Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson’s disease

Abstract

The pathophysiology of Parkinson’s disease (PD) is a complex process of the interaction between genetic and environmental factors. Studies on the genetic component of PD have predominantly focused on single nucleotide polymorphisms (SNPs) using a cross-sectional case–control design in large genome-wide association studies. This approach while giving insight into a significant portion of the genetics of PD does not fully account for all the genetic components resulting in missing heritability. In this study, we approached this problem by focusing on the non-reference genome transposable elements (TEs) and their impact on the progression of PD using a longitudinal study design within the Parkinson’s progression markers initiative (PPMI) cohort. We analyzed 2886 Alu repeats, 360 LINE1 and 128 SINE-VNTR-Alus (SVAs) that were called from the whole-genome sequence data which are not within the reference genome. The presence or absence of these non-reference TE variants is known as a retrotransposon insertion polymorphism, and measuring this polymorphism describes the impact of TEs on the traits. The variations for the presence or absence of the non-reference TE elements were modeled to align with the changes in the 114 outcome measures during the five-year follow-up period of the PPMI cohort. Linear mixed-effects models were used, and many TEs were found to have a highly significant effect on the longitudinal changes in the clinically important PD outcomes such as UPDRS subscale II, UPDRS total scores, and modified Schwab and England ADL scale. In addition, the progression of several imaging and functional measures, including the Caudate/Putamen ratio and levodopa equivalent daily dose (LEDD) were also significantly affected by the TEs. In conclusion, this study identified the overwhelming effect of the non-reference TEs on the progression of PD and is a good example of the impact the variations in the “junk DNA” have on complex diseases.

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

“…For example, an SVA insertion in the TAF1 gene's intron was found to cause X-linked Dystonia Parkinsonism (XDP) 13 – 15 . Our recent studies also suggest that polymorphic non-reference transposable elements and reference SVAs are involved in PD progression 16 , 17 . In the present study, we focused on reference LINE-1 insertion polymorphisms, which means that these elements are generally found in the human reference genome, however, these elements can be polymorphic for their presence or absence in the population.…”

“…This difference with more than 10 points on this clinical scale may make the difference if a PD patient is able to exert the activities mentioned before or not anymore. The study presented here focused on reference LINE-1 elements, however, in our previous study we showed that non-reference (non-ref) transposable elements were also able to affect PD progression 16 . These non-ref elements are not fixed in the reference human genome and can therefore be variable for presence or absence in the genome.…”

“…These non-ref elements are not fixed in the reference human genome and can therefore be variable for presence or absence in the genome. In total, 2886 Alu , 360 LINE-1, and 128 SVA elements were analysed which showed the highest number of effects on two PD progression traits, namely primary diagnosis (268 hits) and UPDRS2 score (224 hits) 16 . More specifically, when looking at non-ref LINE-1 elements, the most common traits affected were UPDRS2 score, primary diagnosis, and ipsilateral count density ratio of caudate/putamen (ips-CDR).…”