Whole genome sequencing as tool to unravel rare variants associated with ALS survival
published: July 21, 2017, recorded: May 2017, views: 764
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Background: Amyotrophic lateral sclerosis (ALS) usually leads to death within 3 to 5 years, but a high variability in patient survival has been observed, with 5% of the patients surviving more than 10 years (1). To date, several clinical factors have been associated with patient survival, e.g. gender, age at onset, site of onset, presence of frontotemporal dementia, … (2). Additionally, also genetic variants, like the C9orf72 repeat expansions, have been shown to associate with survival. Recent genomewide association studies (GWAS) using common genetic variant could only reveal the association of a small number of loci with ALS survival, leaving a large number of cases genetically unexplained. Objectives: To identify rare genetic variants that associated with ALS survival using whole genome sequencing (WGS) data. Methods: We used WGS data from 1,577 Belgian and Dutch ALS patients, sequenced as part of Project MinE. Cox-regression was applied on a genome wide scale using the GenABEL-package, while correcting for age at onset, site of onset, gender, sequencing technology and the first 10 PCA's for population stratification. Results: Cox regression analysis revealed 196 rare variants associated with ALS survival with a P-value between 5e-8 and 3.7e-13 and a minor allele frequency between 0.03% and 8.8%. The hazard ratio of the variants ranged from 0.5 to 3.8. Discussion and conclusions: The fact that several rare variants associate with survival, underscores the importance to consider the effect of rare variants in ALS pathology, especially in survival. The discovery of these novel loci as survival modifiers in ALS is important, as they can lead to an improved understanding of the disease process, which is of crucial importance in the development of treatment options. But due to the nature of rare variants, the incidence of the variants is low and caution should be taken with possible false positive finding, making validation in other cohorts desirable. The fact that these samples are part of the Project MinE will give us an ideal opportunity to validate our finding in a larger cohort.
References: 1. Pupillo E, Messina P, Logroscino G et al Ann Neurol. 2014; 75:287–297. 2. Chio A, Calvo A, Dossena M et al ALS. 2009; 10 205–209. Acknowledgements: Samples were sequenced as part of the MinE project. Belgian samples were collected at UZ Leuven and Dutch samples at UMC Utrecht.
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