Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort.

Abstract

Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population. The three groups were compared to two independent control groups. The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p = 0.015) and prominent lower motor neuron involvement (p = 0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.