BackgroundDose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention.MethodsWe conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma.ResultsWe identified a locus consisting of low-frequency variants in intron 13 ofGRID2associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 (p= 2.03 × 10−8, all patients,p= 6.36 × 10−9, taxane treated). Gene-level burden analysis identified rare coding variants associated with increased PN risk in the C-terminus ofGPR68(p= 1.59 × 10−6, all patients,p= 3.47 × 10−8, taxane treated), a pH-sensitive G-protein coupled receptor (GPCR). The variants driving this signal were found to alter predicted arrestin binding motifs in the C-terminus ofGPR68. Analysis of snRNA-seq from human dorsal root ganglia (DRG) indicated that expression ofGPR68was highest in mechano-thermo-sensitive nociceptors.ConclusionsOur genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study ofGPR68in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13073-023-01193-4.