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Paternal age, de novo mutations and schizophrenia

Molecular Psychiatry volume 19, pages 274–275 (2014)Cite this article

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Advanced parental age at childbirth has been identified as a risk factor for a number of developmental disorders, including Down’s syndrome,1 Marfan’s syndrome,2 achondroplasia3 and even some cancers.4 There has been considerable recent interest in the potential role of parental age, particularly paternal age, as a risk factor for autism5 and for schizophrenia.6 While claims of an association of parental age and risk for schizophrenia have been made for over 50 years, the issue attracted serious attention after a report by Malaspina et al.6 in a sample of 638 Israeli patients with schizophrenia, which found that the age of their fathers at childbirth significantly increased the odds of their being ill, by upwards of 1.2-fold per decade of advancing age. A number of subsequent studies have provided additional evidence for this association, which in a recent meta-analysis has been found to represent an overall increase of risk of ∼1.3-fold, especially for fathers who are 55 years or older at childbirth.7 Maternal age tends not to be significantly associated with risk for schizophrenia.6 The popular interpretation of these data has been that de novo mutations, which are known to become more abundant in sperm of older men,2 are the mechanism. Indeed, a recent high-profile publication by Kong et al.8 demonstrated, in a sample of 78 families, a linear relationship between paternal age and the number of de novo mutations in offspring, with approximately two de novo mutations per year of advancing paternal age. Kong et al.8 interpret their data in the context of evidence that older fathers have increased risk of offspring with developmental disorders such as autism and schizophrenia, suggesting that they are causally linked.

There has been considerable front-page mass media attention to the possible conclusion that the two associations (that is, paternal age and risk for schizophrenia and paternal age and de novo mutations) are linked causally, including suggestions that younger males should consider sperm cryopreservation for later parenting (for example, NY Times, 22 August 2012). Despite the intuitive appeal of this causal link, it is conceivable that these two associations, though each valid, may be unrelated. In fact, they have not been linked in the same data, and the conclusion of a causal link is still premature. Indeed, other possibilities for the association with paternal age merit consideration. For example, a recent study of over 2.2 million people in Denmark replicated the paternal age effect on risk for schizophrenia, but suggested that de novo mutations could not account for it.9 These investigators found that the association was explained by the age of the father at the birth of his first child, not by the age at which the father had a child who developed schizophrenia. It is thus conceivable that some fathers have inherited traits that are linked both to higher risk for schizophrenia and to difficulty or slowness in becoming married, or perhaps to parenting. Moreover, there is evidence that very young paternal age also increases risk for schizophrenia, a finding that would not be explained by age-associated de novo mutations.7

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Acknowledgements

We thank Sally Cheung for her tireless help with assembling the birth-order data. This study was supported by the Lieber Institute for Brain Development and NIMH IRP funding of the Weinberger Lab.

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Authors and Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    A E Jaffe, R E Straub & D R Weinberger

  2. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    W W Eaton

  3. Clinical Brain Disorders Branch, IRP, NIMH, Bethesda, MD, USA

    S Marenco

  4. Departments of Psychiatry, Neurology, Neuroscience, the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    D R Weinberger

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  1. A E Jaffe
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Correspondence to D R Weinberger.

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The authors declare no conflict of interest.

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DRW and AEJ planned the study; DRW and SM collected the data; all authors contributed to the data analysis and writing of the manuscript.

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Jaffe, A., Eaton, W., Straub, R. et al. Paternal age, de novo mutations and schizophrenia. Mol Psychiatry 19, 274–275 (2014). https://doi.org/10.1038/mp.2013.76

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