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transcription. Methylation levels are much lower when the G allele is present, and transcription can
[5-8]
occur [Figure 1]. Therefore, the effect of outside factors on expression levels in the gene (e.g., oxidative
[7]
damage-induced hypomethylation) can be seen mostly for chromosomes with the G allele .
This level of regulation of PM20D1 expression has been described as an on-off switch that acts in all human
tissues. Additionally, specifically in adipocytes, a variant near the gene is involved in expression regulation
[36]
by the peroxisome proliferator-activated receptor γ (PPARγ) transcription factor (see the section on
obesity).

The role of rs708727 as an mQTL appears to be consistent across populations of different ancestries.
Differential methylation in PM20D1’s promoter that has been reported among Caucasian American,
African- American, and Han Chinese American individuals can be explained by differences in allele
frequencies at the rs708727 locus [42,43] . Additionally, the association between rs708727 genotype and PM20D1
[8]
methylation has also been reported in a sample of Costa Rican women .

ALZHEIMER’S
In 2018, in a very thorough study, Sánchez-Mut et al. reported for the first time an association of
methylation status of the PM20D1 promoter with Alzheimer’s disease . They found the promoter to be
[6]
consistently hypermethylated in individuals with advanced-stage AD. The gene’s promoter had been
[43]
previously shown to be differentially methylated between human populations of different ethnic origins .
The authors proceeded to identify several SNPs that correlated in an allele-dose-dependent manner with
PM20D1 methylation; rs708727 has been found in later studies to show the most significant association and
acts as an mQTL (as described in the previous section). Moreover, they found that PM20D1 expression
[7,8]
was inversely correlated with the methylation of its promoter. Variant rs708727 and several SNPs in linkage
[34]
disequilibrium with it have been previously described as eQTLs for PM20D1 . Additionally, using
peripheral blood, another recent study detected an association of a differentially methylated region in
PM20D1 with the rate of cognitive decline in AD, as well as with the transition from cognitively healthy to
the presence of cognitive impairment .
[44]

There is also functional evidence linking PM20D1 to AD. In cell culture, PM20D1 expression increased after
treatment with neurotoxic insults related to AD, such as reactive oxygen species (ROS) and amyloid-β .
[5,6]
Additionally, in a mouse model with AD-related pathologies (APP/PS1), PM20D1 expression was higher in
the frontal cortex at symptomatic stages than in pre-symptomatic stages and control mice . Finally, in vitro
[6]
overexpression of PM20D1 has been shown to decrease ROS-induced cell death and levels of amyloid-β in
vitro, as well as reduce the amount of amyloid plaque and improve cognitive performance in mice . These
[5,6]
results suggest a neuroprotective role of PM20D1, but at first glance seem to be in contradiction with the
hypermethylation (and presumed reduced expression) reported in individuals with advanced AD .
[6,8]
In the meantime, a mechanistic model has been proposed for the role of PM20D1 in AD , which explains
[5-7]
the apparent contradiction. In individuals with hypermethylated PM20D1 (induced in part by the A allele
rs708727), there is no transcription and therefore no PM20D1-mediated-protection against damage. On the
other hand, in individuals without the methylation-inducing allele in rs708727 (i.e., individuals with the GG
genotype), expression is increased in the presence of AD-related stress in order to reduce ROS-induced cell
death, reduce Aβ levels, and prevent cognitive damage. Studies with longitudinal data have shown that
hypomethylation occurs before the symptomatic onset of the disease, and therefore pre-diagnosis [7,45] ,
potentially to increase gene expression and generate protection from damage. Then, a gradual increase in
methylation is seen during disease progression in individuals with AD, leading to a decrease in gene