Reference LINE-1 insertion polymorphisms correlate with Parkinson’s disease progression and differential transcript expression in the PPMI cohort

Abstract Long interspersed nuclear element-1 (LINE-1/L1) retrotransposons make up 17% of the human genome. They represent one class of transposable elements with the capacity to both mobilize autonomously and in trans via the mobilization of other elements, primarily Alu and SVA elements. Reference LINE-1 elements are, by definition, found in the reference genome, however, due to the polymorphic nature of these elements, variation for presence or absence is present within the population. We used a combination of clinical and transcriptomic data from the Parkinson’s Progression Markers Initiative (PPMI) and applied matrix expression quantitative trait loci analysis and linear mixed-effects models involving 114 clinical, biochemical and imaging data from the PPMI cohort to elucidate the role of reference LINE-1 insertion polymorphism on both gene expression genome-wide and progression of Parkinson’s disease (PD). We demonstrate that most LINE-1 insertion polymorphisms are capable of regulating gene expression, preferentially in trans, including previously identified PD risk loci. In addition, we show that 70 LINE-1 elements were associated with longitudinal changes of at least one PD progression marker, including ipsilateral count density ratio and UPDRS scores which are indicators of degeneration and severity. In conclusion, this study highlights the effect of the polymorphic nature of LINE-1 retrotransposons on gene regulation and progression of PD which underlines the importance of analyzing transposable elements within complex diseases.