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Schizophrenia Bulletin vol. 33 no. 6 pp. 1270–1273, 2007
doi:10.1093/schbul/sbm093
Advance Access publication on September 28, 2007
Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age
to Schizophrenia
Mary C. Perrin2, Alan S. Brown3,4, and
Dolores Malaspina1,2
2
Department of Psychiatry, School of Medicine, New York
University, New York, NY; 3New York State Psychiatric Institute,
New York, NY; 4Department of Psychiatry, Columbia University,
New York, NY
The causal mechanism underlying the well-established relation between advancing paternal age and schizophrenia is
hypothesized to involve mutational errors during spermatogenesis that occur with increasing frequency as males age.
Point mutations are well known to increase with advancing
paternal age while other errors such as altered copy number
in repeat DNA and chromosome breakage have in some
cases also been associated with advancing paternal age.
Dysregulation of epigenetic processes may also be an important mechanism underlying the association between
paternal age and schizophrenia. Evidence suggests that advancing age as well as environmental exposures alter epigenetic regulation. Errors in epigenetic processes, such as
parental imprinting can have serious effects on the offspring
both pre- and postnatally and into adulthood. This article will
discuss parental imprinting on the autosomal and X chromosomes and the alterations in epigenetic regulation that may
lead to such errors.
Key words: methylation/imprinting/X-chromosome
inactivation/schizophrenia
Advancing Paternal Age and Schizophrenia
Although a relationship between paternal age and schizophrenia has been investigated intermittently since the
1950s,1 only in the past decade has a clear link between
the 2 been established and sources of confounding ruled
out. In 2001, Malaspina et al2 showed that the incidence
of schizophrenia increased progressively with increasing
paternal age, the risk being 2-fold and 3-fold for offspring
of fathers aged 45–49 and 50 or more years, compared
1
To whom correspondence should be addressed;
tel: 212-263-6214, fax: 212-263-5717, e-mail: Dolores.
[email protected].
with those of fathers aged less than 25 years. That seminal
work was based on a study in a large prospective cohort.
Nine of 10 investigations, published in 8 articles3–10 as
well as a meta-analysis,11 have confirmed the original
finding. Together, these studies demonstrated that the
effect of paternal age on risk of schizophrenia was not
explained by a variety of factors such as family history,
maternal age, parental education and social ability, family social integration, social class, birth order, birth
weight, and birth complications. Other evidence points
to a role for paternal age in learning and cognition. Offspring of older rodents showed deficits in learning compared with those of younger fathers.12 In humans, the
incidence of autism was increased nearly 6-fold in offspring of fathers in their 40s and 50s compared with those
of fathers aged up to 30 years.13 IQ was reduced in the
offspring of older fathers, independently of effects of maternal age.14 In another study, paternal age greater than
40 years was associated with an increased likelihood that
the offspring would be placed in special education tracks
in school.15
A question arose as to whether effects of paternal age
on schizophrenia might be explained by psychiatric
problems that might delay childbearing in the parents
and be inherited by their offspring. For this to be true,
we would anticipate paternal age effects to be stronger
in familial cases than in sporadic ones. In studies that
examined whether the relation between paternal age
and schizophrenia was modified by family history,6–9
one actually observed the reverse effect7 while the others
did not observe any modification of the relation by family
history.6,8,9
The Effects of Advancing Paternal Age on Spermatogenesis
Spermatogonial stem cells are constantly dividing and
undergo hundreds of replications during the lifetime.16
Crow17 proposed that there is a higher frequency of point
mutations in males, the frequency of which increases with
age. In fact, paternal age has been associated with birth
defects in several studies.18–20 Other forms of mutation,
eg, altered copy number in repeat DNA, and chromosome breakage, also occur in the male germline and in
some cases have been related to male aging.21–23 Paternal
Ó The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: [email protected].
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Epigenetics, Paternal Age, and Schizophrenia
age may then be, in part, a marker for genetic alterations
that occur during spermatogenesis in older men underlying the association between paternal age and schizophrenia. In addition to genetic changes, aberrant epigenetic
regulation, the subject of this article, may also underlie
the association between advancing paternal age and
schizophrenia.
Aberrant Epigenetic Regulation
Epigenetic processes lead to heritable changes in gene expression through DNA methylation and demethylation
and changes in chromatin structure, rather than changes
in DNA sequence; methylation of genes silences them
preventing transcription while demethylation allows transcription. An epigenetic process of interest in schizophrenia and other neuropsychiatric disorders is parental
imprinting.
There are approximately 70 autosomal loci known to
be parentally imprinted, and others are suspected on the
sex chromosomes.24 Imprinted genes play a critical role
in growth of the placenta and fetus and central nervous
system.24–26 Genes are differentially marked during
gametogenesis after the methylation patterns of the
previous generation are ‘‘erased’’ and the new parent
of origin-specific methylation and additional changes
in chromatin are established.27,28 This differential marking silences or imprints the maternal or paternal allele.
Imprinted genes generally occur in large clusters29 containing both maternally and paternally imprinted genes.
A gene that is imprinted in some tissues may not be
imprinted in other tissues; in the brain, it is thought
that imprinting may even be cell specific and differ according to the stage of development.24
Errors associated with imprinting can occur during imprint erasure, establishment, and maintenance. Loss of
imprinting whereby the epigenetic mark is not established
or erased can result in partial or complete biallelic expression of a gene. For instance, loss of imprinting of
the insulin-like growth factor 2 (IGF2) gene has been
linked to both Beckwidth-Wiedeman syndrome30 and
colorectal neoplasia.31 In Angelman syndrome and
Prader-Willi syndrome (PWS) there are errors in imprinting the correct parental chromosome.32 This failure
to correctly imprint in some cases has been attributed to
a microdeletion in the imprinting center of 15q11–13,33
while in other cases, it has been attributed to a primary
epimutation which can occur during erasure, establishment, or maintenance of the imprint.32 Though both
these syndromes are associated with behavioral, cognitive, and neurologic impairment, in the case of PWS,
5%–10% of cases experience schizophrenia-like psychotic
symptoms.34 Interestingly, the chromosomal region involved in these syndromes lies adjacent to a region,
15q13–14, which has been linked to schizophrenia in
many but not all studies.35 Imprinting errors could in-
crease the risk of schizophrenia through multiple pathways including direct effects on the expression of genes
involved in neuropsychiatric pathology or indirectly
through imprinting errors in genes related to the normal
functioning of the placenta.
X-chromosome Inactivation
X-chromosome inactivation is a special form of epigenetic
silencing. Females receive the X chromosome of both
parents while males receive only the maternal X chromosome. To maintain dosage compensation in females, 1 X
chromosome is randomly silenced by a nontranslating
RNA called the X inactive–specific transcript36 and other
changes resulting in a 50:50 mosaic of cells with the paternal or maternal X chromosome inactivated. Deviations
from this norm are common37–39 and more than 15% of
genes on the inactivated X chromosome escape silencing.40
Parent of origin effects suggested the presence of imprinted
genes on the X chromosome in a study of the sporadic
disorder, Turner syndrome. Turner syndrome is characterized by complete or partial loss of the paternal or maternal
X chromosome. Skuse et al41 reported that females who
had only the paternal X chromosome had better verbal
skills and higher executive functioning than females who
had only the maternal X chromosome. In addition to providing support for the presence of imprinted genes on the X
chromosome, these results also supported the hypothesis
that imprinted genes reside on the X chromosome related
to cognition and behavior. Kesler et al42 found that there
were differences in brain morphology between Turner syndrome patients who inherit the paternal versus a maternal
X chromosome. Imprinted genes on the X chromosome
have been posited as one of several explanations for sex differences in neuropsychiatric disorders.43
Effects of Aging and Environmental Exposures on
Epigenetic Processes
Though epigenetic traits are generally stably inherited
through numerous cell divisions, over time, epigenetic
errors do occur in somatic cells. The frequency appears
to increase with age and thought to be more frequent
than mutations.44 In mice, epigenetic loss of repression
of a gene was reported in older mice compared with
younger mice.44 In humans, a study observed that young
monozygotic twins were virtually identical on measures of
5-methylcytosine DNA and histone acetylation, whereas
in older twins, the differences in these measures were often
fairly striking.45 These differences in older twins might
have occurred independently of or in concert with exogenous exposures.46 These findings suggest that epigenetic
regulation in the rapidly dividing spermatogonia cells
may also be disrupted as a consequence of aging or as
an accumulation of exogenous or endogenous exposures
over time. In fact, it was recently reported that there
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M. C. Perrin et al.
were changes in chromatin packaging and integrity in spermatozoal cells in older rats compared with younger rats,47
while investigators from China reported that older paternal age was associated with a loss of imprinting of IGF2,
a maternally imprinted gene, in cord blood.48
DNA Methyltransferases
There are a number of different DNA methyltransferases
(DNMTs) that differ in whether they initiate or sustain methylation and are more active at certain times in
development but less during others.49 In aging fibroblast
cell lines, there is a progressive loss of a maintenance
DNMT1 and an increase in one of the de novo DNMTs.50
It has been observed in mouse testis that DNMTs levels
peak postnatally and decrease to steady adult levels about
a month later51; it is possible that some DNMTs levels
could decrease and others could increase with aging. Altered levels of the DNMTs in older men could contribute
to the disruption of epigenetic processes affecting the erasure, establishment, and maintenance of paternal imprints
during spermatogenesis and after fertilization. Environmental exposures over the course of males’ lifetime may
also cause defective epigenetic regulation. Several environmental exposures, eg, arsenic and nickel are associated
with epigenetic changes,52,53 and exposure to these and
other toxins may affect spermatogenesis. One study reported that early embryos of male rats chronically exposed
to a chemotherapy drug, cyclophosphamide, had defects in
epigenetic programming.54
Conclusion
Advancing paternal age may be a marker of epigenetic
dysregulation leading to errors in imprinting and other
epigenetic processes, the consequence of which may be
a susceptibility to schizophrenia and other neuropsychiatric disorders in the offspring. Interest in the epigenetic
origins of neuropsychiatric disease has concomitantly increased with the mounting evidence of the importance of
paternal age as a risk factor in schizophrenia and other
disease outcomes. Currently, there are more questions
than answers, providing opportunities for translational
research across many disciplines.
Funding
National Institute of Mental Health (R01 MH59114 to
D.M., 2K24 MH01699 to D.M., 1R01 MH 63264 to
A.S.B., 1K02 MH 65422 to A.S.B., 1R01 MH 60249
to A.S.B., 1R01 MH 073080 to A.S.B.); National
Alliance for Research on Schizophrenia and Depression
(NARSAD) Independent Investigator Award (to
A.S.B.). National Cancer Institue (ROI CA 80197 for
MCP).
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