Genetic factors associated with neuropathic pain
Background and Aim: Neuropathic pain (NP) is a common chronic pain state, affecting approximately 7-10% of the general population. NP is multifactorial, with evidence of both genetic and environmental factors contributing to its development. Although the genetic contribution to NP susceptibility has been recognised in recent decades, the underlying mechanism remains elusive. The aim of this research was to identify genetic variants associated with NP susceptibility. Methods: Firstly, a comprehensive systematic review and meta-analysis of all published human genetic association studies of NP was conducted using electronic literature databases. Secondly, a discovery genome-wide association study (GWAS) of NP was performed in Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) and replication of significant findings was tested in United Kingdom Biobank (UKBB) cohort using dispensed medication records. Thirdly, NP cases and non-NP (NNP), and no-pain controls were identified based on an internationally agreed NP phenotyping method, using self-completed questionnaires from GoDARTS and Generation Scotland: Scottish Family Health Study (GS:SFHS) participants. A two-stage meta-analysis of discovery GWAS (GODARTS and GS:SFHS) was performed in study-I, comparing possible NP cases and NNP controls using a linear mixed model. Then, results were combined with GWAS from UKBB. Similarly, a two-stage meta-analysis of GWAS was conducted comparing NP cases and no pain controls in study-II. Subsequently, previously known variants were tested for replication in these study populations. A post-GWAS analysis was performed in all studies using bioinformatics resources. Finally, replication analysis of prior SNPs associated with NP was performed using diabetic NP cases and controls from GoDARTS. Results: The systematic review identified twenty-nine published human genetic studies, includes molecular genetics and genetic association studies, on NP in different populations between January 1996 and April 2017. A total of fifty-six SNPs in or near twenty-six genes associated with NP conditions in twenty-five published genetic association studies. A meta-analysis found variants in HLA alleles were associated with NP, and that SNPs in neither COMT nor OPRM1 were associated with NP. he GWAS using dispensed medication records identified a novel genome-wide significant NP susceptibility locus near PRL, and replicated this in UKBB. The largest meta-analysis of the discovery GWAS of NP using questionnaire data found promising borderline significant SNPs near BBS9, and BPI in study-I, and a genome-wide significant SNP near EPHA3 in study-II. Interestingly, these SNPs are also associated with nervous system related disorders and infectious diseases in in-silico look-ups in GeneATLAS. Gene-based GWAS using the discovery GWAS results identified two genome-wide significant genes, NKX1-1 and CRIPAK, in study-I and a genome-wide significant gene, TNFRSF14, in study-II. In study-I, the overall meta-analysis found a novel suggestive variant near PTPRJ which has also been shown to be significantly associated with BMI-related traits in GeneATLAS. In study-II, the overall meta-analysis identified a genome-wide significant SNP near SLC25A3. Notably, a previously identified SNP in CACNG2 was consistently replicated in both the prescribing based and questionnaire based GWAS of NP (study-I). Also, a previously reported variant in the iron metabolism gene, B2M, was replicated in study-II. Finally, of all 56 prior SNPs, six SNPs near GCH1, CDH18, IL13 and IL10 were significantly associated with diabetic NP. Conclusions: The studies presented in this thesis using two NP phenotyping methods are the largest GWAS of NP to date and have revealed novel genetic variants and replicated prior candidate SNPs that merit further investigations and functional validation. The findings from this project provide new insights into genetic architecture underpinning NP and important information for further studies.
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