Paternal Age and Increased Risk of Schizophrenia, Providing Evidence for De Novo Mutations

Schizophrenia is a severe mental illness that afflicts approximately one percent of the world's population and yet its etiology is relatively unknown. There is a clear link between schizophrenia and genes in familial cases, demonstrated by heritability. However there is also evidence that genes contribute to the onset of schizophrenia in sporadic cases (where there is no history of the disease in the family) due to accumulating 'de novo' mutations in ageing fathers. One experiment suggests that up to 26% of sporadic cases of schizophrenia are due to paternal age (Malaspina, Harlap, Fennig, Heiman, Nahon, Feldman & Susser, 2001). A number of studies have demonstrated an effect of paternal age on schizophrenia, and have supported the de novo mutation hypothesis to explain the maintenance of schizophrenia in the population (Malaspina et al, 2001; Byrne, Agerbo, Ewald, Eaton, Mortensen, 2003; Zammit, Allebeck, Dalman, Lundberg, Hemmingson, Owen & Lewis, 2003; Sipos, Rasmussen, Harrison, Tynelius, Lewis, Leon and Gunnel, 2004). De novo refers to a new and spontaneous mutation; spontaneous meaning that it has not previously been seen in the generation (Zammit et al, 2003). Firstly, this essay will look at past experiments that explore the link between paternal age and schizophrenia and the findings that support and discredit this connection, with an emphasis on four recent extensive studies. It will then look the theory of de novo mutations and how this could explain paternal age's contribution to maintaining the prevalence of schizophrenia in the population.

The link between paternal age and schizophrenia was first suggested by Book (1953) and demonstrated by Johanson in 1958, it has since been replicated by several others (Gregory, 1959; Hare & Moran, 1979; Kinnell, 1983; Raschka, 1998 as cited in Zammit et al, 2003). These case-control designs, used population statistics for control comparisons. The findings were consistent in indicating an effect of paternal age, although it has been argued that selection bias was possible and that urban area controls could have been used (Bertranpetit & Fananas, 1993). Bertranpetit and Fananas (1993) matched for age, gender, place of birth, employment and neighborhood, but didn't find an association between schizophrenia and paternal age (Bertranpetit & Fananas, 1993).

This led to some speculation in the theory, but since then there have been a number of studies that have taken these variables into account and found an association. Although the age of risk varies slightly, they have large sample sizes and have adjusted for a number of different environmental variables. Four recent, relatively large studies (Malaspina et al, 2001; Zammit et al, 2003; Byrne et al, 2003; Sipos et al, 2004) all found an association between paternal age and schizophrenia.

Malaspina et al (2001) looked at 87 907 people in Jerusalem in a cohort study. The experiment controlled for maternal age, sex, ethnicity, education (measuring socioeconomic status), and marriage duration in proportional hazards regression. They found that for every 10 years the father was above 30 there was a 40% increase in risk, and that over a quarter of sporadic cases in their study could be explained by paternal age.

Zammit et al (2003) in another cohort study, looked at 50 087 adolescent males and adjusted for social interaction to rule out confounding, using factors such as parental drug use and IQ. They found a 2 and 3 fold increase in risk when fathers were over the age of fifty, but found little difference in adjusting for social interaction, supporting the de novo hypothesis.

Byrne et al (2003) did a case control study using 7704 participants in Denmark and individually matched the controls for age and sex. They separated those with a family history to help identify sporadic mutations. The results showed that there was a significant risk for parents greater than 50 years of age and this again supported the de novo mutation hypothesis.

Sipos et al (2004) in an extensive study looked at 754 330 people in Sweden. They adjusted for birth related exposures, socioeconomic factors, family history of psychosis and early parental death. They also looked at family history, sex, birth weight and Apgar score. The study found the overall hazard ratio for each 10 year increase in paternal age to be 1.47 and a risk when paternal age was greater than 30. They also found that the association between paternal age and schizophrenia was significantly larger in those with no family history of schizophrenia, supporting the hypothesis that accumulating de novo mutations in the gene lines of older fathers plays an important role in the aetiology of schizophrenia.

A number of smaller studies (Dalman & Allebeck, 2002; Brown, Schaefer, Wyatt, Begg, Goetz, Bresnahan, Harkavy-Friedman, Gorman, Malaspina, & Susser, 2002) also support the association between schizophrenia and paternal age. Despite these findings, a few still argue that maternal age or a large age gap between parents has a greater impact. Bourne (2004) argued that Zammit et al's (2003) findings that paternal age was significant while maternal age was not, was due to a large age gap of greater than 10 years, between paternal and maternal age. He argued that this led to a psychological risk of being the child of an odd couple, rather than de novo mutations (Bourne, 2004, as cited in Zammit et al, 2004). Zammit et al revoked this by responding that their findings showed that advancing maternal age was also associated with schizophrenia but that this association could be explained by the correlation with paternal age. They showed that once paternal age was taken into account maternal age was no longer of importance (Zammit et al, 2004).

Nonetheless, a study in Ireland found maternal age to be important (Dalйn, 1977). They hypothesized that the excess of schizophrenia in the republic of Ireland was due to the high maternal age (Dalйn, 1977). However it is highly probable that this is due to paternal age not being taken into account. A few other studies have failed to find associations (Granville-Grossman, 1966; Costello et al, 1968; Gillberg, 1982, as cited in Zammit et al, 2003), however inefficient statistical tests and small sample sizes are likely explanations for these findings (Moran, 1968). This is also true for Bertranpetit & Faсanбs (1993) study of 120 schizophrenic patients and 176 controls in Barcelona, Spain which also failed to find an association.

Overall however there is strong evidence to suggest that there is a link between paternal age at conception and schizophrenia by the more comprehensive studies (Malaspina et al, 2001; Zammit et al, 2003; Byrne et al, 2003; Sipos et al, 2004). These studies

...