Advanced paternal age is a risk factor for schizophrenia in Iranians

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.

Paternal germ line aging: DNA methylation age prediction from human sperm

“…One of the biggest questions that remains if such associations exist is the potential impact of this age acceleration. Such a pattern could potentially result in increased risk to offspring health, as epidemiological data clearly shows increased incidence of neuropsychiatric disease in the offspring of older fathers [10][11][12][13][14][15]. This increase in risk may not mean that the altered methylation pattern itself causes these offspring abnormalities, but instead the methylation signatures of age are simply a good indicator of the overall state or age of the sperm.…”

Reviewing the epigenetics of schizophrenia

“…Others investigated brain features such as cerebellar weight and pre-frontal cortex variations, levels of methylation in brain or blood tissues, associations between epigenetic processes and smoking, age, medication use and physical activity, studies of x-chromosome linkage, and paternal age and its association with schizophrenia diagnoses (e.g. DeLisi et al, 2000;Glatt et al, 2011;Melas et al, 2012;Naserbakht, Ahmadkhaniha, Mokri, & Smith, 2011). propensities to receive a schizophrenia diagnosis produced a mixed picture within which the few significant variations identified were attributed throughout to epigenetic processes, but without any direct test of these processes ever being conducted.…”

DNA methylation in schizophrenia: progress and challenges

“…It has been proposed that DNA methylation alterations in candidate genes mediate environmental risk factors, such as famine [46] and advanced paternal age [47] in the pathomechanism of SZ (schematic representation shown in Fig. 1).…”