TY - JOUR
T1 - The distinct traits of the UNC13A polymorphism in amyotrophic lateral sclerosis
AU - Tan, Harold H G
AU - Westeneng, Henk-Jan
AU - van der Burgh, Hannelore K
AU - van Es, Michael A
AU - Bakker, Leonhard A
AU - van Veenhuijzen, Kevin
AU - van Eijk, Kristel R
AU - van Eijk, Ruben P A
AU - Veldink, Jan H
AU - van den Berg, Leonard H
N1 - Funding Information:
This study was funded by the Netherlands ALS Foundation (Stichting ALS Nederland). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 772376 ? EScORIAL).
Publisher Copyright:
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - 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 patients with ALS.METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. 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). UNC13A was 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 the UNC13A single nucleotide polymorphism (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 counseling. ANN NEUROL 2020;88:796-806.
AB - 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 patients with ALS.METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. 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). UNC13A was 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 the UNC13A single nucleotide polymorphism (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 counseling. ANN NEUROL 2020;88:796-806.
KW - Aged
KW - Amyotrophic Lateral Sclerosis/complications
KW - Female
KW - Genotype
KW - Humans
KW - Male
KW - Middle Aged
KW - Nerve Tissue Proteins/genetics
KW - Phenotype
KW - Polymorphism, Single Nucleotide
UR - http://www.scopus.com/inward/record.url?scp=85088154822&partnerID=8YFLogxK
U2 - 10.1002/ana.25841
DO - 10.1002/ana.25841
M3 - Article
C2 - 32627229
SN - 0364-5134
VL - 88
SP - 796
EP - 806
JO - Annals of Neurology
JF - Annals of Neurology
IS - 4
ER -