Questioning the Association of the Dinucleotide Repeat With Amyotrophic Lateral Sclerosis.

Objectives: Recently, the number of dinucleotide CA repeats in an intron of the gene was reported to be associated with an increased risk for amyotrophic lateral sclerosis (ALS). Therefore, we sought to replicate this observation in an independent group of ALS patients and a much larger control group.

Methods: Here, we used whole-genome sequencing and tested the CA repeat in a case-control cohort of the European genetic background and in genomes from various populations in the gnomAD cohort to attempt to replicate this proposed association.

Results: We find that repeats well above the previously reported pathogenic threshold of 19 are commonly observed in unaffected individuals across different populations. Furthermore, we did not observe an association between longer CA repeats and ALS phenotype.

Discussion: In summary, our results do not support a role of CA repeats toward ALS risk. As TDP-43 aggregation is central to ALS pathogenesis, lowered expression of could be used as a biomarker for ALS. Therefore, a variant associated both with the risk for ALS and the level of expression would be clinically useful. However, for a variant to be actionable, it must be strongly replicated in independent cohorts and exceed the rigorous statistical thresholds applied.