The distinct traits of the UNC13A polymorphism in amyotrophic lateral sclerosis.

OBJECTIVE The rs12608932 single nucleotide polymorphism in UNC13A is 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 of UNC13A in ALS patients. METHODS We included 2,216 ALS patients without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 ALS patients 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, C/C 65.5, p<0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, C/C 43.1%, p<0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, C/C 9.5%, p=0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, C/C 86.5, p<0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, C/C 26.6, p<0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, C/C 76.6, p=0.037) and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4% C/C 27.7%, p=0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A SNP (p=0.045 and p=0.036). INTERPRETATION Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counselling. This article is protected by copyright. All rights reserved.