Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Schizophrenia Research (Impact Factor: 3.92). 08/2005; 76(2-3):337-42. DOI: 10.1016/j.schres.2005.03.004
Source: PubMed


Advanced paternal age at birth as a risk for schizophrenia in the adult offspring has been reported in previous studies exclusively conducted in Western countries and Israel. The question has arisen whether this finding could be replicated in countries with socially and culturally different attitudes toward marriage, including factors such as age at marriage. To address this question, we conducted a case-control study of a Japanese population.
The subjects were representative inpatients with a DSM-IV diagnosis of schizophrenia. Unrelated healthy volunteers were recruited as control subjects. This study was conducted as one of a series of the projects by use of "The Mother and Child Health Handbooks (MCHHs)," from which information on parental characteristics around the time of birth, including parental ages at birth, had been extracted and recorded on computer.
Ninety-nine subjects with schizophrenia and 381 healthy control subjects enrolled for the study. Advanced paternal, but not maternal, age was associated with an elevated risk for schizophrenia. Reproducibility of the association across different cultures is suggestive of a causal link.

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    • "In total, 17 cohort studies and 10 case-control studies investigated the association between increased paternal age and SCZ, ASD, MDD and/or BPD in the offspring (Brown et al., 2002; Byrne et al., 2003; Croen et al., 2007; Dalman and Allebeck, 2002; Durkin et al., 2008; Ekeus et al., 2006; Frans et al., 2008; Gillberg, 1982; Glasson et al., 2004; Grether et al., 2009; King et al., 2009; Lauritsen et al., 2005; Laursen et al., 2007; Lopez-Castroman et al., 2009; Malaspina et al., 2002; Malaspina et al., 2001; Menezes et al., 2010; Petersen et al., 2011; Rasmussen, 2006; Reichenberg et al., 2006; Sasanfar et al., 2010; Shelton et al., 2010; Sipos et al., 2004; Torrey et al., 2009; Tsuchiya et al., 2008; Tsuchiya et al., 2005; Zammit et al., 2003). Several studies with up to 13 297 patients (Miller et al., 2010) found that higher paternal age doubles or triples the risk for SCZ in the offspring of men above 40 years of age (Brown et al., 2002; Byrne et al., 2003; Dalman and Allebeck, 2002; Laursen et al., 2007; Malaspina et al., 2002; Malaspina et al., 2001; Rasmussen, 2006; Sipos et al., 2004; Torrey et al., 2009; Tsuchiya et al., 2005; Zammit et al., 2003). ASD was reported to be associated with both increased maternal and paternal age, with a recent emphasis for an increased paternal age (Croen et al., 2007; Durkin et al., 2008; Glasson et al., 2004; Grether et al., 2009; King et al., 2009; Lauritsen et al., 2005; Reichenberg et al., 2006; Sasanfar et al., 2010; Shelton et al., 2010; Tsuchiya et al., 2008). "
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    ABSTRACT: We measured the association between paternal age and schizophrenia (SCZ), autism spectrum disorders (ASD), major depressive disorder (MDD), and bipolar disorder (BPD) in the Dutch population. In total, 14231 patients and 56924 matched controls were collected and analyzed for an association with paternal age by logistic regression. ASD is significantly associated with increased paternal age: Older fathers >40 years of age have a 3.3 times increased odds of having a child with ASD compared to young fathers <20 years of age. SCZ has significant associations for fathers aged >35 years (OR=1.27, 95% Confidence Interval: 1.05 and 1.53). For MDD, both younger and older fathers have increased odds. No association was found for BPD. The effects of paternal age as a risk factor are different for ASD and SCZ on one hand, and the affective disorders on the other hand. Different types of association might indicate different biological or psychosocial mechanisms. Late paternity (associated with predispositions to psychiatric disorders) seems the most probable explanation for the association with paternal age.
    Full-text · Article · Jul 2011 · Schizophrenia Research
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    • "Advanced paternal age is associated with a broad range of disease outcomes in children, ranging from an increased risk for neural tube defects and cleft palate (McIntosh et al., 1995), intellectual impairments (Malaspina et al., 2005; Saha et al., 2009), epilepsy (Vestergaard et al., 2005), and bipolar disorder (Frans et al., 2008). The most robust and replicated studies in this field have demonstrated a link between APA and elevated risk for the neurodevelopmental disorders autism (for example, Reichenberg et al., 2006; Durkin et al., 2008; Tsuchiya et al., 2008; Lundstrom et al., 2010; Shelton et al., 2010) and schizophrenia (Malaspina et al., 2001; Brown et al., 2002; Dalman and Allebeck, 2002; Byrne et al., 2003; El-Saadi et al., 2004; Tsuchiya et al., 2005). One study assessed a cohort of 132,271 individuals and found that children of men aged 40 years or older had a nearly six-fold increased risk of ASD compared to the children of men aged 30 years or younger (Reichenberg et al., 2006). "
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    ABSTRACT: Offspring of older fathers have an increased risk of various adverse health outcomes, including autism and schizophrenia. With respect to biological mechanisms for this association, there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte. This leads to more opportunities for copy error mutations in germ cells from older fathers. Evidence also suggests that epigenetic patterning in the sperm from older men is altered. Rodent models provide an experimental platform to examine the association between paternal age and brain development. Several rodent models of advanced paternal age (APA) have been published with relevance to intermediate phenotypes related to autism. All four published APA models vary in key features creating a lack of consistency with respect to behavioral phenotypes. A consideration of common phenotypes that emerge from these APA-related mouse models may be informative in the exploration of the molecular and neurobiological correlates of APA.
    Full-text · Article · Jun 2011 · Frontiers in Behavioral Neuroscience
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    • "Advanced paternal age has been associated with the risk for schizophrenia in cohort studies in Israel (Malaspina et al., 2001; Brown et al., 2002), Denmark, (Byrne et al., 2003), Sweden (Zammit et al., 2003; Sipos et al., 2004), Japan (Tsuchiya et al., 2005), and the United States (Torrey et al., 2009). In the Israeli study, a quarter of the risk for schizophrenia was attributable to paternal age and the risk in offspring of fathers aged 50+ at birth was three-fold that of children whose fathers were younger than 25 at birth (Malaspina et al., 2001). "
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    ABSTRACT: Paternal age related schizophrenia (PARS) has been proposed as a subgroup of schizophrenia with distinct etiology, pathophysiology and symptoms. This study uses a k-means clustering analysis approach to generate hypotheses about differences between PARS and other cases of schizophrenia. We studied PARS (operationally defined as not having any family history of schizophrenia among first and second-degree relatives and fathers' age at birth ≥ 35 years) in a series of schizophrenia cases recruited from a research unit. Data were available on demographic variables, symptoms (Positive and Negative Syndrome Scale; PANSS), cognitive tests (Wechsler Adult Intelligence Scale-Revised; WAIS-R) and olfaction (University of Pennsylvania Smell Identification Test; UPSIT). We conducted a series of k-means clustering analyses to identify clusters of cases containing high concentrations of PARS. Two analyses generated clusters with high concentrations of PARS cases. The first analysis (N=136; PARS=34) revealed a cluster containing 83% PARS cases, in which the patients showed a significant discrepancy between verbal and performance intelligence. The mean paternal and maternal ages were 41 and 33, respectively. The second analysis (N=123; PARS=30) revealed a cluster containing 71% PARS cases, of which 93% were females; the mean age of onset of psychosis, at 17.2, was significantly early. These results strengthen the evidence that PARS cases differ from other patients with schizophrenia. Hypothesis-generating findings suggest that features of PARS may include a discrepancy between verbal and performance intelligence, and in females, an early age of onset. These findings provide a rationale for separating these phenotypes from others in future clinical, genetic and pathophysiologic studies of schizophrenia and in considering responses to treatment.
    Full-text · Article · Feb 2011 · Schizophrenia Research
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