Next-generation DNA methylation sequencing: loci and regions differentially methylated in adolescents with chronic postsurgical pain.

Authors

Siva Athitya Lakshamana Vijayarajan, Kristen N Krolick, Xue Zhang, Lisa J Martin, Susan Glynn, Kristi Cole, Victor Garcia, Hong Ji, R J Ramamurthi, L M Einhorn, C L Monitto, A Ganesh, Vidya Chidambaran

Published in

Neurobiology of pain (Cambridge, Mass.). Volume 20. Pages 100229. Epub Aug 01, 2026.

Abstract

DNA methylation (DNAm) may link environmental exposures to pain susceptibility. We examined preoperative DNAm patterns (using next-generation enzymatic-methylation sequencing) associated with chronic postsurgical pain (CPSP), a major biopsychosocial problem in adolescents undergoing musculoskeletal surgeries, recruited across six sites (n = 166; 15.5 (IQR 14.3-16.8) years; 51% male). Pain and functional measures were followed longitudinally. CPSP was defined as pain>3/10 beyond two months post-surgery. We identified 289 differentially methylated loci (DML; HB p < 0.1) that satisfied robustness criteria after bootstrapping, and 20 regions (DMR) (FDR p < 0.05) associated with CPSP. Using CPSP-specific background, DMLs, annotated to 57 genes, were enriched for biological processes (Cellular response to cAMP (p = 0.001), neuronal action potential (p = 0.01), sodium ion transmembrane transport (p = 0.03), potassium ion transmembrane transport (P = 0.035) and regulation of postsynaptic membrane potential (P = 0.041)), molecular functions (Intracellular camp-activated cation channel activity (p = 0.001), cAMP binding (p = 0.003), voltage-gated sodium channel activity (p = 0.01), and voltage-gated potassium channel activity (p = 0.02)), and cellular components (HCN channel complex (p = 0.002), presynaptic active zone membrane (p = 0.006), and postsynaptic membrane (p = 0.049)). DMRs did not enrich gene pathways but showed transcription factor motif enrichment for stress response (TGF-β/SMAD), neuronal differentiation/plasticity (NR4A/TEAD), inflammation/immunity (STATs), and circadian signaling (RORA/RORB/NPAS2). Study findings suggest potential DNAm signatures associated with CPSP and generate hypotheses regarding their possible role in CPSP development.

PMID:
42602478
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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