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Advanced paternal age is associated with altered DNA methylation at brain-expressed imprinted loci in inbred mice: implications for neuropsychiatric disease

Molecular Psychiatry volume 18, pages 635–636 (2013)Cite this article

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Advanced paternal age is epidemiologically-linked to an increased risk of several human neuropsychiatric conditions including autism, schizophrenia and early-onset bipolar disorder (EOBD).1 Previously, we employed a rodent model to show that the offspring of older fathers have reduced exploratory and social behaviour compared with the offspring of young fathers.2 Behavioural differences have been also reported in other models of advanced paternal age, with a divergent range of phenotypes observed in the offspring of older fathers.3 The mechanism(s) behind the paternal age effect on behaviour and neuropsychiatric disease are not known. One hypothesis is that the effects of advanced paternal age are mediated by epigenetic changes accumulating over time in the male germ line that are subsequently transmitted to the offspring.4 Age-related DNA methylation changes have been widely reported,5 with individual sperm cells demonstrating significant intra- and inter-individual epigenetic variation as a function of increasing male age.6 Although the epigenome is largely reprogrammed during gametogenesis to enable the establishment of totipotency, certain regions of the genome appear to partially escape complete reprogramming, including highly methylated repetitive sequences and the differentially methylated regions (DMRs) associated with certain imprinted loci and highly-methylated repetitive sequences.7 Interestingly, a recent study has shown that DNA methylation in newborn babies is correlated with parental age at multiple loci, including several known imprinted genes.8

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Authors and Affiliations

  1. Institute of Psychiatry, King's College London, London, UK

    R G Smith, A Reichenberg, R L Kember, L C Schalkwyk, C Fernandes & J Mill

  2. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

    A Reichenberg & J D Buxbaum

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  1. R G Smith
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  2. A Reichenberg
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  3. R L Kember
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  4. J D Buxbaum
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  5. L C Schalkwyk
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  6. C Fernandes
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  7. J Mill
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Correspondence to J Mill.

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Smith, R., Reichenberg, A., Kember, R. et al. Advanced paternal age is associated with altered DNA methylation at brain-expressed imprinted loci in inbred mice: implications for neuropsychiatric disease. Mol Psychiatry 18, 635–636 (2013). https://doi.org/10.1038/mp.2012.88

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