Vidya Chidambaran1, Xue Zhang2, Valentina Pilipenko2, Xiaoting Chen3, Benjamin Wronowski3, Kristie Geisler1, Lisa J Martin2,4, Artem Barski2,3,4, Matthew T Weirauch3,4, Hong Ji5. 1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. 2. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. 3. Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. 4. Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA. 5. Department of Anatomy, Physiology & Cell biology, California National Primate Research Center, University of California, Davis, CA 95616, USA.
Abstract
Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).
Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).
Authors: Michael D Rushton; Louise N Reynard; David A Young; Colin Shepherd; Guillaume Aubourg; Fiona Gee; Rebecca Darlay; David Deehan; Heather J Cordell; John Loughlin Journal: Hum Mol Genet Date: 2015-10-13 Impact factor: 6.150
Authors: Shan V Andrews; Shannon E Ellis; Kelly M Bakulski; Brooke Sheppard; Lisa A Croen; Irva Hertz-Picciotto; Craig J Newschaffer; Andrew P Feinberg; Dan E Arking; Christine Ladd-Acosta; M Daniele Fallin Journal: Nat Commun Date: 2017-10-24 Impact factor: 14.919
Authors: Adam J Dourson; Adam Willits; Namrata G R Raut; Leena Kader; Erin Young; Michael P Jankowski; Vidya Chidambaran Journal: Can J Pain Date: 2022-05-10