Pytte, Julia, Flynn, Loren L, Anderton, Ryan S, Mastaglia, Frank L, Theunissen, Frances, James, Ian, Pfaff, Abigail, Koks, Sulev 
ORCID: 0000-0001-6087-6643, Saunders, Ann M, Bedlack, Richard et al (show 6 more authors)
(2020)
Disease-modifying effects of an <i>SCAF4</i> structural variant in a predominantly <i>SOD1</i> ALS cohort.
NEUROLOGY-GENETICS, 6 (4).
e470-.
Abstract
<h4>Objective</h4>To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (<i>SOD1</i>) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease.<h4>Methods</h4>Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with <i>SOD1</i> was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (<i>SCAF4</i>), a gene that is adjacent to <i>SOD1</i>, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection.<h4>Results</h4>In a North American cohort of predominantly <i>SOD1</i> fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T <i>SCAF4</i> allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; <i>p</i> = 4.0e-11), but also within non-<i>SOD1</i> cases (n = 27; OR 5.3; 95% CI 1.9-14.5; <i>p</i> = 0.0014). This finding suggests genetically <i>SOD1</i>-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6-40.8; <i>p</i> = 0.014), but did not affect age at onset of disease.<h4>Conclusions</h4>The findings in this fALS cohort suggest that rs573116164 could have <i>SOD1</i>-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Brain Disorders, ALS, Neurosciences, Neurodegenerative, Clinical Research, Genetics, Rare Diseases, 2 Aetiology, 2.1 Biological and endogenous factors, Neurological |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 Sep 2020 08:54 |
| Last Modified: | 12 Apr 2024 09:54 |
| DOI: | 10.1212/NXG.0000000000000470 |
| Open Access URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC73574... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3101376 |
Dimensions
Dimensions
