Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

Neurology. 2017 Oct 31;89(18):1915-1922. doi: 10.1212/WNL.0000000000004606. Epub 2017 Oct 4.


Objective: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.

Methods: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.

Results: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).

Conclusions: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics*
  • C9orf72 Protein
  • Genotype
  • Lithium Carbonate / therapeutic use
  • Nerve Tissue Proteins / genetics
  • Neuroprotective Agents / therapeutic use*
  • Pharmacogenetics*
  • Proportional Hazards Models
  • Proteins / genetics
  • Randomized Controlled Trials as Topic*


  • C9orf72 Protein
  • C9orf72 protein, human
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Proteins
  • UNC13B protein, human
  • Lithium Carbonate