Genome-wide association reveals a locus in neuregulin 3 associated with gabapentin efficacy in women with chronic pelvic pain

• Published in: iScience Vol. 27; no. 8; p. 110370
• Main Authors: Mackenzie, Scott C., Rahmioglu, Nilufer, Romaniuk, Liana, Collins, Frances, Coxon, Lydia, Whalley, Heather C., Vincent, Katy, Zondervan, Krina T., Horne, Andrew W., Whitaker, Lucy H.R.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.08.2024; Elsevier
• Subjects: Association analysis; Neurogenetics; Pain management in health technology; Quantitative genetics; Quantitative genetics; Association analysis; Neurogenetics; Pain management in health technology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110370

Chronic pelvic pain (CPP) in women with no obvious pelvic pathology has few evidence-based treatment options. Our recent multicenter randomized controlled trial (GaPP2) in women with CPP and no obvious pelvic pathology showed that gabapentin did not relieve pain overall and was associated with more side effects than placebo. We conducted an exploratory genome-wide association study using eligible GaPP2 participants aiming to identify genetic variants associated with gabapentin response. One genome-wide significant association with gabapentin analgesic response was identified, rs4442490, an intron variant located in Neuregulin 3 (NRG3) (p = 2·11×10−8; OR = 18·82 (95% CI 4·86–72·83). Analysis of a large sample of UK Biobank participants demonstrated phenome-wide significant brain imaging features of rs4442490, particularly implicating the orbitofrontal cortex. NRG3 is expressed predominantly in central nervous system tissues and plays a critical role in nervous system development, maintenance, and repair, suggesting a neurobiologically plausible role in gabapentin efficacy and potential for personalized analgesic treatment. [Display omitted] •Gabapentin response GWAS was performed in a cohort of women with chronic pelvic pain•A locus in Neuregulin 3 (NRG3) was associated with gabapentin analgesic efficacy•NRG3 is expressed in nervous system tissues and involved in regulation and repair•There may be potential for a personalised medicine approach to gabapentin treatment Association analysis; Neurogenetics; Pain management in health technology; Quantitative genetics