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.
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