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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly of motor neurons, resulting in progressive weakness of voluntary muscles and death from respiratory failure due to diaphragmatic paralysis, typically within three years of onset.There is a strong genetic contribution to amyotrophic lateral sclerosis (ALS) risk
Three genes passed our inclusion criteria: UNC13A, identified from genomewide association studies; EPHA4, identified by a genome-wide morpholino-based zebrafish knockdown screen followed by testing in humans; and KIFAP3, identified in a genome-wide association study, not subsequently confirmed as a survival gene in other studies [5,6,7,8,9]
We have shown that rare variation in the UNC13A gene may modify survival in ALS in a UK sample set, but this is not replicated in a second sample set from the Netherlands
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly of motor neurons, resulting in progressive weakness of voluntary muscles and death from respiratory failure due to diaphragmatic paralysis, typically within three years of onset. There is a strong genetic contribution to ALS risk. 5% to 20% of cases have a family history of ALS or frontotemporal dementia; the remaining cases are sporadic, having no known family history. Genes for ALS have been identified in about 70% of those with a family history and 15% of those without. Risk genes do not strongly predict phenotype in most cases, with only a few having any reliable relationship with prognosis. Homozygosity for the p.D91A mutation of SOD1 is associated with slowly progressive ALS, and the p.A5V mutation of SOD1 with rapid disease, but such a relationship is unusual
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