Genome-wide association study of multisite chronic pain in UK Biobank

Abstract

Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ‘chronic pain grade’, have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual’s overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.

Genetic, lifestyle and environmental risk factors for chronic pain revealed through GWAS

“…In line with a recent GWAS on multisite chronic pain [36] and other studies [58,82], we found that depression (including major depressive disorder) and anxiety may increase the risk of CP. This finding is important as so far, studies have been conflicting with regard to whether depression increase the risk of pain or vice versa [13,24,32,35,70,82].…”

“…Using Complex Traits Genetics Virtual Lab (CTG-VL) [18], we explored whether those SNPs have been previously associated to other traits. We observed that rs10660361 was also identified by a recent GWAS on back pain (P-value = 7.77×10 −8 ) [25] and multisite chronic pain (P-value = 1.9×10 −9 ) [36]. However, rs113313884 was only associated with multisite chronic pain at a suggestive level (P-value = 6.9×10 −3 ) highlighting the importance of studying phenotypes using different definitions.…”

“…The SNP rs10660361 was closest to LEMD2 , a gene implicated in embryonic development and the regulation of several signalling pathways [46]. However, we note that this locus was reported in a previous GWAS on multisite chronic pain mapping to the gene MLN [36]. It is important to note that we were unable to map the genes likely affected by these SNPs through more robust approaches (rather than only based on proximity) such as eQTLs.…”

“…Furthermore, DCAKD has also been associated with osteoarthritis which is also a potential cause of pain [39]. NMT1 was already reported to be associated to multisite chronic pain [36], in addition to pulse pressure and insomnia [27,36]. Besides DCAKD and NMT1 , the fastBAT gene-based test also revealed significant associations with MLN and IP6K3 .…”

“…Evidence for the role of genetic factors in CP comes from twin and family studies [38] where its heritability is estimated to be as high as 60% [11,37]. More recently, large-scale genome-wide association studies (GWAS) have identified multiple genetic variants associated with chronic back pain [25,75] and multisite chronic pain [36] as further evidence of a genetic contribution to CP. However, their causal relationship has yet to be adequately examined.…”