The Distinct Traits of the UNC13A Polymorphism in Amyotrophic Lateral Sclerosis

Objective The rs12608932 single nucleotide polymorphism inUNC13Ais associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype ofUNC13Ain patients with ALS. Methods We included 2,216 patients with ALS without aC9orf72mutation to identify clinical characteristics associated with theUNC13Apolymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. Results Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5;p< 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%;p< 0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%;p= 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5;p< 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6;p< 0.001).UNC13Awas associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6;p= 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%;p= 0.045). Thinner left inferior temporal and right fusiform cortex were associated with theUNC13Asingle nucleotide polymorphism (SNP;p= 0.045 andp= 0.036). Interpretation Phenotypical distinctions associated withUNC13Amake it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020