Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Analysis
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Frans, E.M. et al. Autism risk across generations: a population-based study of advancing grandpaternal and paternal age. JAMA Psychiatry 70, 516–521 (2013).

    Article  Google Scholar 

  2. Hultman, C.M., Sandin, S., Levine, S.Z., Lichtenstein, P. & Reichenberg, A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol. Psychiatry 16, 1203–1212 (2011).

    Article  CAS  Google Scholar 

  3. Malaspina, D. et al. Advancing paternal age and the risk of schizophrenia. Arch. Gen. Psychiatry 58, 361–367 (2001).

    Article  CAS  Google Scholar 

  4. Pedersen, C.B., McGrath, J., Mortensen, P.B. & Petersen, L. The importance of father's age to schizophrenia risk. Mol. Psychiatry 19, 530–531 (2014).

    Article  CAS  Google Scholar 

  5. Petersen, L., Mortensen, P.B. & Pedersen, C.B. Paternal age at birth of first child and risk of schizophrenia. Am. J. Psychiatry 168, 82–88 (2011).

    Article  Google Scholar 

  6. McGrath, J.J. et al. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry 71, 301–309 (2014).

    Article  Google Scholar 

  7. Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  Google Scholar 

  8. Malaspina, D. et al. Schizophrenia risk and paternal age: a potential role for de novo mutations in schizophrenia vulnerability genes. CNS Spectr. 7, 26–29 (2002).

    Article  Google Scholar 

  9. Weinberg, W. Zur Vererbung des Zwergwuchses. Arch. Rass. Gesamte Biol. 9, 710–718 (1912).

    Google Scholar 

  10. Crow, J.F. The high spontaneous mutation rate: is it a health risk? Proc. Natl. Acad. Sci. USA 94, 8380–8386 (1997).

    Article  CAS  Google Scholar 

  11. Haldane, J.B.S. The mutation rate of the gene for haemophilia, and its segregation ratios in males and females. Ann. Eugen. 13, 262–271 (1947).

    Article  CAS  Google Scholar 

  12. Vogel, F. & Rathenberg, R. Spontaneous mutation in man. Adv. Hum. Genet. 5, 223–318 (1975).

    Article  CAS  Google Scholar 

  13. Crow, J.F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).

    Article  CAS  Google Scholar 

  14. Michaelson, J.J. et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431–1442 (2012).

    Article  CAS  Google Scholar 

  15. Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).

    Article  CAS  Google Scholar 

  16. Neale, B.M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

    Article  CAS  Google Scholar 

  17. O'Roak, B.J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).

    Article  CAS  Google Scholar 

  18. Sanders, S.J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).

    Article  CAS  Google Scholar 

  19. MacArthur, J.A. et al. The rate of nonallelic homologous recombination in males is highly variable, correlated between monozygotic twins and independent of age. PLoS Genet. 10, e1004195 (2014).

    Article  Google Scholar 

  20. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).

    Article  CAS  Google Scholar 

  21. Miller, B. et al. Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr. Bull. 37, 1039–1047 (2011).

    Article  Google Scholar 

  22. Mehta, D. et al. Evidence for genetic overlap between schizophrenia and age at first birth in women. JAMA Psychiatry 73, 497–505 (2016).

    Article  Google Scholar 

  23. Day, F.R. et al. Physical and neurobehavioral determinants of reproductive onset and success. Nat. Genet. http://dx.doi.org/10.1038/ng.3551 (2016).

  24. Goriely, A., McGrath, J.J., Hultman, C.M., Wilkie, A.O. & Malaspina, D. “Selfish spermatogonial selection”: a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. Am. J. Psychiatry 170, 599–608 (2013).

    Article  Google Scholar 

  25. Power, R.A. et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry 70, 22–30 (2013).

    Article  Google Scholar 

  26. Uher, R. The role of genetic variation in the causation of mental illness: an evolution-informed framework. Mol. Psychiatry 14, 1072–1082 (2009).

    Article  CAS  Google Scholar 

  27. Sullivan, P.F., Kendler, K.S. & Neale, M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003).

    Article  Google Scholar 

  28. Lichtenstein, P., Carlström, E., Råstam, M., Gillberg, C. & Anckarsäter, H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am. J. Psychiatry 167, 1357–1363 (2010).

    Article  Google Scholar 

  29. Ronald, A. & Hoekstra, R.A. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 156B, 255–274 (2011).

    Article  Google Scholar 

  30. Gratten, J., Visscher, P.M., Mowry, B.J. & Wray, N.R. Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease. Nat. Genet. 45, 234–238 (2013).

    Article  CAS  Google Scholar 

  31. Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881–885 (2014).

    Article  CAS  Google Scholar 

  32. Goriely, A. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat. Genet. 41, 1247–1252 (2009).

    Article  CAS  Google Scholar 

  33. Moloney, D.M. et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat. Genet. 13, 48–53 (1996).

    Article  CAS  Google Scholar 

  34. Rahbari, R. et al. Timing, rates and spectra of human germline mutation. Nat. Genet. 48, 126–133 (2016).

    Article  CAS  Google Scholar 

  35. Sanders, S.J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015).

    Article  CAS  Google Scholar 

  36. Lauritsen, M.B., Pedersen, C.B. & Mortensen, P.B. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychol. Psychiatry 46, 963–971 (2005).

    Article  Google Scholar 

  37. Lichtenstein, P. et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239 (2009).

    Article  CAS  Google Scholar 

  38. Leitsalu, L. et al. Cohort profile: Estonian Biobank of the Estonian Genome Center, University of Tartu. Int. J. Epidemiol. 44, 1137–1147 (2015).

    Article  Google Scholar 

  39. Power, R.A. et al. Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat. Neurosci. 18, 953–955 (2015).

    Article  CAS  Google Scholar 

  40. Klei, L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3, 9 (2012).

    Article  Google Scholar 

  41. Lee, S.H. et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet. 44, 247–250 (2012).

    Article  CAS  Google Scholar 

  42. Wood, A.R. et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

    Article  CAS  Google Scholar 

  43. Collins, F.S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).

    Article  CAS  Google Scholar 

  44. International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

  45. Levinson, D.F. et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am. J. Psychiatry 168, 302–316 (2011).

    Article  Google Scholar 

  46. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    Article  CAS  Google Scholar 

  47. Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).

    Article  CAS  Google Scholar 

  48. Sandin, S. et al. The familial risk of autism. J. Am. Med. Assoc. 311, 1770–1777 (2014).

    Article  CAS  Google Scholar 

  49. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  50. Keightley, P.D. Rates and fitness consequences of new mutations in humans. Genetics 190, 295–304 (2012).

    Article  Google Scholar 

  51. Grether, J.K., Anderson, M.C., Croen, L.A., Smith, D. & Windham, G.C. Risk of autism and increasing maternal and paternal age in a large North American population. Am. J. Epidemiol. 170, 1118–1126 (2009).

    Article  Google Scholar 

  52. Falconer, D.S. The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann. Hum. Genet. 29, 51–71 (1965).

    Article  Google Scholar 

  53. Reich, T., James, J.W. & Morris, C.A. The use of multiple thresholds in determining the mode of transmission of semi-continuous traits. Ann. Hum. Genet. 36, 163–184 (1972).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Jacob Gratten.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3577

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing