Abstract
BackgroundSince 1958 many, but not all studies have demonstrated that paternal age is a risk factor for schizophrenia. There may be many different explanations for differences between studies, including study design, sample size, collection criteria, heterogeneity and the confounding effects of environmental factors that can for example perturb epigenetic programming and lead to an increase in disease risk. The small number of children in Western families makes risk comparisons between siblings born at different paternal ages difficult. In contrast, more Eastern families have children both at early and later periods of life. In the present study, a cross-sectional population study in an Iranian population was performed to compare frequency of schizophrenia in younger offspring (that is, older paternal age) versus older offspring.MethodsA total of 220 patients with the diagnosis of schizophrenia (cases) from both psychiatric hospitals and private clinics and 220 individuals from other hospital wards (controls), matched for sex and age were recruited for this study. Patients with neurological problem, substance abuse, mental retardation and mood disorder were excluded from both groups.ResultsBirth rank comparisons revealed that 35% vs 24% of the cases vs the controls were in the third or upper birth rank (P = 0.01). Also, the mean age of fathers at birth in case group (30 ± 6.26 years) was significantly more than the control group (26.45 ± 5.64 years; P = 0.0001). The age of 76 fathers at birth in case group was over 32 versus 33 fathers in control group. Individuals whose fathers' age was more than 32 (at birth) were at higher risk (2.77 times) for schizophrenia versus others (P < 0.0001, 95% CI 1.80 to 4.27). The maternal age at parturition of the case versus controls groups was 26.1 ± 5.41 vs 25.07 ± 4.47 (P = 0.02). Logistic regression analysis suggests that maternal age is less likely to be involved in the higher risk of schizophrenia than advanced parental age.DiscussionThis study demonstrates a relationship between paternal age and schizophrenia in large families of an Iranian population. Arguments have been put forth that DNA bases changes or epigenetic changes in sperm account for the increased risk associated with older fathers. However, it would not be surprising that both de novo germline mutations and epigenetic changes contribute to disease occurrence because DNA replication and DNA methylation are closely linked at both the macromolecular level (that is, methylation closely follows replication), and at the metabolic level (both processes require folate), and susceptible to modulation by the environment. Further research on samples such as those collected here are needed to sort out the contributions of de novo mutations versus epigenetic changes to schizophrenia.
Highlights
Schizophrenia is a chronic and disabling disorder with an approximate 1% incidence in the population, and 120 million afflicted individuals worldwide [1]
The difference in the occurrence of psychiatric disorders, including schizophrenia, schizoaffective disorder and major mood disorders in first-degree relatives was significant in case versus control groups (P = 0.04): 20.5% versus 13.2%, respectively (Table 1)
Our results linking advanced paternal age to schizophrenia are comparable to observations in other populations
Summary
Schizophrenia is a chronic and disabling disorder with an approximate 1% incidence in the population, and 120 million afflicted individuals worldwide [1]. Paternal age has been linked to schizophrenia since 1958 [15]. Most studies including a recent metaanalysis have confirmed paternal age as a risk factor for schizophrenia [16,17,18,19,20,21,22,23,24], negative results exist in the literature [25]. The link between paternal age and schizophrenia, argues that de novo changes to DNA can lead to schizophrenia, because the sole biological contribution of fathers to progeny is DNA. Since 1958 many, but not all studies have demonstrated that paternal age is a risk factor for schizophrenia. The small number of children in Western families makes risk comparisons between siblings born at different paternal ages difficult. A cross-sectional population study in an Iranian population was performed to compare frequency of schizophrenia in younger offspring (that is, older paternal age) versus older offspring
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