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Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations

Abstract

The offspring of older fathers have higher risk of psychiatric disorders such as schizophrenia and autism. Paternal-age-related de novo mutations are widely assumed to be the underlying causal mechanism, and, although such mutations must logically make some contribution, there are alternative explanations (for example, elevated liability to psychiatric illness may delay fatherhood). We used population genetic models based on empirical observations of key parameters (for example, mutation rate, prevalence, and heritability) to assess the genetic relationship between paternal age and risk of psychiatric illness. These models suggest that age-related mutations are unlikely to explain much of the increased risk of psychiatric disorders in children of older fathers. Conversely, a model incorporating a weak correlation between age at first child and liability to psychiatric illness matched epidemiological observations. Our results suggest that genetic risk factors shared by older fathers and their offspring are a credible alternative explanation to de novo mutations for risk to children of older fathers.

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Figure 1: Model of independent major mutations with and without selfish selection.
Figure 2: Liability threshold model of major mutations.
Figure 3: Liability threshold model of major mutations on a polygenic background.
Figure 4: Correlation between disorder liability and age at first child.
Figure 5: Power to detect a correlation R between disorder liability and age at first child.

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Acknowledgements

This work was supported by Australian National Health and Medical Research Council (NHMRC) grants to N.R.W. and J.G. (1087889) and to J.G. and P.M.V. (1067795 and 1103418) and by Australian Research Council grant DP130100563 to M.E.G. N.R.W. is supported by an NHMRC Principal Research Fellowship (1078901), P.M.V. is supported by an NHMRC Senior Principal Research Fellowship (1078037), and J.J.M. is supported by grant 1056929 from the John Cade Fellowship from the NHMRC.

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P.M.V., N.R.W., and M.E.G. conceived the idea. J.G., N.R.W., W.J.P., P.M.V., and M.E.G. performed analyses. J.G., P.M.V., and N.R.W. drafted the manuscript, and J.J.M. provided critical feedback. All authors contributed to editing and approval of the final manuscript.

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Correspondence to Jacob Gratten.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Note. (PDF 9538 kb)

Supplementary Code

R scripts for models 1–5. (TXT 47 kb)

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Gratten, J., Wray, N., Peyrot, W. et al. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations. Nat Genet 48, 718–724 (2016). https://doi.org/10.1038/ng.3577

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