Polygenic risk of paclitaxel-induced peripheral neuropathy: a genome-wide association study

Background: Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood. Methods: We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest. Results: In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1, associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association (P < 1 x 10(-5)) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r(2) = 0.53; P = 1.54 x 10(-35)). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 x 10(-6)) and neuronal system (R-HSA-112316; adjusted P = 3.33 x 10(-7)). Conclusions: Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN.