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Garro-Núñez et al. J Transl Genet Genom 2022;6:361-74 https://dx.doi.org/10.20517/jtgg.2022.10 Page 369

patients [57,63] , while introns and UTR regions have not been deeply explored. Therefore, the existence of
unknown variants involved in PD cannot be ruled out.

[82]
There is one report of hypermethylation of PM20D1 in PD . Additionally, several studies have focused on
genetic variants that correlate with the expression level of the gene. The rs708723-T variant in RAB29 has
been reported to be associated with Parkinson’s disease and correlates with increased methylation of CpG
sites in PM20D1 in frontal cortex and cerebellar tissues, but also with the expression of RAB29 and
NUCKS1 . In the same tissues, the risk PD variant rs823118-T, located between RAB29 and NUCKS1,
[56]
[64]
increases PM20D1 methylation and affects the expression of RAB29 and NUCKS1 . Goldstein et al. (2021)
found evidence suggesting that the risk non-coding variant rs823114-A, located upstream of the NUCKS1
[83]
gene, has an eQTL and mQTL effect on PM20D1 and other genes in the PARK16 locus . Additionally,
Cibulka et al. (2022) reported that minor allele A for rs708727 in SLC41A1 is associated with PD in the
Slovak population . As mentioned in previous sections, the Alzheimer-associated rs708727 is an mQTL
[37]
and eQTL for PM20D1, and the A allele is associated with higher methylation of the PM20D1 promoter and
absent expression [Figure 1]. In addition, dementia is a common diagnosis in patients with PD,
[5-8]
manifesting mainly in late stages of the disease [84,85] . This suggests that there may be common mechanisms in
the development of PD and AD, including mechanisms of epigenetic regulation .
[37]

OTHER PHENOTYPES
As evidenced in the previous sections, PM20D1 is closely related to AD, obesity, and PD; however, PM20D1
has been associated with a wide variety of other phenotypes. Among those is asthma, where the
hypomethylation of probe cg14893161 was initially shown in babies born to mothers with asthma and
[86]
atopic mothers without asthma . A direct association between hypermethylation of PM20D1 and
respiratory allergy, specifically for probe cg11965913, has also been identified; expression of PM20D1 is
[87]
regulated by the TLR5 pathway, which is closely related to allergic responses . In addition to a respiratory
allergic response, hypomethylation in the gene has also been associated with food allergies .
[88]
Changes in the methylation levels of PM20D1 have been reported in several additional phenotypes. In the
[89]
case of psoriasis, an upregulation in gene methylation has been reported in affected individuals . A
differentially methylated region at PM20D1 has also been identified for multiple sclerosis .
[90]
PM20D1 is also susceptible to epigenetic changes as a result of external factors, such as lifetime events and
environmental conditions. In individuals who have suffered child abuse, there is evidence of
[91]
hypermethylation of PM20D1 . PM20D1 has also been involved in the response mechanism of cold
exposure, in which there is an upregulation of PM20D1 under conditions of constant exposure to cold .
[92]
There is increasing evidence that PM20D1 plays a role in several metabolic conditions, such as obesity and
diabetes (discussed above). Additionally, a suggestive pleiotropic association with polycystic ovary
syndrome has been described for the gene; this is a metabolic condition closely related with obesity and
diabetes . For familial hypercholesterolemia, DMRs have been found within PM20D1, specifically in the
[93]
cg14893161 probe . On the other hand, decreased serum PM20D1 has been associated with severity in
[94]
[95]
carotid atherosclerosis patients .
Furthermore, the very diverse phenotypes related to PM20D1 include stroke, a condition that was
[96]
determined to present hypermethylation within PM20D1 independent of the body mass index . A study of
[97]
breast tissue from healthy women found differences in PM20D1 methylation according to ethnic origin .
Additionally, in an epigenome-wide association study for COVID-19 severity, the PM20D1 gene was found