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Parental age, birth order and neurodevelopmental disorders

Molecular Psychiatry volume 21, pages 728–730 (2016)Cite this article

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Advanced paternal age is a well-established risk factor for the development of schizophrenia (SZ),1, 2, 3 and an increased rate of de novo mutations with increasing paternal age has been proposed as the chief explanation for this association.4 However, the paternal age effect could also be as a result of other potential explanations. For example, analyses of Danish registry data revealed that the paternal age effect was attributable to paternal age at birth of the first child in the sibship, rather than to age at birth of the child with SZ,5 which suggests that some explanation other than de novo mutations may explain the reported paternal age association with SZ. Furthermore, advanced maternal age, that has also been implicated in the risk of neurodevelopmental disorders (NDDs) via unknown mechanisms (that is, not de novo mutation), should also be incorporated in this conceptualization.6, 7 Therefore, findings regarding de novo mutations as the explanation for the association between advanced paternal age and SZ are inconclusive because covariates, such as maternal age8 and family size,9 which may index other potential mechanisms than paternally derived de novo mutations, have not been simultaneously considered in most prior analyses.

Studies of birth order effects in SZ in both population-based samples10, 11 and clinical samples12, 13 have yielded conflicting findings. Nevertheless, Jaffe et al.14 consider affected proband birth order as a proxy for de novo mutations. Their analyses did not support an association between paternal age and birth order as an index of de novo mutations in a SZ data set after controlling for maternal age and family size. In order to determine if this was a robust finding, we attempted to replicate this work in our local SZ data using similar methods to those described by Jaffe et al.14 Furthermore, because both advanced paternal age and increased de novo mutations have also been reported among cases of autism spectrum disorder (ASD)15 and other NDDs,2 we examined whether the paternal age/proband birth order association is specific to SZ or is more broadly related to NDDs by extending the analyses to an ASD sample.

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Acknowledgements

The authors are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman), and appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org. The authors acknowledge funding from the Wellcome Trust (UK), Science Foundation Ireland, the National Institute of Mental Health (USA) and the Meath Foundation (Ireland).

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Authors and Affiliations

  1. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    A K Merikangas

  2. Department of Psychiatry & Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland

    A K Merikangas, E Kelleher, D Hogan, C Delaney, M Gill, L Gallagher, A P Corvin & E A Heron

  3. Centre for Support and Training in Analysis and Research, University College Dublin, Dublin, Ireland

    R Segurado

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Merikangas, A., Segurado, R., Kelleher, E. et al. Parental age, birth order and neurodevelopmental disorders. Mol Psychiatry 21, 728–730 (2016). https://doi.org/10.1038/mp.2015.127

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