Cracking the pain code: new genetic clues to neuropathic pain

Aims: Neuropathic pain is a complex condition with limited understanding of its potential genetic basis. This study aimed to identify genetic associations with neuropathic pain using a deeply phenotyped cohort, focusing on diabetic polyneuropathy as the most common etiology.

Methods: Cases of neuropathic pain were compared to controls—individuals exposed to similar injuries or diseases but without neuropathic pain. Sensory profiles were assessed and established using standardized quantitative sensory testing protocols. A genome-wide association study was conducted in 1,541 individuals with diabetic polyneuropathy. Whole-exome sequencing targeted 45 known pain-related genes, and polygenic risk scores were calculated for depression, C-reactive protein, and fasting insulin. Gene burden analysis and nociceptor profile comparisons were also performed.

Results: The genome-wide association study identified a significant association at the KCNT2 locus with pain intensity (rs114159097, P = 3.55 × 10-8). Gene-based analyses identified associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk scores highlighted depression as a risk factor for having neuropathic pain across all participants, with associations between C-reactive protein and fasting insulin levels with neuropathic pain. Gene-burden analysis of candidate pain genes found associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Subgroup analysis of participants with irritable versus non-irritable nociceptor pain phenotypes identified an association with a variant in the ANK2 gene (rs72669682, P = 4.39 × 10-8).

Conclusions: This study confirmed genetic associations between neuropathic pain and known pain-related genes (KCNT2, SCN9A, and OPRM1). In addition, it identified novel associations with LHX8 and pain and with ANK2 and a specific pain phenotype.

Comments: The present study advances the understanding of the genetic architecture of neuropathic pain and highlights opportunities for targeted interventions and future research. The combination of genome-wide association studies, whole-exome sequencing, and polygenic risk score analyses showcase a comprehensive and innovative approach. The identification of novel genetic associations with LHX8 and ANK2 is particularly noteworthy. Strengths of this study include the use of a deeply phenotyped cohort and advanced genetic analyses, enabling subgroup analyses stratified by sensory pain phenotypes. This nuanced approach rightfully challenges the existing dogma that neuropathic pain is a uniform condition requiring identical treatments. The limitations include the relatively small sample size for some analyses and potential lack of generalizability. Overall, the study offers valuable insights and sets a foundation for future explorations into pain genetics in diabetes.

Johan Røikjer

Reference: Åkerlund M, Baskozos G, Li W, Themistocleous AC, Pascal MMV, Rayner NW, Attal N, Baron R, Baudic S, Bennedsgaard K, Bouhassira D, Comini M, Crombez G, Faber CG, Finnerup NB, Gierthmühlen J, Granovsky Y, Gylfadottir SS, Hébert HL, Jensen TS, John J, Kemp HI, Lauria G, Laycock H, Meng W, Nilsen KB, Palmer C, Rice ASC, Serra J, Smith BH, Tesfaye S, Topaz LS, Veluchamy A, Vollert J, Yarnitsky D, van Zuydam N, Zwart JA, McCarthy MI, Lyssenko V, Bennett DL. Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort. Pain. 2024 Oct 29. doi: 10.1097/j.pain.0000000000003463. Epub ahead of print. PMID: 39471050.

🔗 https://journals.lww.com/pain/fulltext/9900/genetic_associations_of_neuropathic_pain_and.756.aspx