CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established. Using whole-genome sequencing data from more than 6000 individuals in the multinational Project MinE consortium, we examined whether CYP2D6 variants and genotype-inferred metaboliser phenotypes influence ALS risk and survival. We used both multivariable logistic regression and multivariable Cox proportional hazards regression for the analyses, controlling for important clinical covariates. We then sought replication in a smaller cohort of 133 participants from the MIROCALS clinical trial. Reduced CYP2D6 activity, driven by the common loss-of-function CYP2D6*4 and other *-alleles causing either decrease or loss of the enzyme function, was associated with increased risk of ALS. Although CYP2D6 variation had no overall effect on survival, in patients receiving riluzole we observed a protective association, with poor metabolisers showing the greatest survival advantage compared with normal metabolisers. A concordant effect was seen in the replication cohort, although this should be interpreted cautiously given the limited sample size. These findings suggest that variation in CYP2D6 contributes to ALS susceptibility and can modify treatment response. However, the underlying mechanisms remain unclear, and prospective studies are needed to validate these findings, particularly to define the contribution of CYP2D6-mediated metabolism to treatment response in ALS. Still, incorporating CYP2D6 genetic profiling into ALS clinical trials could reduce pharmacokinetic variability and improve detection of therapeutic effects. More broadly, this work provides a rationale for integrating pharmacogenomics into ALS research and care as a step towards precision medicine in neurodegeneration.