Paternal age as a risk factor for schizophrenia: How important is it?
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.
References (38)
- et al.
Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring
Biol. Psychiatry
(2008) - et al.
Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia
Schizophr. Res.
(2004) - et al.
Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population
Schizophr. Res.
(2005) - et al.
Minor physical anomalies in schizophrenia: a meta-analysis
Schizophr. Res.
(2007) - et al.
Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database
Nat. Genet.
(2008) Incidence of advanced maternal age in mothers of one thousand state hospital patients
Arch. Neurol. Psychiatry
(1945)- et al.
Paternal age in schizophrenia in a case-controlled study (letter)
Br. J. Psychiatry
(1993) - et al.
Die Beziehung der Schizophrenia zum Alter der Eltern der Patienten [The relation of schizophrenia to the age of parents of the patient]
Nervenarzt
(1967) - et al.
Applied Mixed Models in Medicine
(1999) - et al.
Paternal age and risk of schizophrenia in adult offspring
Am. J. Psychiatry
(2002)
Parental age and risk of schizophrenia: a case-control study
Arch. Gen. Psychiatry
Schizophrenia and migration: a meta-analysis and review
Am. J. Psychiatry
Paternal age and schizophrenia: further support for an association
Am. J. Psychiatry
A systematic review and meta-analysis of northern hemisphere season of birth studies in schizophrenia
Schizophr. Bull.
Seasonality of birth in schizophrenia: an insufficient stratification of control population?
Soc. Psychiatry Psychiatr. Epidemiol.
Advancing paternal age and bipolar disorder
Arch. Gen. Psychiatry
Schizophrenia and complications of pregnancy and labor: an individual patient data meta-analysis
Schizophr. Bull.
Parental age in child psychiatric clinic attenders
Acta Psychiatr. Scand.
Parental age and schizophrenia
Br. J. Psychiatry
Cited by (72)
Did the human genome project affect research on Schizophrenia?
2024, Psychiatry ResearchModelling the effects of the exposome score within the extended psychosis phenotype
2024, Journal of Psychiatric ResearchThe risky business of advanced paternal age: neurodevelopmental and psychosocial implications for children of older fathers
2022, Fertility and SterilityCitation Excerpt :Meta-analyses have also found a significant increased risk of schizophrenia in the offspring of older fathers. A 2009 meta-analysis noted a 2.22 (95% CI: 1.46–3.37) relative risk of schizophrenia for offspring of fathers ≥55 years as compared with the reference group of fathers aged 25–35 years (12). More recently, a 2018 meta-analysis found relative risk of 2.04 (95% CI, 1.26–1.56) for schizophrenia in the male and female offspring of fathers aged >50 years (13).
White matter development in infants at risk for schizophrenia
2019, Schizophrenia ResearchCitation Excerpt :However, it is also quite possible that controlling for maternal education removes true associations between risk status and diffusion properties as cognitive impairment and less educational attainment is a common feature of schizophrenia. Higher paternal age is associated with increased risk of schizophrenia in the offspring (Wohl and Gorwood, 2007; Torrey et al., 2009; Miller et al., 2011), perhaps due to an increase in the rate of de novo genetic mutation in older fathers. In our study, paternal age did not appear to impact the results.