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Global Translational Medicine TEs link to Parkinson’s risk and progression

with increased GBA expression (Figure 3A, P = 1.66 × 10 ). between the SMYD3 gene and tumor progression ,
−7
[59]
Similarly, an ALU insertion (chr4_159704892_ALU), emerging evidence suggests a correlation between this
located downstream of the PD risk gene GAMK2D at gene and endothelial senescence . Given the age-related
[60]
approximately 46 Mb on chromosome 4, exhibited a association of PD, it is worth further exploring whether
significant association with increased GAMK2D expression epigenetic regulation of the SMYD3 gene in the brain is
(Figure 3B, P = 5.03 × 10 ). In addition, a LINE1 insertion linked to neuronal death. Furthermore, the PD progression
−6
(chr6_13190783_LINE1), located downstream of the PD associated locus chr8_114592257_ALU is positioned at
risk gene RPS12 at approximately 119 Mb on chromosome 1.1 Mb downstream of CSMD3, which is predominantly
6, was linked to elevated RPS12 expression (Figure 3C, expressed in developing cortical neurons. The absence of
-6
P = 4.62 × 10 ). Interestingly, in contrast to the prevailing CSMD3 expression is related to abnormal synaptic formation
trend observed in most cis TE-eQTL loci, which are and neurodevelopmental disorders, ultimately resulting
[61]
associated with the downregulation of gene expression, in developmental delay . Current evidence suggests that
these three long-distance TE insertion events were linked TE-derived sequences regulate gene expression by both
to the upregulation of gene expression. maintaining and shaping 3D genome architecture . Further
[62]
studies involving epigenomics data, such as ATAC-seq, 4C,
4. Discussion Hi-C, and ChIP-seq, may aid in elucidating the causal effects
TEs occupy nearly half of the human genome, yet TE of TEs on the development of PD.
polymorphisms have been overlooked in many disease To date, the association between the immune system
GWAS studies. In this pilot study, we investigated the and PD has been supported by multiple lines of evidence ,
[63]
genetic association between TE polymorphisms and both with immune cell dysfunction playing a key role in the
the onset and progression of PD by integrating data from development of PD . Our interaction cis-TE-eQTL analysis
[64]
nearly 2,000 subjects. Our analysis led to the identification revealed that eGenes were enriched in immune-related
of a TE locus linked to PD onset (Figure 2A) and two TE loci signaling pathways, suggesting that TE polymorphisms
associated with PD progression (Figure 2B and C). Notably, may be linked to abnormal gene expression in the
the TE locus associated with PD risk, chr1_246429040_ immune system. We propose that elucidating how TE
ALU, is located near the SMYD3 gene, which encodes a polymorphisms affect immune dysregulation in PD
histone methyltransferase. SMYD3 gene plays a pivotal pathogenesis could not only deepen our understanding
role in epigenetic mechanisms. While numerous studies of the disease but also facilitate the development of novel
have consistently demonstrated a significant association therapy strategies.

A B C

Figure 3. TE polymorphisms link to the expression alternation of PD risk genes. In non-interaction TE-eQTL analysis: (A) the expression of GBA was
significantly upregulated in carriers of chr1_111353551_SVA compared to non-carriers; (B) the expression of GAMK2D was significantly upregulated
in carriers of chr4_159704892_ALU compared to non-carriers; (C) the expression of RPS12 was significantly upregulated in carriers of chr6_13190783_
LINE1 compared to non-carriers. The lines within the boxes represent the median value, while the upper and lower ends of the boxes represent the
interquartile range.
Abbreviation: TPM: transcripts per million; TE: Transposable element; PD: Parkinson’s disease; TE-eQTL: Transposable element-expression quantitative
trait locus.

Volume 2 Issue 3 (2023) 8 https://doi.org/10.36922/gtm.1583