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. 2025 Jan;29(1):e4764.
doi: 10.1002/ejp.4764.

A genome-wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity

Francesca Minnai  1   2 , Morena Shkodra  3   4 , Sara Noci  5 , Martina Esposito  1 , Cinzia Brunelli  3 , Alessandra Pigni  3 , Ernesto Zecca  3 , Frank Skorpen  6   7 , Pål Klepstad  6   8 , Stein Kaasa  4   9 , Oscar Corli  10 , Maria C Pallotti  11 , Marco C Maltoni  12 , Augusto T Caraceni  3   13 , Francesca Colombo  1
Affiliations

A genome-wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity

Francesca Minnai et al. Eur J Pain. 2025 Jan.

Abstract

Background: Opioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome-wide association study (GWAS).

Methods: We genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole-genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.

Results: The GWAS identified five non-coding variants on chromosome 20 with a p-value <5.0 × 10-8. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.

Conclusions: Our results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.

Significance statement: This genome-wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Polymorphisms on chromosome 20 (20q13.33) are significantly associated with pain intensity. Manhattan plot of the results from the GWAS with the inverse‐normal transformed residuals of the linear regression model for pain intensity phenotype, with sex, age, opioid type, cancer diagnosis, chemotherapy treatment, country of origin, study of enrolment and genotyping batch, as covariates. Each dot represents a polymorphism whose coordinates are determined according to the genomic position (GChr38, hg38 release) on the x‐axis and p‐values (−log10(P)) of the association with the phenotype on the y‐axis. The horizontal red line represents the threshold of significance (p‐value <5.0 × 10−8), while the blue line is a suggestive threshold at p‐value <1.0 × 10−5.
FIGURE 2
FIGURE 2
The minor allele of the lead variant is associated with low pain intensity. Pain intensity values in the three genotyping groups of patients, according to the top‐significant variant, rs6062363 (0, GG; 1, GA; 2, AA). The line within each box represents the median pain intensity values; the upper and lower edges of each box are the 75th and 25th percentiles, respectively; the upper and lower bars indicate the highest and lowest values, respectively; outliers are indicated as circles.
FIGURE 3
FIGURE 3
Zoom plot of the locus on chromosome 20 identified in the GWAS. The plots span the region from 64,292,800 to 64,080,100 bp. Polymorphisms are plotted according to their position on chromosome 20, along the x‐axis, and to p‐values (−log10 P) for their association with pain intensity, on the y‐axis. Genome‐wide (p‐value <5.0 × 10−8) and suggestive (p‐value <1.0 × 10−5) thresholds of significance are represented as red and blue dashed lines, respectively. Dot colour indicates linkage disequilibrium (r 2) between each polymorphism and the lead variant (rs6062363, purple diamond).
FIGURE 4
FIGURE 4
The genetic factors modulating pain intensity and gene expression in blood are not the same. Colocalization plots for the OPRL1 (a), PCMTD2 (b) and PPDPF (c) genes using the whole‐blood tissue expression data from the eQTLGen database (numbers of SNPs included in the analyses were 755, 224 and 293, respectively). Dots are coloured based on linkage disequilibrium (r 2) with the lead variants, rs6062363 (a, b) and rs7270745 (c; PPDPF expression was not associated with the 5 top‐significant variants associated with pain intensity).
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