title: 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.
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Benjamin
authors: B
authors: Gaastra
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Aleksey
authors: A
authors: Shatunov
authors: b University Medical Centre Utrecht , Utrecht , The Netherlands.
authors: Sara
authors: S
authors: Pulit
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Ashley R
authors: AR
authors: Jones
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: William
authors: W
authors: Sproviero
authors: c Department of Statistical Genetics, King's College London , Institute of Psychiatry, Psychology and Neuroscience , London, UK.
authors: Alexandra
authors: A
authors: Gillett
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Zhongbo
authors: Z
authors: Chen
authors: d Sheffield Institute for Translational Neuroscience , Sheffield, UK.
authors: Janine
authors: J
authors: Kirby
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Isabella
authors: I
authors: Fogh
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: John F
authors: JF
authors: Powell
authors: e Brighton and Sussex Medical School , Brighton, UK , and.
authors: P Nigel
authors: PN
authors: Leigh
authors: f Faculty of Medicine , University of Southampton , Southampton , UK.
authors: Karen E
authors: KE
authors: Morrison
authors: d Sheffield Institute for Translational Neuroscience , Sheffield, UK.
authors: Pamela J
authors: PJ
authors: Shaw
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Christopher E
authors: CE
authors: Shaw
authors: b University Medical Centre Utrecht , Utrecht , The Netherlands.
authors: Leonard H
authors: LH
authors: van den Berg
authors: b University Medical Centre Utrecht , Utrecht , The Netherlands.
authors: Jan H
authors: JH
authors: Veldink
authors: c Department of Statistical Genetics, King's College London , Institute of Psychiatry, Psychology and Neuroscience , London, UK.
authors: Cathryn M
authors: CM
authors: Lewis
authors: a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.
authors: Ammar
authors: A
authors: Al-Chalabi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality*; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D036122:Receptor, EphA4 / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C484407:KIFAP3 protein, human; D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human; D036122:Receptor, EphA4
keywords: ALS; UNC13A; genetic modifiers; sequencing; survival