An individual’s genetics contributes to their risk of developing amyotrophic lateral sclerosis (ALS), however there is still a large proportion of the heritability of ALS to be understood. Part of this missing heritability may lie in complex variants yet to be evaluated, such as the long interspersed element-1 (L1) retrotransposon which are a source of polymorphic insertions in the population. The majority of L1s are no longer able to retrotranspose, however to date 276 retrotransposition competent (RC) L1s have been reported. We hypothesise that L1s could influence disease development either through their effects on endogenous genes or due to the properties that enable them to retrotranspose.  Therefore, using whole genome sequencing data from the New York Genome Center ALS consortium we characterised L1 variation and then focused on the subset of RC-L1s.

In 4393 whole genomes we identified 205 reference and 2598 non-reference polymorphic L1 elements. Association analysis did not identify any individual L1 elements associated with disease, however we did identify an increased number of RC-L1s in the genomes of individuals diagnosed with ALS compared to controls (p=6.02x10^-5). The presence of ≥51 RC-L1s showed the strongest association with ALS (padj=0.0005, OR=1.14 (1.07-1.21)). Age at onset analysis identified a L1 whose presence was significantly associated with a lower age at onset (52.7 years) compared to homozygous absent individuals (59.2 years) (padj=0.009).

Our study has identified novel genetic factors for both disease risk and age at onset in ALS providing further evidence for the role of L1 retrotransposons in neurodegenerative disease.