Genome-wide Association Reveals a Locus in Neuregulin 3 Associated with Gabapentin Efficacy in Women with Chronic Pelvic Pain

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 () ( = 2·11×10; 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. 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.