Assessment of ATXN2 Repeat Expansion Length and Risk of ALS: A Meta-Analysis

ATXN2 expansions of [≥]33 CAG-repeats are associated with spinocerebellar ataxia type 2, while "intermediate" length expansions have been associated with amyotrophic lateral sclerosis (ALS). Yet, no consensus is established regarding the lengths that define a true association with ALS risk, with recent studies debating between a lower limit of [≥]29 or [≥]31 repeats. Here, we assessed the risk of ALS imparted by various ATXN2 repeat lengths to establish an accepted lower limit of repeats that impart risk of disease in the largest meta-analysis to-date. We identified 19 studies with carrier counts of expansions ranging from 24 to [≥]34 repeats in cohorts of individuals with ALS and controls that we meta-analysed with the ATXN2 repeat lengths of the large-scale Project MinE ALS Consortium dataset (total individuals with ALS = 19202; total controls = 22177) and determined a lower limit of 30 repeats defining significant ALS risk. These findings were validated with a secondary assessment of the individuals with ALS captured within the meta-analysis using the gnomAD short tandem repeat dataset as a proxy control cohort. We also applied our defined ATXN2 repeat risk threshold to explore relationships with ALS clinical outcomes. While we did not observe a significant relationship between ATXN2 repeat lengths and age of ALS onset, we did identify a significant inverse correlation between ATXN2 repeat lengths as a continuous metric and duration of disease and found that individuals with ALS carrying the risk variant allele of [≥]30 repeats had significantly shorter times to diagnosis than those without the repeat expansion. Our comprehensive analyses propose a lower-limit threshold of [≥]30 ATXN2 trinucleotide repeats in length defining true ALS risk. These findings are imperative for allowing improved accuracy in risk interpretation and guidance for patients and their families, particularly as clinical genetic testing efforts continue to expand and there becomes increased need for guiding targeted clinical trial inclusion criteria. Our results may also aid in future analyses assessing ATXN2 pathogenic mechanisms and therapeutic strategies.