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are associated with genes widely expressed
throughout the body and that the placenta may
be a critical transducer of adverse events in
pregnancy to the fetal brain
. Using publically
available data, the authors first determined that
indeed many of the genes randomly selected
from the cohort of schizophrenia risk genes
that associated with ELCs were also highly
enriched in expression in the placenta. They
then created a new PRS based on genes that are
highly expressed in placenta from pregnancies
involving pre-eclampsia or intrauterine growth
restriction and looked for an association
between the schizophrenia risk genes impacted
by ELCs and schizophrenia versus those that
were not. The genes identified as being strongly
associated with schizophrenia in individuals
with complications had increased expression
in all compartments of the placenta (amnion,
basal plate, chorion, villi and trophoblast)
during both the second and third trimester
when compared to those not as strongly
associated with schizophrenia and having no
interaction with ELCs. They identified no
effect association of pregnancy complications
with expression of the schizophrenia risk genes
in other tissues.
The authors go on to suggest
complications during pregnancy could
be a confounding variable in attempts
to identify genetic associations for
schizophrenia using GWASs, which
generally do not take into account
nongenetic variables. This is because
the stronger genetic association with
schizophrenia seen in individuals with
ELCs versus those without may actually
be a determining factor in why some
genes become significantly associated with
schizophrenia. These genes modified by
an early-life event could thereby crowd out
or obscure other seemingly weaker genetic
associations that could help explain liability
of disease in those not experiencing ELCs.
So, what are the placental genes being
modified by ELCs and how could they
contribute to risk of developing schizophrenia?
The authors found that the genes whose
expression was modified by ELCs are involved
in regulation of oxidative and cellular stress
as well as inflammation, whereas non-ELC-
modified genes that are still associated with
schizophrenia risk are classic modifiers of brain
via synaptic functioning and calcium handling.
This observation emphasizes the value in
the authors’ approach of using biological or
phenotypic qualifiers in order to deconstruct
genomic risk using GWAS datasets.
Lastly, citing the clinical evidence that men
are at a higher risk for schizophrenia diagnosis
than women and the preclinical evidence
in mouse and rat models that males exhibit
more dysregulated physiology and behavior
following prenatal stress as well as more
severely compromised placental function than
, the authors also explored whether
the ELC–PRS interaction they observed was
stronger in male placenta. The authors were
not able to carry out a case versus control
analysis using this dataset, but nonetheless,
schizophrenia risk genes were more highly
expressed in male placenta and were higher
still in those from pregnancies with pre-
eclampsia compared to female placenta.
Thus, the greater incidence of schizophrenic
diagnosis in men may have its beginnings in
a temporary organ external to the fetus and
discarded at birth—i.e., the placenta.
How will we begin to understand the
impact on the brain of amorphous changes
in the stress responses of the placenta? A
good start may be the analysis of other
complimentary datasets, such as magnetic
resonance imaging (MRI) of individuals with
schizophrenia and controls to assess the impact
of ELCs on neuroanatomical endpoints.
Likewise, targeted hypothesis-driven studies
in animal models in which highly associated
schizophrenic risk genes can be selectively
deleted in the placenta will allow for the
identification of causal connections between
placental function, brain and behavior.
One of the more compelling questions
raised by this study is: why are males
at a greater risk for schizophrenia from
pregnancy complications? Both animal
and human studies are converging on
the conclusion that even under healthy
conditions males have a higher inflammatory
‘tone’ in the brain as it develops
, and this
may have its origins in the maternal immune
system more vigorously targeting male
versus female fetuses. This is evident in
the high maternal antibody titers against a
Y chromosome gene in the circulation of
women who have had male offspring
does not explain why schizophrenia risk
genes are more highly expressed in the male
placenta, although the origins could be the
same, but one feasible scenario is that more
severely compromised placental function in
male fetuses has an amplified effect in a male
brain that is already more inflamed. These are
testable hypotheses and highlight the many
exciting, new avenues to be explored on the
basis of the current report. But perhaps the
most important take-home message of the
report is this: if we really want to prevent
mental health disorders and the devastation
of schizophrenia, addressing prenatal stress
and promoting healthy pregnancy and
delivery is an excellent place to start. ❐
Margaret M. McCarthy
Department of Pharmacology and Program in
Neuroscience, University of Maryland School of
Medicine, Baltimore, MD, USA.
Published online: 6 June 2018
1. Lewis, D. A., & Levitt, P. Annu. Rev. Neurosci. 25, 409–432 (2002).
2. Ursini, G. et al. Nat. Med. https://doi.org/10.1038/s41591-018-
3. Walker, C. K. et al. JAMA Pediatr. 169, 154–162 (2015).
4. Bale, T. L. Dialogues Clin. Neurosci. 18, 459–464 (2016).
5. McCarthy, M. M., Nugent, B. M. & Lenz, K. M. Nat. Rev. Neurosci.
18, 471–484 (2017).
6. Bogaert, A. F. et al. Proc. Natl. Acad. Sci. USA 115, 302–306 (2018).
The author declares no competing interests.
NATURE MEDICINE | VOL 24 | JUNE 2018 | 703–710 | www.nature.com/naturemedicine
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
Reducing diabetes risk at an early age
A large retrospective study involving 62,565 Danish men shows that those who have been overweight in childhood
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iabetes has now reached epidemic
proportions on a global scale. The
estimated worldwide prevalence of
adults with diabetes increased from 108
million in 1980 to 422 million in 2014 (ref.
As most (85–95%) cases of diabetes in adults
are type 2, this observed rise in diabetes
prevalence is quite likely due to increases
in type 2 diabetes. In the United States