Polygenic risk scores indicates genetic overlap between peripheral pain syndromes and chronic postsurgical pain

Roel R I Van Reij,Jan Willem Voncken,Nynke J Van Den Hoogen,Elbert A J Joosten

doi:10.1007/s10048-020-00614-5

Abstract

Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R2 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R2 = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients’ nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.

Highlights

Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that affects patients who underwent surgery and has a substantial effect on the quality of life (QoL) and socioeconomic status [1,2,3]
A significant genetic overlap was found between 3 chronic pain disorders and CPSP: chronic widespread pain (p value threshold = 0.003, R2 0.06, p = 0.003) and rheumatoid arthritis (p value threshold = 0.0177, R2 = 0.04, p = 0.017) and Sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045)
No significant genetic overlap was found with osteoarthritis, cluster headache and migraine (Fig. 1, Supplementary Table 1)

Summary

Introduction

Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that affects patients who underwent surgery and has a substantial effect on the quality of life (QoL) and socioeconomic status [1,2,3]. CPSP is defined as “pain developed or increased after a surgical procedure, which is present for at least three months, and affecting the QoL” [4, 5]. Neurogenetics (2020) 21:205–215 targeted studies) defines a potential role for genetic risk factors in CPSP, the limited CPSP sample size in comparison with studies of other chronic pain syndromes has far not provided clear candidate genes for CPSP [9,10,11,12]. While increasing sample size for GWAS analyses holds the potential for unambiguous identification of genetic risk factors, genetic mechanisms underlying CPSP may be probed indirectly by determination of common genetic factors with other pain syndromes. Establishing the intersection and/or overlap of genetic networks between various chronic pain syndromes may help define common mechanisms in chronic pain and provide starting points for functional and intervention studies

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