Journal
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
Volume 17, Issue 7-8, Pages 593-599Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/21678421.2016.1213852
Keywords
ALS; survival; UNC13A; genetic modifiers; sequencing
Categories
Funding
- EU [MR/L501529/1]
- United Kingdom, Medical Research Council
- United Kingdom, Economic and Social Research Council
- Netherlands, ZonMW
- National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust
- King's College London
- NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
- European Community [259867]
- MND Association
- Wellcome Trust
- Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester
- Economic and Social Research Council [ES/L008238/1] Funding Source: researchfish
- Medical Research Council [MR/L501529/1, G0900688, MC_G1000733, G0600974] Funding Source: researchfish
- Motor Neurone Disease Association [AlChalabi-Talbot/Apr14/926-794] Funding Source: researchfish
- National Institute for Health Research [ACF-2012-17-022, NF-SI-0512-10082] Funding Source: researchfish
- ESRC [ES/L008238/1] Funding Source: UKRI
- MRC [G0600974, MC_G1000733, G0900688] Funding Source: UKRI
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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 x 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.
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