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

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.

Omics approaches to discover pathophysiological pathways contributing to human pain

“… 78 The scores are not only useful for diagnostic and prognostic purposes but also for highlighting the shared genetic burden of painful conditions. 40 , 42 , 81 Alongside genes, the environment also has a great deal of say in the variability of pain sensitivity and in the development of painful conditions. Moreover, there are also interactions between genetics and environmental factors (termed GxE), which are now possible to investigate using genome–environment interaction studies.…”

Pain predict genetics: protocol for a prospective observational study of clinical and genetic factors to predict the development of postoperative pain

“… 75 We will consider seeking other available cohorts for validation and applying other statistical methods to validate our findings in future studies, such as polygenic risk scores. 76 Another potential limitation is that loss of follow-up of patients might result in lower patient numbers than expected. Despite this potential concern, we still expect a sufficient sample size as additional centres will start patient inclusion, and the measurements are mainly from patient-reported outcomes via digital follow-up.…”

“…Furthermore, chronic pain assessment is more complex than acute pain,74 and GWAS findings are sometimes incidental 75. We will consider seeking other available cohorts for validation and applying other statistical methods to validate our findings in future studies, such as polygenic risk scores 76. Another potential limitation is that loss of follow-up of patients might result in lower patient numbers than expected.…”

Identification and characterization of genetic risk shared across 24 chronic pain conditions in the UK Biobank

“…Similar approaches have emerged in pain research, informed by studies of the co-occurrence of pain conditions in large samples [105, 113, 66, 72, 3] and the recognition that different forms of pain are related to similar alterations in the nervous system [65, 76, 54, 63]. Some studies have examined genetic correlations among pain syndromes [129] and genetic risks of having pain in more than 1 of 7 locations on the body [56, 59]. However, a systematic assessment of shared susceptibility across a broad spectrum of pain conditions is lacking, and common factors underlying general pain susceptibility have not yet been characterized.…”