Dataset Information

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis.

ABSTRACT: Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ?0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57?×?10-3). SNV rs10419420:G?>?A was found exclusively in long survivors (3/25) and rs4808092:G?>?A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.

SUBMITTER: Gaastra B

PROVIDER: S-EPMC5125285 | biostudies-literature | 2016 Oct - Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis.

Gaastra Benjamin B Shatunov Aleksey A Pulit Sara S Jones Ashley R AR Sproviero William W Gillett Alexandra A Chen Zhongbo Z Kirby Janine J Fogh Isabella I Powell John F JF Leigh P Nigel PN Morrison Karen E KE Shaw Pamela J PJ Shaw Christopher E CE van den Berg Leonard H LH Veldink Jan H JH Lewis Cathryn M CM Al-Chalabi Ammar A

Amyotrophic lateral sclerosis & frontotemporal degeneration 20160901 7-8

Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passi ...[more]

PMID: 27584932

Similar Datasets

Project description:Background and Objectives To characterize the clinical and cognitive behavioral phenotype and brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene. Methods The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent 18F-FDG-PET. Results The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18–2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33–3.92; A/A + C/C: 2.90 years, IQR 1.74–5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain 18F-FDG-PET extending to frontal and precentral areas of the right hemisphere. Discussion C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on 18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.

Project description:BackgroundThe UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial.MethodsGenotype data of the UNC13A rs12608932 SNP (A-major allele; C-minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) - Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models.ResultsThe rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33-0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (-11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered.ConclusionOverall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement.

Dataset Information

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis.

Publications

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets