Paternal age as a risk factor for schizophrenia: How important is it?

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Abstract

Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p = 0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55 years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48), 1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.

Introduction

For more than half a century, there have been claims that advanced maternal (Barry, 1945) and paternal (Johanson, 1958) ages are risk factors for the offspring to develop schizophrenia. In 1983 it was even said that “there are few areas of schizophrenia research where one finds such an impressive concordance of results from different studies as that of parental age” (Kinnell, 1983). Commonly proffered explanations for these claims have been germline mutations in older adults, schizophrenia-predisposing genetic traits in parents who conceive children late in life, and the psychological effects of having older parents, including parental death, on growing children.

In recent years, interest in paternal age as a risk factor has become more widespread following the publication by Malaspina et al. (2001) of paternal birth data for 638 individuals with schizophrenia in Israel. The authors estimated that each decade of paternal age increased the relative risk of schizophrenia by 1.40 in male offspring and 1.26 in female offspring. The authors concluded: “We found that a quarter (26.6%) of the cases could be attributed to paternal age” and favored genetic mutations as an explanation. In a follow-up study of 68 individuals with schizophrenia and schizophrenia spectrum disorders published by the same group, the authors claimed to have “demonstrated a significant, dose-dependent association between advancing paternal age and risk of schizophrenia and other schizophrenia spectrum disorders” (Brown et al., 2002). Since then, six additional studies of paternal age have been published as well as a meta-analysis, but the results have been inconsistent (Byrne et al., 2003, Dalman and Allebeck, 2002, El-Saadi et al., 2004, Sipos et al., 2004, Tsuchiya et al., 2005, Wohl and Gorwood, 2007, Zammit et al., 2003).

In view of its importance and because we had access to a unique birth cohort for examining this question, the authors conducted a new study to test the hypothesis that increased paternal age is associated with offspring psychosis and schizophrenia. We also reviewed all previously published studies on this topic and conducted a meta-analysis.

Section snippets

Method

The study sample was drawn from 25,025 surviving offspring at three sites (Boston, Providence, and Philadelphia) from the 1959 to 1966 Collaborative Perinatal Project. Data, including maternal and paternal age, were collected from pregnant women who, along with their offspring, were extensively studied for seven years.

As described elsewhere (Buka et al., 2008), individuals from this birth cohort who have developed schizophrenia and other psychoses were identified. This was done through linkage

Results

In the present study, there were a total of 168 cases of psychosis, including 88 cases with narrowly defined schizophrenia, available for analysis. The mean paternal age for the cases was 29.6 ± 7.8 years and for controls was 28.9 ± 6.8 years, a difference that was not significant (p = 0.28). Cases and controls were compared using three alternative definitions of advanced paternal age (35 years of age and older; 40 years of age and older; 45 years of age and older) for both all psychosis and for

Discussion

The results of the present study indicate that individuals with schizophrenia and related disorders have fathers who are slightly older than matched controls, but this difference did not achieve statistical significance. When this study is added to nine other studies and subjected to meta-analyses by age cohort, it becomes apparent that the increased paternal age for fathers of individuals with schizophrenia is most pronounced among fathers in the oldest age cohort of 55 and over. This finding

Role of funding source

All support for the study came from the Stanley Medical Research Institute (SMRI), a nonprofit research organization.

Contributors

Drs. Torrey, Buka, Cannon, and Yolken designed the study, helped analyze the data, and contributed to the manuscript. Drs. Goldstein, Seidman, Hadley, Rosso, and Bearden assisted in the collection of data.

Conflict of interest

The authors report no conflict of interest.

Acknowledgments

We thank Dr. John Bartko for his statistical assistance and Ms. Judy Miller for administrative support.

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