Key words: chronic post-surgical pain, genetics, zebrafish, Dopamine, genome-wide association study, SNP

"Genetic Risk Factors in prediction and tratment of Chronic Post-Surgical Pain"

Chronic Postsurgical Pain (CPSP) remains a major clinical problem affecting on average 20% of all patients undergoing surgery. CPSP has a major impact on the quality of life of both the patients affected and their relatives, and leads to an increase in health care consumption and associated costs. Although clinical, psychological and demographical risk factors of CPSP have been identified, a good understanding of the genetic risk factors and its putative role in CPSP is still lacking to date. This thesis investigated the genetic risk factors of CPSP and the functional effects of genetic variation on nociception and chronic pain in both clinical and preclinical studies. It was shown that there is a central modulatory role for dopaminergic neurotransmission in both prevention and treatment of CPSP. This has been further studied in a preclinical zebrafish model whereby genetic and pharmacological modulation confirmed the therapeutic potential of dopamine in nociception and pain. Furthermore, the thesis reported the first genome-wide association study on CPSP in which a potential risk locus was identified, although not genome-wide significant, for CPSP (IQGAP1 and CRTC3). Furthermore it was shown that there is genetic overlap across different peripheral pain syndromes and the underlying mechanisms are associated with immunological and neuronal processes. Lastly, through transcriptome-wide mendelian randomization the research identified several genes potentially causally associated with CPSP based on gene expression. Further analysis of these genes further confirmed the involvement of both immune and neuronal processes. The studies in this thesis form a first step in future use of genetic (pre-operative) screening to minimize development and occurrence of chronic post surgical pain.