Paternal Factors and Schizophrenia Risk: De Novo Mutations and Imprinting

This article has reviewed data that support an association
between schizophrenia risk and advancing paternal age.
As such, schizophrenia may be one of a number of neurodevelopmental
disorders caused by de novo mutations
in the male germ line. This mutation mechanism may contribute
a significant proportion of schizophrenia risk
within a population in proportion to the demographics of
paternal childbearing age. Furthermore, this risk may
have implications for public health and for the primary
prevention of schizophrenia.






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Schizophrenia Bulletin 2001 27(3):379-393;
© 2001 by Oxford University Press and the Maryland Psychiatric Research Center (MPRC)
This Article




© Oxford University Press


Paternal Factors and Schizophrenia Risk: De Novo Mutations and Imprinting
Dolores Malaspina, M.D., M.S.P.H., Associate Professor
Clinical Psychiatry at Columbia University Department of Psychiatry/New York State Psychiatric Institute, New York New York

Send reprint requests to Dr. D. Malaspina, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032; e-mail: dm9@Columbia.edu

There is a strong genetic component for schizophrenia risk, but it is unclear how the illness is maintained in the population given the significantly reduced fertility of those with the disorder. One possibility is that new mutations occur in schizophrenia vulnerability genes. If so, then those with schizophrenia may have older fathers, because advancing paternal age is the major source of new mutations in humans. This review describes several neurodevelopmental disorders that have been associated with de novo mutations in the paternal germ line and reviews data linking increased schizophrenia risk with older fathers. Several genetic mechanisms that could explain this association are proposed, including paternal germ line mutations, trinucleotide repeat expansions, and alterations in genetic imprinting in one or several genes involved in neurodevelopment. Animal models may be useful in exploring these and other explanations for the paternal age effect and they may provide a novel approach for gene identification. Finally, it is proposed that environmental exposures of the father, as well as those of the mother and developing fetus, may be relevant to the etiology of schizophrenia.

From the body of the paper:
Mutations May Occur in Any One of a Number of
Genes Involved in Neurodevelopment. Thousands of
genes are estimated to play a role in neurodevelopment;
therefore, it is possible that mutations in many genes
could cause schizophrenia as a final common phenotype.
Mutations arising in the male germ line would be
amplified in clones of spermatozoa over the repeated
cell divisions that occur with paternal aging. Although a
full discussion of the agents that augment mutations in
spermatogenesis is beyond the scope of this article, it is
worth mentioning that they are, by and large, the same
ones that induce mutations in somatic cells, including
DNA repair enzyme insufficiency, free radicals, oxidative
damage, radiation, nutritional deficiency,
chemotherapy, and high temperature (Cummins et al.
1994; Robbins 1996; see Cohen 1986). Cigarette smoking
has also been linked to genetic damage in spermatozoa,
and free radical-induced mutations are theorized to
be a common cause of male infertility; both of these
exposures have been implicated in the etiology of childhood
cancer (Aitken 1999; Shen and Ong 2000; Zenzes
2000).
Despite the high fidelity of DNA replication, a
small number of new mutations are generated at every
cell division and are fixed by repair enzymes. The
amount of new mutations tolerated by an organism is a
trade-off between the cellular energy expenditures by
DNA proofreading and repair and the loss of offspring
viability from mutations. Because most mutations
decrease fitness, evolution will sustain genomes with
efficient DNA repair enzymes. However, there has
likely been little evolutionary pressure to maintain high
DNA replication accuracy in older men (Drake et al.
1998). Of note, the offspring of very young fathers also
have an elevated risk for de novo genetic disorders,
which may result from the immaturity of spermatids or
from low activity of DNA repair or antioxidant
enzymes. This leads to a "U-shaped curve" for paternal
age and the offspring's risk for several genetic conditions,
including type 1 diabetes mellitus (Tai et al.
1998), cardiac ventricular and atrial septal deficits
(Olshan et al. 1994), and neural tube defects (Mclntosh