title: UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort.
abstract: To investigate the association of functional variants of the human UNC13A gene with the risk of ALS, survival and the disease progression rate in a Spanish ALS cohort. 136 sporadic ALS (sALS) patients and 487 healthy controls were genotyped for the UNC13A rs12608932 variant. Clinical characterization of ALS patients included gender, age at first symptom, initial topography, disease progression rate, and survival. Genetic association was analyzed under five inheritance models. The sALS patients with the rs12608932(CC) genotype had an increased risk of ALS under a recessive genetic model [OR 2.16; 95 % CI (1.23, 3.8), p = 0.009; corrected p = 0.028]. Genotypes with a C allele are also associated with increased risk [OR 1.47; 95 % CI (1.11, 1.95); p = 0.008; corrected p = 0.023] under an additive model. sALS patients with a C/C genotype had a shorter survival than patients with A/A and A/C genotypes [HR 1.44; 95 % CI (1.11, 1.873); p = 0.007] under a recessive model. In an overdominant model, heterozygous patients had a longer survival than homozygous patients [HR 0.36; 95 % CI (0.22, 0.59); p = 0.001]. The rs12608932 genotypes modify the progression of symptoms measured using the ALSFRS-R. No association with age of onset, initial topography or rate of decline in FVC was found. Our results show that rs12608932 is a risk factor for ALS in the Spanish population and replicate the findings described in other populations. The rs12608932 is a modifying factor for survival and disease progression rate in our series. Our results also corroborated that it did not influence the age of onset.
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain. josevidal@ub.edu.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain. josevidal@ub.edu.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Vidal-Taboada
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Alan
authors.initials: A
authors.lastname: Lopez-Lopez
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d'Hebron 119, 08035, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Salvado
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d'Hebron 119, 08035, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Lorenzo
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d'Hebron 119, 08035, Barcelona, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garcia
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mahy
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain.
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Rodríguez
authors.affiliation: ALS Unit, Neurology Department, Hospital Universitari Vall d'Hebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d'Hebron 119, 08035, Barcelona, Spain. josepgamez.bcn@gmail.com.
authors.forename: Josep
authors.identifier: http://orcid.org/0000-0003-3127-7486
authors.initials: J
authors.lastname: Gamez
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012306:Risk; D013030:Spain
chemical_list: D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human
keywords: ALS; Amyotrophic lateral sclerosis; Modifying gene; Susceptibility; UNC13A; rs12608932