Deep sequencing analysis to identify novel and rare variants in pain-related genes in patients with acute postoperative pain and high morphine use.

PURPOSE: Most of the genetic variants that are reported to be associated with common pain phenotypes and analgesic use are common polymorphisms. The objective of our study was to identify new variants and investigate less common genetic variants that are usually not included in either small single-gene studies or high-throughput genotyping arrays. PATIENTS AND METHODS: From a cohort of 1075 patients who underwent a scheduled total abdominal hysterectomy, 92 who had higher self-rated pain scores and used more morphine were selected for the re-sequencing of 105 genes. RESULTS: We identified over 2400 variants in 104 genes. Most were intronic with frequencies >5%. There were 181 novel variants, of which 30 were located in exons: 17 nonsynonymous, 10 synonymous, 2 non-coding RNA, and 1 stop-gain. For known variants that are rare (population frequency <1%), the frequencies of 54 exonic variants and eight intronic variants for the sequenced samples were higher than the weighted frequencies in the Genome Aggregation Database for East and South Asians (P-values ranging from 0.000 to 0.046). Overall, patients who had novel and/or rare variants used more morphine than those who only had common variants. CONCLUSION: Our study uncovered novel variants in patients who reported higher pain and used more morphine. Compared with the general population, rare variants were more common in this group.