We sought to investigate whether older paternal age at the time of birth is associated with schizophrenia and other schizophrenia spectrum disorders among the offspring. Several lines of evidence support a relation between older paternal age and schizophrenia spectrum disorders. First, most previous studies that examined this relationship have demonstrated positive associations (1
), although these studies have been criticized for methodologic limitations. Most recently, Malaspina et al. (1
), in a large Israeli birth cohort, demonstrated a robust and “dose-related” effect of paternal age on risk of schizophrenia and related disorders, a finding that was unaltered after adjusting for maternal age.
A second reason for examining paternal age in relation to schizophrenia is that older age of the father at the time of birth has been associated with several congenital disorders (6
). The etiology of these associations is believed to involve new, autosomal dominant mutations in the male germ cell line. If a disruption of fetal development plays a role in the pathogenesis of schizophrenia, then new mutations secondary to advanced paternal age may operate to increase the risk of this disorder by adversely affecting brain development.
In the present investigation, we used data from the birth cohort of the Prenatal Determinants of Schizophrenia study (11
) to address the relation of paternal age to schizophrenia. We hypothesized that the risk of schizophrenia would increase with advancing paternal age.
The Prenatal Determinants of Schizophrenia study had several design advantages that permitted us to address significant limitations of previous studies. First, most prior studies relied on exposure data from a variety of sources, some of questionable reliability. In contrast, the Prenatal Determinants of Schizophrenia study offered prospectively acquired data on paternal age from a direct interview, serving to diminish the likelihood of exposure misclassification. Second, most prior studies relied on case series to identify patients for study; the present investigation addressed this limitation by employing a cohort design that included continuous follow-up for ascertainment of cases of schizophrenia. These first two features help to minimize selection bias, as well as biases arising from the use of prevalent rather than incident cases of schizophrenia spectrum disorders. Third, previous investigations generally relied on chart diagnoses of schizophrenia spectrum disorders by older and less reliable diagnostic systems, or on hospital registry data; in our study, most cases were identified by means of face-to-face standardized research interviews and consensus procedures that used modern diagnostic criteria. Fourth, most prior studies did not control for maternal age, and nearly all failed to adjust for other confounders; the comprehensive data set of our study permitted us to control for these factors. Finally, unlike previous studies, our study assessed and confirmed biological paternity of the offspring in the majority of subjects.