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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited therapeutic options. Riluzole remains the only widely available treatment in ALS, yet its benefits are modest and highly variable across patients. Genetic variation in cytochrome P450 2D6 (CYP2D6), a major enzyme in drug metabolism, detoxification of environmental toxins, and biotransformation of endogenous transmitters, has been implicated as a risk factor in neurodegenerative diseases. It has been observed to play a role in the development of both Parkinson’s disease and Alzheimer’s disease, but its role 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. 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. These findings suggest that variation in CYP2D6 contributes to ALS susceptibility and can modify treatment response. 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.
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