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

Kosar Hooshmand; David Goldstein; Hannah C Timmins; Tiffany Li; Michelle Harrison; Michael L Friedlander; Craig R Lewis; Justin G Lees; Gila Moalem-Taylor; Boris Guennewig; Susanna B Park; John B Kwok

doi:10.1186/s12967-022-03754-4

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

J Transl Med. 2022 Dec 6;20(1):564. doi: 10.1186/s12967-022-03754-4.

Authors

Kosar Hooshmand^{1

2}, David Goldstein³, Hannah C Timmins^{1

2}, Tiffany Li^{1

2}, Michelle Harrison⁴, Michael L Friedlander³, Craig R Lewis³, Justin G Lees⁵, Gila Moalem-Taylor⁵, Boris Guennewig^{1

2}, Susanna B Park^#^{1

2}, John B Kwok^#^{6

7}

Affiliations

¹ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
² Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
³ Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁴ Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
⁵ School of Biomedical Sciences, University of New South Wales, UNSW Sydney, Sydney, NSW, Australia.
⁶ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia. john.kwok@sydney.edu.au.
⁷ Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia. john.kwok@sydney.edu.au.

^# Contributed equally.

Abstract

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 × 10^-5) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r² = 0.53; P = 1.54 × 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 × 10^-6) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10^-7).

Conclusions: Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN.

Keywords: Axon; Chemotherapy-induced Peripheral Neuropathy; Genome-wide association study; Paclitaxel.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computational Biology
Gene Ontology
Genome-Wide Association Study*
Humans
Paclitaxel / adverse effects
Peripheral Nervous System Diseases* / chemically induced
Peripheral Nervous System Diseases* / genetics

Substances

Paclitaxel