Introduction
Anxiety is a predisposing factor for poor pain coping and transition to chronic postsurgical pain (CPSP). While there is high interindividual variability in CPSP and anxiety predisposition, a genetic basis has been elusive due to lack of replicability of genetic association studies1 and inconsistent results2. A systems biology approach integrates genetic-level data with biologic processes, pathways and networks thereby overcoming the pitfalls of hypothesis-driven candidate marker association studies. We have used this approach to identify unique and shared genetic pathways involved in chronic postsurgical pain (CPSP) and anxiety.
Methods
A systematic review of literature (01/01/1997 - 10/31/2017) was performed to identify genes associated with postoperative pain and CPSP in humans. The identified genes were then used to perform a systems biology-based integrative computational analysis using ToppGene Suite (https://toppgene.cchmc.org), a comprehensive platform for functional enrichment analyses and machine learning based candidate gene identification and ranking. We also curated gene sets associated with anxiety- related responses (Mouse phenotype – knockout studies), and did a pathway enrichment analysis. We then compared the top 100 processes and pathways associated with postoperative pain and CPSP, gene sets involved in the three phenotypes. 
Results
Systematic review identified a training set of 22 genes associated with postoperative pain, 23 genes with CPSP and 5 genes common to both. The training sets were used together for enrichment. Significant enrichment (p-value 0.05; Benjamini-Hochberg correction) was found for known and novel biologic processes (network presented in Figure 1). We identified 23 biological pathways common to postoperative pain and CPSP, 33 unique to CPSP and 10 unique to postoperative pain. For anxiety, we found 122 genes associated with low anxiety, 169 with high anxiety and 30 genes with both low and high anxiety. We found 40- 50% overlap among the genes enriched in pain and anxiety; seven genes were common to CPSP and anxiety (DRD2, HTR2A, IL1R1, BDNF, COMT, HTR1A, OPRM1) (Fig 2).
Conclusion
Using a systems biology-based approach, we identified unique and shared biological processes involved in CPSP and anxiety. This information provides a framework for future research in mechanistic processes and treatment of CPSP.
References:
1. Kim H et. al. J Pain 2009;10(7):663-93.
2. Mogil JS. Proc Natl Acad Sci USA 1999;96(14):7744-51.


04 / Systems biology based approach to identify unique and shared genetic pathways for chronic postoperative pain and anxiety.