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

<i>Objective</i>: 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 <i>UNC13A</i>, have attracted considerable attention. The <i>UNC13A</i> rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. <i>Methods</i>: 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 <i>UNC13A</i> genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. <i>Results</i>: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; <i>p</i> < 0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (<i>p</i> = 0.015) and prominent lower motor neuron involvement (<i>p</i> = 0.007) than those with the AA and AC genotypes. <i>Conclusions</i>: 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.