The investigation of short structural variants within JAG1, ADGRL1, and PLXNB1 for associations with sporadic amyotrophic lateral sclerosis

Delenn A Eddy

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neurone disease, with a worldwide prevalence of 5.4/100,000 and a lifetime risk estimate of 1 in 347 for men and 1 in 436 for women. Current heritability estimates suggest that there is a genetic contribution in ~65% of ALS patients, however to date, only ~10% of genetic variants associated with sporadic (s)ALS have been identified. Furthermore, there are currently no curative therapeutics for ALS with over 70 failed randomised drug trials in ALS disease history. With these clinical limitations believed to be contributed to by the high heterogeneity in ALS clinical and genetic features, stratification of patients into more homogeneous, genetically defined subgroups for future clinical trials may improve the clinical success rate. Investigations into short genomic variants other than SNPs, termed short structural variants (SSVs), as markers of sALS disease risk and/or modification may provide a deeper understanding of the heritability of sALS. Methods: Three novel candidate SSVs were identified using an established SV evaluation algorithm. The polymorphic status of variants in JAG1 (rs33967297), ADGRL1 (rs74181774), and PLXNB1 (rs1166591503) were characterised through PCR and Sanger sequencing, and capillary electrophoresis was used to determine allele-specific genotypes. Case-control analyses were then performed in a large North American cohort, using Pearson’s chi-squared, general linear regression, and one-way ANOVA tests to determine allelic effects on sALS risk and age of onset. Results: SSVs of interest in JAG1, ADGRL1, and PLXNB1, all showed polymorphic traits. No associations were observed between SSV alleles and ALS disease risk or age of onset. When stratified by site of onset, PLXNB1, and ADGRL1 SSV genotypes revealed differences in age of onset for bulbar-onset and upper limb onset subgroups concerning ADGRL1, and lower limb onset patients concerning PLXNB1. Conclusion: The findings in this study suggest that ADGRL1 and PLXNB1 alleles may be associated with disease modifying effects, including in the age of disease onset when stratified by anatomical site of disease onset. Further studies in additional single centre sALS cohorts with longitudinal data are needed to assess these SSVs for association with disease progression and age at death.

The investigation of short structural variants within JAG1, ADGRL1, and PLXNB1 for associations with sporadic amyotrophic lateral sclerosis

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