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

Benjamin Gaastra, Aleksey Shatunov, Sara Pulit, Ashley R. Jones, William Sproviero, Alexandra Gillett, Zhongbo Chen, Janine Kirby, Isabella Fogh, John F. Powell, P. Nigel Leigh, Karen E. Morrison, Pamela J. Shaw, Christopher E. Shaw, Leonard H. van den Berg, Jan H. Veldink, Cathryn M. Lewis, Ammar Al-Chalabi

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)593-599
Number of pages7
JournalAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Issue number7-8
Early online date1 Sept 2016
Publication statusPublished - 2 Sept 2016


  • Adaptor Proteins, Signal Transducing
  • Amyotrophic Lateral Sclerosis
  • Cohort Studies
  • Cytoskeletal Proteins
  • Databases, Bibliographic
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins
  • Polymorphism, Single Nucleotide
  • Receptor, EphA4
  • Survival Analysis
  • Time Factors
  • United Kingdom
  • Journal Article


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