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R
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S
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.
14
E. Dempster etal.
Instead, more conventional epidemiological approaches
that consider a spectrum of confounding factors, includ-
ing tissue/cell type, age, sex, medication exposure, and
reverse causation, have to be used.
One of the major challenges in studying epigenetic
changes in neuropsychiatric disorders is availability of
samples of the primary target tissue, ie, the brain. Because
it is not yet possible to perform in vivo epigenetic studies in
the brain, only retrospective study designs using postmor-
tem brain samples are viable. These experiments are lim-
ited by access to high-quality, well-phenotyped samples.
There are a number of potential confounders that could
infuence epigenetic analyses of such samples, including
postmortem interval, storage time, pH, and cellular het-
erogeneity.
3
The small number of brain samples available
for SZ epigenetic research means that many investigations
are limited in terms of their power to detect signifcant
associations, especially given the small absolute changes
that are likely to be uncovered and the heterogeneous cel-
lular composition of the cerebral cortex. Ultimately, given
the cell-specifc differences identifed in epigenetic gene
regulation, it may be optimal to isolate specifc cell types
(eg, neurons, glia, and astrocytes) from brain tissue via
processes such as laser capture microdissection.
In reality, it may not be feasible to undertake adequately
powered studies of SZ using postmortem brain material,
especially if numbers approaching those used in GWAS
analyses are required. Akey question in epigenetic epide-
miology, particularly in regard to the study of neuropsy-
chiatric disease, therefore concerns the extent to which
easily accessible peripheral tissues such as blood can be
used to ask questions about interindividual phenotypic
variation manifest in inaccessible tissues such as the brain.
4
We recently undertook the frst within-individual cross-
tissue (multiple brain regions plus blood) characterization
of the DNA methylome.
30
Although, as expected, distinct
tissue-specifc patterns of DNA methylation were identi-
fed and between-tissue variation was found to greatly
exceed between-individual differences within any one tis-
sue, it was striking that some interindividual variation was
signifcantly correlated between blood and brain tissue,
indicating that peripheral sources of DNA may have util-
ity in epidemiological studies of complex neurobiological
phenotypes. As shown in table1, several studies have suc-
cessfully used peripheral samples to identify signifcant
disease-associated epigenetic variation in blood, although
it remains important to establish whether these differences
are also refected in SZ-relevant regions of thebrain.
Another important issue concerns the ability to dis-
tinguish between cause and effect; the disease-associated
modifcations described in table 1 may arise prior to ill-
ness and contribute directly to the disease phenotype or
could alternatively be a secondary effect of the disease
process or the medications used in treatment.
11
It is clear
that a range of factors, including genotype, age, and sex,
are correlated with epigenetic variation,
31
and so including
these as covariates in analyses is important. The analysis
of SZ-discordant MZ twins represents a powerful strategy
for overcoming many of these issues as both twins have
their genomes, parents, birth date, and gender in common
and are likely to have been exposed to a highly similar
pre- and perinatal environment. An optimal study design
would involve the longitudinal assessment of epigenetic
changes in MZ twins, examining within-pair epigenomic
variation as they become discordant for disease. Finally,
because many psychotropic drugs have been shown to
alter the epigenome,
11
such longitudinal study designs
would allow us to determine whether epigenetic changes
are independent of, or are mediated by, medication.
Experimental Approaches and Limitations
Most studies of epigenetic processes in SZ have focused
on DNA methylation. There is, however, a diverse range
of enrichment strategies and mapping platforms that
have been employed to assess DNA methylation in SZ.
This has made comparisons between studies diffcult,
although the recently released Illumina 450K Methylation
Beadchip that is being widely adopted for EWAS analy-
ses offers an economical balance between coverage and
precision. The majority of probes on this array, however,
are still located in CpG-rich promoters and may not be
optimal for identifying the most phenotypically relevant
epigenetic variation. Recent studies highlight the impor-
tance of DNA methylation outside of promoter CpG
islands, fnding functionally relevant epigenomic varia-
tion primarily at nonpromoter CpG islands, low CG
content promoters, and the gene body.
1,30
With the cost of
whole-genome bisulfte sequencing on a rapid downward
trajectory, the era of whole-methylome analyses of disor-
ders such as SZ is not far away. Anumber of additional
DNA modifcations (5-hydroxymethlcytosine, 5-formyl-
cytosine, and 5-carboxylcystosine) have recently received
considerable attention. For example, 5-hydroxymethlcy-
tosine is believed to result from the active demethylation
of methylated cytosine and appears to be abundant in
brain tissue, warranting further investigation in the con-
text of neuropsychiatric phenotypes.
2
Posttranslational
histone modifcations are another major source of epi-
genetic regulation, which have been largely neglected in
epidemiologically informative study designs ofSZ.
Finally, rather than investigating genetic and epigen-
etic factors independently, it is clear that an integrative
etiological research paradigm is required.
32
It has been
demonstrated, eg, that DNA sequence variation can
directly infuence DNA methylation in cis
33
and evidence
has been found for an enrichment of methylation quan-
titative trait loci (mQTLs) amongst psychosis-nominated
GWAS loci.
34
The interpretation of GWAS data could be
improved by incorporating such epiallelic information
into analyses
32
; although mQTLs provide a functional
mechanism for apparently noncoding genetic variation,
15
Epigenetic Studies of Schizophrenia
other epigenetic patterns may complicate the direct iden-
tifcation of disease-associated loci, contributing toward
the missing heritability of complex diseases by mask-
ing direct associations between genotype and phenotype.
Because epigenetic processes are infuenced by a spectrum
of external environmental factors, including diet, toxins,
drugs, and stress, the observation that polymorphisms
can also exert an effect on gene function via epigenetic
processes occurring in cis suggests a common pathway
behind both genetic and environmental effects and a
potential mechanism for geneenvironment interaction.
Into theFuture
Technological advances in epigenomic profling meth-
odologies mean that it will soon be feasible to economi-
cally map the epigenome at single base-pair resolution
in large cohorts of samples. Moving forward, it will be
important to establish cause and effect in epigenetic
studies of SZ and broaden our horizons beyond DNA
methylation. Furthermore, maximum information will be
obtained from studies integrating epigenomic informa-
tion with genomic, transcriptomic, and proteomic data
obtained from the same samples. Ultimately, the dynamic
and reversible nature of epigenetic processes holds huge
promise for the development of novel diagnostic and
therapeutic measures for SZ.
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