Parental age, birth order and neurodevelopmental disorders.

Abstract

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.