms may be used as a potential biomarker of the general anaesthetics. Among opioid analgesics, the HERC2 gene was significantly associated with the κ and μ receptor agonists, and a recent meta-analysis reported that a polymorphism of the HERC2 gene affects opioid analgesic effects62. GRAMD1B was highly clustered with the DAMAGED and DATADAW genes for the general anaesthetics, and this gene has been added to the tertiary metal-binding protein family63. The BUD13 gene was associated with general anaesthetics, although it was not significantly associated with the general anaesthetics in the eWAS, and the gene was highly clustered with the DAMAGED and DATADAW genes for the anaesthetics administered to the nasal cavity. a3f8a02ae1