The Origins of Schizophrenia

An increasing risk of schizophrenia with advancing paternal age has been demonstrated through epidemiologic studies during the past decade. Before 2001, the results of research studying paternal age and schizophrenia were inconsistent with regard to risk of schizophrenia and advancing paternal age (Granville-Grossman, 1966; Hare & Moran, 1979; Kinnell, 1983; Malama et al., 1988; Bertranpetit & Fananas, 1993). However, in a large prospective cohort study in Jerusalem, Malaspina et al. (2001) reported that the risk of schizophrenia doubled with each 10-year increment of paternal age. Other studies confirmed that older paternal age is a risk factor for schizophrenia (Brown et al., 2002; Dalman & Allebeck, 2002; Byrne et al., 2003; Zammit et al., 2003; El-Saadi et al., 2004; Sipos et al., 2004; Tsuchiya et al., 2005), although two others did not find an association (El-Saadi et al., 2004; Pulver et al., 2004). Collectively, these studies strengthened the evidence that paternal age at birth is an important risk factor for schizophrenia. In this chapter we will outline (1) the epidemiologic evidence supporting the relationship between advanced paternal age and schizophrenia; (2) animal and human models pointing to a role for paternal age in learning and cognition; and (3) genetic and epigenetic mechanisms that may underlie the relationship between advanced paternal age and schizophrenia.

The maintenance of schizophrenia in the population despite the reduced fecundity of affected individuals has been one of the enigmatic features of the disease. One possible explanation could be the replenishment of disease genes through new mutations. Paternal age is reported to be the major source of de novo mutations in humans and other mammals, likely due to the constant cell replication cycles that occur in spermatogenesis. Following puberty, spermatogonia undergo some 23 divisions per year. At ages 20 and 40, a man’s germ cell precursors will have undergone about 200 and 660 such divisions, respectively. During a man’s life, the spermatogonia are vulnerable to DNA damage, and mutations may accumulate in clones of spermatogonia as men age (Crow, 1999). We hypothesize, therefore, that advanced paternal age might increase the risk of schizophrenia in the offspring through de novo genetic changes.

The Jerusalem Perinatal Study (JPS) is a population-based cohort that contains information on all 92,408 individuals born in West Jerusalem between 1964 and 1976. Information on maternal conditions, obstetric complications and interventions during labor and delivery, parental ages, immigration status, ethnicity, and occupation was recorded at birth. Postpartum and antepartum interviews of the mothers occurred from 1965 to 1968 and 1974 to 1976, respectively. Staff from the Israeli Ministry of the Interior linked the JPS data to the Israeli Psychiatric Case Registry in order to identify subjects with psychiatric diagnoses and maintain full confidentiality. In 2001, Malaspina and colleagues reported a monotonic increase in the risk of schizophrenia as paternal age increased (Malaspina et al., 2001).

Malaspina’s finding was replicated in numerous studies in the United States (Malaspina et al., 2001; Brown et al., 2002), Europe (Dalman & Allebeck, 2002; Byrne et al., 2003; Zammit et al., 2003; El-Saadi et al., 2004; Sipos et al., 2004), Australia (El-Saadi et al., 2004), and Japan (Tsuchiya et al., 2005). Many studies used a cohort design (Malaspina et al., 2001; Brown et al., 2002; Zammit et al., 2003; El-Saadi et al., 2004; Sipos et al., 2004), but others employed a case-control design in a large population data set (Dalman & Allebeck, 2002; Byrne et al., 2003; El-Saadi et al., 2004; Pulver et al., 2004; Tsuchiya et al., 2005; St Clair, 2009). Details of these studies are provided in tables 5.1 and 5.2.

Collectively, the studies showed a tripling of risk for schizophrenia in the offspring of the oldest group of fathers, in comparison with the risk from younger fathers. Furthermore, the research demonstrated that the paternal age effect is not explained by other factors, including family history of psychosis, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, or birth complications.

Several approaches have been employed to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, animal models were used to examine whether paternal age is related to specific outcomes that are relevant to schizophrenia. A translational approach using an animal model offers the opportunity to identify candidate genes, epigenetic mechanisms, or both that may explain the association of cognitive functioning with advancing paternal age. Second, epidemiologic studies have examined whether advanced paternal age is related to specific cognitive or social deficits in offspring.

Auroux was the first scientist to report that paternal age could negatively affect the learning capacity of Wistar rats sired by aged males (Auroux, 1983). Between 10 and 13 weeks of age, rat offspring were evaluated for learning capacity with an avoidance conditioning test. The results demonstrated that offspring of aged fathers had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies.

In the laboratory of Jay Gingrich, this effect was replicated in inbred mice: the behavioral performance of progeny of 18- to 24-month-old sires was inferior to the performance of progeny of 4-month-old sires (Bradley-Moore et al., 2002). This study demonstrated significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires. Other investigations showed that offspring of 10-month-old sires had significantly fewer social and exploratory behaviors than offspring of two-month-old sires (Smith et al., 2009) and that aged rats sired offspring with a reduced capacity for passive-avoidance learning (Garcia-Palomares et al., 2009). Male progeny of older rats are also reported to have alterations in cortical growth, which are perhaps relevant to the behavioral findings (Foldi et al., 2010). These studies strongly indicate that advancing paternal age is related to cognitive, social, and anatomic changes in offspring.

A relationship between cognitive function and later paternal age in humans was explored by Auroux and colleagues, following their discovery of paternal age effects in rodents. The authors demonstrated a “U shaped” relationship between paternal age and cognition in a study of 1,700 male military recruits in Nancy, France, in 1985, wherein sons of very young fathers and of much older fathers did less well on psychometric tests without significant maternal age effects (Auroux et al., 1989).

Another study showed that higher paternal age (35 years or older) was associated with decreased reading ability in girls, although not in boys (St Sauver et al., 2001). A study that included more than 44,000 of the offspring from the JPS population-based cohort showed that maternal and paternal age exerted independent effects on intelligence in late adolescence (Malaspina et al., 2005). These results were adjusted for parental education, social class, sex, birth order, birth weight, and birth complications. They showed reductions in performance intelligence only for the offspring of the oldest fathers, whereas later maternal age comparably lowered verbal and nonverbal intelligence.

An effect of later paternal age on cognition in children was demonstrated in a sample of 33,437 offspring from the U.S. Collaborative Perinatal Project (CPP). In models that adjusted for potential confounders (including maternal age), they reported that children of older fathers were more likely to be cognitively impaired. Later paternal age was associated with worse performance in five out of six cognitive measures, whereas later maternal age was linked with better performance on intelligence tests (Saha et al., 2009).

The pathophysiology linking paternal age to intelligence is yet to be elucidated. Numerous genes participate in determining intelligence, and any of these might undergo mutations. As described here, paternal age is the most robust factor in determining the human spontaneous mutation rate (Crow, 1993). Both schizophrenia and autism entail reduced learning ability, so these findings may be relevant to the mechanism linking later paternal age to these conditions (Reichenberg et al., 2006; Corbett et al., 2009; Koenen et al., 2009; Mesholam-Gately et al., 2009).

This work is still nascent, and many explanations remain to be proposed and tested to explain the linkage of paternal age to intelligence and learning. For example, cigarette smoking can damage DNA in germ cells (Zenzes, 2000), and there may be higher rates of smoking in older cohorts. As detailed later in this chapter, changes may occur in the epigenetic processes in sperm cells with male aging. Epigenetic mechanisms are heritable regulators of gene expression that are independent of DNA sequence (Oakes et al., 2003) (see chapter 9 in this book). Socioeconomic status is also related to cognition in offspring (Turkheimer et al., 2003; Lawlor et al., 2006). In the study of paternal age and cognition in the CPP that was mentioned here, adjustment for socioeconomic status reduced the difference in intelligence scores for offspring of older and younger fathers, although it did not account for the paternal age effect (Saha et al., 2009). Additional large studies are needed to elucidate better the relationship between advanced paternal age and cognition. As childbearing is increasingly delayed, this association, if confirmed, could have important public health implications.

A persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents—problems that both delay childbearing and are heritable by their offspring. If so, then advanced paternal age would be more common among familial cases than sporadic cases; however, this is not so (Sipos et al., 2004). It is also possible that de novo genetic events in the paternal germ line are affecting the same genes that influence the risk in familial cases. Available evidence suggests this is not the case. The few genetic studies that examined familial and sporadic cases separately found that the “at-risk haplotypes” linked to familial schizophrenia were not associated with sporadic cases, including dystrobrevin-binding protein (Van Den Bogaert et al., 2003) and neuregulin (Williams et al., 2003). Segregating sporadic cases from the analyses actually strengthened the magnitude of the genetic association in the familial cases, consistent with etiologic heterogeneity between familial and sporadic groups. Furthermore, sporadic cases have more de novo copy number variants (CNVs) than do familial cases in which CNVs are more likely to be inherited (Xu et al., 2008.).

Individuals with schizophrenia who have no family history of psychosis may have different phenotypes than familial cases. For example, only sporadic subjects showed a significant improvement in negative symptoms after changing from a “medication-free” condition to one where they received antipsychotic treatment (Malaspina et al., 2000). Sporadic subjects also have significantly more disruptions in their smooth pursuit eye movement quality (Malaspina et al., 1998) and have distinct intelligence test profiles (Wolitzky et al., 2006). The sporadic group of subjects had greater hypofrontality, with increased medial temporal lobe activity (frontotemporal imbalance), whereas the familial group had left lateralized temporoparietal hypoperfusion along with widespread regional cerebral blood flow (rCBF) changes in cortico-striato-thalamo-cortical regions (Malaspina et al., 2004). These findings support the hypothesis that familial and sporadic cases of schizophrenia may have distinct neural underpinnings.

Several genetic mechanisms might explain the relationship between paternal age and the risk for schizophrenia. Spermatagonial stem cells divide constantly, undergoing hundreds of replications throughout a lifetime. Males have a higher frequency of point mutations, and the frequency increases with age and higher rates of de novo genetic disorders and birth defects in offspring (Crow, 1999).There are other possible explanations for the paternal age effects, as described in the sections that follow.

Approximately 20% of birth defects are attributed to new mutations (Nelson & Holmes, 1989; Crow, 1997). Single base pair changes are the most frequently occurring mutations in paternal gametes. These may be random events or they may occur in certain “hot spots.” Achondroplastic dwarfism is an example of a “hot spot” mutation (Wilkin et al., 1998), wherein 90% of cases have a de novo mutation at the same single codon, leading to a missense mutation in the fibroblast growth factor 3 gene (Orioli et al., 1995; Yu et al., 2000).

Trinucleotide repeat disorders are caused by multiple insertions of three specific nucleotides in certain genes. An example is the (CAG)_n repeat in the androgen receptor gene. Multiple insertions of a repeat sequence in genes may lead to repeat sizes that are above the normal threshold. These larger-than-normal repeat lengths may often result in a defective protein or no protein. These disorders are characterized by an autosomal dominant mode of inheritance, a progressive course, and anticipation—i.e., an earlier age of onset and an increasing severity of disease from one generation to the next. Anticipation has been reported in several neuropsychiatric disorders including myotonic dystrophy, spinocerebellar ataxias, and Huntington’s disease. For a detailed review of trinucleotide repeat disorders, see Orr and Zoghbi (2007).

The sex of the transmitting parent may influence anticipation (Telenius et al., 1993); many disorders show greater trinucleotide repeat expansion with paternal inheritance than with maternal inheritance (Duyao et al., 1993; Lindblad & Schalling, 1999; Schols et al., 2004). Consistent with anticipation, onset of schizophrenia may occur earlier in successive generations of multiply affected pedigrees (Gorwood et al., 1995; Petronis et al., 1995; Heiden et al., 1999).

It is not known if anticipation in schizophrenia is more likely for paternal or maternal transmission of the trinucleotide repeats, and the results of studies have been mixed (Gorwood et al., 1997; Johnson et al., 1997; Husted, Scutt, & Bassett, 1998; Imamura et al., 1998). Not all studies find longer trinucleotide repeats in family members with schizophrenia who have an earlier onset than the preceding generation (Morris et al., 1995; O’Donovan et al., 1996; O’Donovan & Owen, 1999; Bowen et al., 2000; Vincent et al., 2000).

Over the last decade there has been an upsurge of interest in the possible role of CNVs in certain genes or regions of the genome in the etiology of schizophrenia, autism, mental retardation, and other neuropsychiatric disorders (St Clair, 2009). Copy number variation refers to a segment of DNA that can be from 1 kilobase to 1 or more megabases (Cook & Scherer, 2008) and that can include one or more genes, copy duplications, copy deletions, or multiallelic or complex rearrangements. A significant number of CNVs are over 50 kilobases in size and are recurrent. They have an increased mutation rate and are located in unstable parts of the genome. CNVs are discussed in more detail in chapter 8.

A difference between the rare inherited variants within some familial cases and de novo variants in sporadic cases of schizophrenia may be related to paternal age, given that the genetic variation is introduced through the paternal line.

Epigenetic phenomena are defined as heritable changes in the genome that are unrelated to the DNA sequence (Feinberg, 2004). Epigenetic mechanisms regulate the expression of genes and include methylation, acetylation, alterations in chromatin structure, and RNAi. Epigenetic changes occur in somatic cells with aging more frequently than mutations do (Bennett-Baker, Wilkowski, & Burke, 2003; Fraga et al., 2005). Epigenetics is described in detail in chapter 9.

A number of genes are imprinted in that they are only expressed from the paternal or maternal allele. Imprinting errors could increase with advancing paternal age through a number of pathways, including environmental exposures. In a recent study, it was reported that paternal occupation as a dry cleaner significantly increased the risk of schizophrenia in the offspring, an effect possibly due to chronic exposure to perchlorethylene, a common dry-cleaning solvent (Perrin et al., 2007).

The association between advancing paternal age and schizophrenia among women may result at least in part from imprinting errors in the paternal X-chromosome of older fathers. X-chromosome inactivation is typically a random process in which 50% of cells have a paternal X-chromosome activated and maternal X-chromosome inactivated and 50% of cells have the maternal X-chromosome activated and the paternal X-chromosome inactivated, resulting in dosage compensation between males and females. A significant number of females have skewed X-chromosome inactivation—i.e., deviating from the 50:50 ratio just described. In females, only one allele is expressed on the X-chromosome and, in combination with skewed X-inactivation, results in a functional loss of heterozygosity (LOH) (Buller et al., 1999). This functional LOH may render women more susceptible to cognitive and neuropsychiatric disorders.

The hypothesis that imprinting errors on the X-chromosome may explain some of the risk in women associated with paternal age is supported by studies in women with Turner’s syndrome (45, X). It has been reported in some but not all studies that among women with Turner’s syndrome there are differences between those women whose X-chromosome has been transmitted through the maternal line (X_M) and those whose X-chromosome has been transmitted through the paternal line (X_P). Some studies have noted differences in social skills and executive function and arithmetic ability between 45, X_P and 45, X_M women (Skuse et al., 1997; Chong et al., 2000). Others have noted that there is strong correlation with cardiovascular disease in X_M women but not X_P women (Chu et al., 1994). Another more recent study reported that X_M and X_P women differed in superior temporal gyrus gray matter but not in white matter (Kesler et al., 2003). On the basis of these and other studies, imprinted genes are expected to be identified on the X-chromosome. Imprinting errors associated with advanced paternal age, coupled with skewed X-chromosome inactivation, could result in partial or complete loss of protein from a paternally expressed allele, increasing the risk of schizophrenia in females.

Among all the epidemiologic evidence examining paternal age in relation to schizophrenia, there have been few failures to replicate either the paternal age effect or its approximate magnitude (El-Saadi et al., 2004; Pulver et al., 2004). The uniformity of the results across different cultures lends further credence to the robust relationship between advanced paternal age and schizophrenia. This relation is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, independent of regional environmental risk factors for schizophrenia. The most plausible explanation is that the relation between advanced paternal age and schizophrenia is mediated through de novo genetic mechanisms and alterations in the epigenetic profile of different alleles.

Current findings on the relationship between paternal age and schizophrenia suggest new directions for research into the etiology of the disease. The studies linking advanced paternal age to the risk of schizophrenia indicate that we should expand this event horizon to consider the effects of environmental exposures on the fidelity of the male germ cell line over the life span of the father. The mutational stigmata of an exposure may remain in spermatogonial cells and be manifested in the clones of spermatozoa that it will subsequently generate over a man’s reproductive life.

Dr. Malaspina is supported by the following grants: National Institute of Mental Health (NIMH) 5K24 MH01699-11 and NIMH 5R01 MH59114-09. M. Perrin is supported by the following grants: National Institutes of Health (NIH) 5K07 CA131094-03, NIH 3K07 CA131094-02S1, and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award. K. Kleinhaus is supported by NIH K08 MH085807.

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