The evolving genetic risk for sporadic ALS

Abstract

Objective: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity.

Methods: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls.

Results: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls.

Conclusions: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.

Figure 1. Admixture and principal components analysis (PCA) plots show the ancestry and sample quality of the sporadic amyotrophic lateral sclerosis (SALS) cohort

(A) An Admixture plot where each bar represents a patient with SALS (in total 96 patients). The height of each colored bar represents the amount of ancestry each individual derives from. Blue = European (CEU), green = East Asian (CHB + JPT), and red = African (YRI). Individuals with less than 90% European ancestry (yellow bar) were removed from further analysis. The 9 patients with SALS with less than 90% European ancestry are indicated with a red asterisk. (B) PCA plot of all 96 individuals with 1,000 genomes data (CEU = Utah residents [CEPH] with northern and western European ancestry; CHB = Han Chinese in Beijing, China; JPT = Japanese in Tokyo, Japan; YRI = Yoruba in Ibadan, Nigeria). Shaded areas represent the area over which the kernel density of each respective 1000 genomes population spans. SALS samples are listed as purple circles. Arrows indicate non-European individuals who were removed from further analysis.

Figure 2. Percentage of sporadic amyotrophic lateral sclerosis (SALS) cases with an identifiable genetic variant likely responsible for disease

The percentage next to each gene indicates what percentage of SALS cases have a rare and pathogenic variant in that gene. A majority (82.8%) of SALS cases have no identifiable genetic variants potentially responsible for their disease.