Dataset Information

Genome-wide association study of acute post-surgical pain in humans.

ABSTRACT:

Aims

Testing a relatively small genomic region with a few hundred SNPs provides limited information. Genome-wide association studies (GWAS) provide an opportunity to overcome the limitation of candidate gene association studies. Here, we report the results of a GWAS for the responses to an NSAID analgesic.

Materials & methods

European Americans (60 females and 52 males) undergoing oral surgery were genotyped with Affymetrix 500K SNP assay. Additional SNP genotyping was performed from the gene in linkage disequilibrium with the candidate SNP revealed by the GWAS.

Results

GWAS revealed a candidate SNP (rs2562456) associated with analgesic onset, which is in linkage disequilibrium with a gene encoding a zinc finger protein. Additional SNP genotyping of ZNF429 confirmed the association with analgesic onset in humans (p = 1.8 x 10(-10), degrees of freedom = 103, F = 28.3). We also found candidate loci for the maximum post-operative pain rating (rs17122021, p = 6.9 x 10(-7)) and post-operative pain onset time (rs6693882, p = 2.1 x 10(-6)), however, correcting for multiple comparisons did not sustain these genetic associations.

Conclusion

GWAS for acute clinical pain followed by additional SNP genotyping of a neighboring gene suggests that genetic variations in or near the loci encoding DNA binding proteins play a role in the individual variations in responses to analgesic drugs.

SUBMITTER: Kim H

PROVIDER: S-EPMC2696643 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Publications

Genome-wide association study of acute post-surgical pain in humans.

Kim Hyungsuk H Ramsay Edward E Lee Hyewon H Wahl Sharon S Dionne Raymond A RA

Pharmacogenomics 20090201 2

<h4>Aims</h4>Testing a relatively small genomic region with a few hundred SNPs provides limited information. Genome-wide association studies (GWAS) provide an opportunity to overcome the limitation of candidate gene association studies. Here, we report the results of a GWAS for the responses to an NSAID analgesic.<h4>Materials & methods</h4>European Americans (60 females and 52 males) undergoing oral surgery were genotyped with Affymetrix 500K SNP assay. Additional SNP genotyping was performed f ...[more]

PMID: 19207018

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Project description:PurposeTo conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development.DesignProspective study of individuals with NOP.ParticipantsThree hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic.MethodsThe Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P < 5 × 10-8. A gene-based analysis was performed using the multimarker analysis of genomic annotation software (in the functional mapping and annotation of GWAS online platform). The 13 865 778 single nucleotide polymorphisms (SNPs) from our GWAS analysis were mapped to 10 834 protein coding genes, and significant genes were run through gene set enrichment analysis.Main outcome measuresIdentification of SNPs and protein products that may be associated with the development of NOP.ResultsOne hundred seventy-one SNPs reached a threshold of P < 10-5, of which 10 SNPs reached the suggestive level of significance of P < 5 × 10-7 and 1 SNP met our genome-wide significance threshold of P < 5 × 10-8. This lead SNP, rs140293404 (P = 1.23 × 10-8), is an intronic variant found within gene ENSG00000287251 coding for transcript ENST00000662732.1. Rs140293404 is in linkage disequilibrium with exon variant rs7926353 (r2 > 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 × 10-5), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 × 10-4), CTC-487M23.8 (P = 1.79 × 10-4), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 × 10-4), and signal recognition particle-19 (SRP19) (P = 2.56 × 10-4). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10-3) and olfactory signaling (false discovery rate = 1.63 × 10-2) pathways were enriched with the most significant genes.ConclusionsOur GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Project description: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.

Dataset Information

Genome-wide association study of acute post-surgical pain in humans.

Aims

Materials & methods

Results

Conclusion

Publications

Genome-wide association study of acute post-surgical pain in humans.

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