One component of neuropathic pain is genetic. Knowing which genes contribute to what types of neuropathic pain can help identify the mechanisms at work behind the disease, develop better drugs, and assess an individual's risk of developing neuropathic pain. This research theme uses different types of genetic analysis to explore these questions.
Neuropathic pain has an estimated heritability of 37%, although the specific genetic variants involved are still poorly understood. We reviewed all genetic variants known to be associated with neuropathic pain and identified "candidate" genes involved in a range of pathways including immune responses, neurotransmission, ion channels, and metabolism. Monogenic pain disorders (such as congenital insensitivity to pain) and extreme pain disorders (such as erythromelalgia) are rare but have highlighted the role of ion channels in human pain and provided novel targets for pain therapy.
Testing known candidate genes and discovering new genetic variants associated with neuropathic pain
We are using existing resources, in particular the new pain phenotype data in UK Biobank, that include rich phenotyping for neuropathy, co-morbidities (anxiety, depression), and quality of life. Neuropathic pain phenotyping of SHARE and follow-up data in GoDARTs will provide a focus on painful diabetic neuropathy, one of the most common causes of neuropathic pain in the community. With this resource, we will perform the largest genome-wide association studies (GWAS) of neuropathic pain to date. We will work with patient partners to decide the outcomes that are most relevant to them.
Describing rare genetic variants with high impact on specific neuropathic pain conditions
We will combine whole exome sequencing (WES) with TWIST technology to provide whole exome coverage on a panel of 45 pain genes. This will enable us to study the role of rare variants in known candidate genes such as SCN9a but will also be informative across the exome. There will be close collaboration with Work Package 6 to optimise the choice of variants for functional analysis.
Studying the shared genetic architecture of neuropathic pain with other pain disorders and trans-ethnic comparison
We have established collaborations to validate and replicate the genetic findings from PAINSTORM. These includes the GeNEUP study (Norway) and IDNC (Denmark). We also have potential collaborations via the University of Dundee to compare our results with those from a study of the genetics of painful diabetic neuropathy in an Indian cohort. The collaborations within the Advanced Pain Discovery Platform will facilitate the study of the shared genetic architecture of neuropathic pain and other pain disorders, such as visceral pain with the ADVANTAGE consortium and sciatica with the FORECAST project.
The aim of this work package has been to understand the genetic associations of neuropathic pain as will help us understand why some people are at risk of this condition and the mechanisms underlying neuropathic pain. We have studied a cohort of over 2000 patients with peripheral neuropathy recruited across Europe (recruited as part of the DOLORisk consortium) and compared those with painful versus painless neuropathy. This has led to a number of novel findings in particular showing an association between pain from diabetic peripheral neuropathy and:
Common variants in the gene KCNT2. This encodes a potassium channel which acts as a brake on the excitability of sensory neurons.
Rare variants in gene SCN9a encoding a voltage gated sodium channel NaV1.7. The variants associated with enhanced risk of neuropathic pain result in the channel becoming over-active and so leading to hyper-excitability of sensory neurons and pain.
Rare variants in the OPRM1 gene which encodes the mu-opioid receptor (MOR). The variants associated with pain lead to loss of function of this protein which normally acts to suppress pain signals at the level of the spinal cord and brain.
With UK-Biobank we worked to improve the questionnaires relating to the assessment of pain. This enabled us to undertake a large genome wide association study of pain intensity. This revealed novel associations with the gene SLC45A4. We have also subsequently found with collaborators that variants in this gene are associated with pain in other populations (in Finland and America) and that it is associated with diabetic neuropathy and osteoarthritis. This has provided new avenues to understanding the pathophysiology of chronic pain because through collaborations with WP6 we have shown that this encodes for a polyamine transporter and demonstrated that it impacts on polyamine transport in human cellular models of pain. We have also found that this effect on polyamine transport directly regulates the excitability of sensory neurons.
To complement these population level studies, we are undertaking detailed genetic analysis (using whole genome sequencing) on the highly phenotyped participants recruited in PAINSTORM. We are comparing the genetic associations of neuropathic pain with other pain states such as visceral pain in collaboration with the ADVANTAGE consortium (and have completed an analysis of associations with the mitochondrial genome). We are also comparing the genetic architecture of neuropathic pain in European populations with other populations across the world such as Asia.
We have improved the tools that we can use to understand how genetic variants impact on pain. For instance, we have generated a database (with WP6) in which we can assess how pain states alter gene expression across different species and tissues (https://livedataoxford.shinyapps.io/drg-directory/).
We have achieved impact of these findings in a number of ways. Firstly, we have identified new mechanisms underlying neuropathic pain. An emerging theme is that ion channels and transporters which control the flow of charged molecules across neuronal membranes have an important role in regulating the excitability of neurons and the risk and severity of neuropathic pain. We hope in the future that these findings will help us determine who is most at risk of developing neuropathic pain. We have provided input to international guidelines as to how we integrate genetic testing into the clinical diagnostic pathway for neuropathic pain.
- This paper reviews genetic factors found to be associated with neuropathic pain: Systematic review and meta-analysis of genetic risk factors for neuropathic pain
- This editorial explains what Genome-wide association studies (GWAS) are and how they are performed. It discusses how they can be used, but also their limits, in the study of chronic pain following surgery. The double-edged scalpel: genome-wide association studies and chronic postsurgical pain
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