Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK
Department of Social Medicine, Gothenburg University, Sweden
Psychiatric Epidemiology, Stockholm Centre of Public Health, Sweden
Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK
Division of Psychiatry, University of Bristol, Bristol, UK
Correspondence: Dr S.G. Zammit, Department of Psychological Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK. Tel: +44 (0)2920 743058; fax: +44 (0)2920 746595; e-mail:zammits{at}cardiff.cardiff.ac.ac.uk
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To investigate this association while adjusting for personality traits related to poor social integration in the subjects.
Method A cohort of 50 087 adolescent males was followed up by record linkage to determine hospital admissions for schizophrenia between 1970 and 1996.
Results Advancing paternal age was associated with an increased risk of developing schizophrenia in adose-dependentmanner. The adjusted odds ratio for each 10-year increase in paternal age was 1.3 (95% CI1.01.5; P=0.015).
Conclusions Advancing paternal age is an independent risk factor for schizophrenia. Adjusting for social integration in subjects made little difference to this association, consistent with the hypothesis that advancing paternal age may increase liability to schizophrenia owing to accumulating germ cell mutations.
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INTRODUCTION |
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More recently, an association between paternal age and schizophrenia has been reported in an Israeli population-based birth cohort (Malaspina et al, 2001). This was the first cohort study to investigate this association and it overcame many of the problems related to study design that affected previous studies. However, it was unable to adjust for personality traits, which may be an important confounder in the relationship between schizophrenia and paternal age.
Two studies since then have reported a marginally significant association but, again, they were unable to adjust for the effects of personality (Brown et al, 2002; Dalman & Allebeck, 2002). In this study we examine the relationship between paternal age and schizophrenia, using data from a Swedish cohort of 50 087 men with a 27-year record linkage follow-up, while controlling for a number of confounders, including personality traits relating to social integration of the subjects.
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METHOD |
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All subjects underwent a structured interview conducted by a psychologist and those reporting any psychiatric symptoms were interviewed by a psychiatrist and given a diagnosis according to ICD8 (World Health Organization, 1974) where applicable. All subjects have been made anonymous, and permission to use the database was granted by the Karolinska Institute Research Ethics Committee and the Swedish Data Inspection Board. Thirty-four cases of psychosis diagnosed at conscription were excluded from the study. Parental age at birth of subjects was obtained from the Statistics of Sweden Registers, blind to diagnosis.
Follow-up
The Swedish National Hospital Discharge Register recorded about 70% of all
psychiatric admissions in 1970, rising to 83% in 1973. Coverage was 97% from
1974 until 1983, 8095% between 1984 and 1986 and has been virtually
complete since 1987. The linkage reported here was from 1970 until 1996 and
covers the period of greatest risk of schizophrenia for men (ages 1845
years). The incomplete registration during some periods is unlikely to have
affected the results in any way. Patients were given clinical diagnoses
according to the Nordic version of ICD8 (ICD9 from 1987).
Swedish psychiatrists tend to use a narrow definition of schizophrenia
(Jablensky, 1986) and show
good agreement with DSMIII criteria
(Kristjansson et al,
1987). In addition, over 90% of people with schizophrenia are
admitted to hospital at some point over a 10-year period
(Geddes & Kendell, 1995),
and outcome misclassification is therefore likely to be low. Outcomes
investigated were schizophrenia (codes 295.00295.99) and other
psychoses (including alcoholic, affective, drug-induced and paranoid
psychoses).
Analysis
Logistic regression was used to calculate odds ratios and 95% confidence
intervals for schizophrenia when given the paternal age, both before and after
adjustment for potential confounders. Likelihood ratio tests were used to
compare different models.
Personality variables concerned with interpersonal relationships, IQ score, place of upbringing, cannabis use and maternal age have been found to be associated with schizophrenia (Andreasson et al, 1987; Lewis et al, 1992; David et al, 1997; Malmberg et al, 1998; Zammit et al, 2002) and were associated with paternal age in this cohort. These were included in the regression models, although some of these variables could lie along the causal pathway between paternal age and schizophrenia rather than confound the relationship. Nevertheless, investigation of these within the models could give important insights into the pathways involved in any association.
For the investigation that paternal age may have a stronger effect in
sporadic rather than familial cases of schizophrenia, the familial cases were
defined as subjects who had a family history of any mental health problems
requiring treatment with psychotropic medication. For the purposes of
analysis, paternal age was subdivided a priori into five categories
(ages 1524, 2534, 3544, 4554 and 55 years)
because a linear effect of paternal age was unlikely, given the prior
knowledge regarding accumulation of paternal germ cell mutations
(Crow, 1997).
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RESULTS |
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A summary of the potential confounders in relation to paternal age is presented in Table 1. For the purposes of this table only, poor social integration and IQ score were treated as dichotomous variables using the 10th percentile as a cut-off point for coding.
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The crude and adjusted odds ratios (ORs) with 95% confidence intervals for
developing schizophrenia when given the paternal age are presented in
Table 2. The crude odds ratio
for schizophrenia when given a linear trend of paternal age was highly
significant (crude OR for linear trend across age categories=1.3, 95% CI
1.11.5, P0.001), and this association persisted after
adjustment for confounders (adjusted OR for linear trend=1.3, 95% CI
1.01.5, P0.02). As a sensitivity analysis we excluded the
oldest age category (55 years), which resulted in an adjusted odds ratio
for a linear trend of 1.2 (95% CI 1.01.5, P=0.04).
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A non-linear (within a logistic model) relationship between paternal age
and risk of schizophrenia was investigated by inclusion of a quadratic term,
but there was no evidence that this fitted the model better than a linear
relationship (likelihood ratio test: 2=0.1, d.f.=1,
P=0.64). The hypothesis that paternal age may have a stronger effect
in sporadic cases rather than familial cases of schizophrenia
(Malaspina et al,
2001) was investigated, but a likelihood ratio test failed to show
evidence of any statistical interaction (likelihood ratio test:
2=9.8, d.f.=1, P=0.20).
Although there was an association between maternal age and schizophrenia in the crude analysis (crude OR for linear trend across maternal age categories=1.1, 95% CI 1.01.2, P=0.006), this disappeared after adjusting for paternal age (adjusted OR for linear trend=1.0, 95% CI 0.91.1, P=0.90).
We also investigated whether paternal age was associated with other (non-schizophrenia) psychoses (n=446). There was no association between paternal age and other psychoses in the crude analysis (OR for linear trend=1.1, 95% CI 1.01.3, P=0.09) and this did not change after adjustment for confounders (adjusted OR=1.1, 95% CI 0.91.3, P=0.46).
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DISCUSSION |
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The persistence of an association with paternal age after adjustment for poor social integration, drug use and low IQ score, all of which are established risk factors for schizophrenia, suggests that these factors are not along the causal pathway. Therefore, if the germ cell mutation hypothesis is correct, advancing paternal age must affect the susceptibility to schizophrenia by other means, perhaps by a more direct influence on cerebral function.
Observations suggest that the accumulation of germ cell mutations is likely to be non-linear and probably exponential in nature (Crow, 1997). The increase in odds ratios for schizophrenia with advancing paternal age was non-linear in this study (an exponential increase in risk with advancing paternal age is equivalent to a linear relationship within a logistic model). Although it has been suggested that paternal age may have a stronger effect in sporadic cases rather than familial cases of schizophrenia if point mutations accumulate with advancing age (Malaspina et al, 2001), we found no evidence of any interaction between family history of psychiatric disease and paternal age on risk of schizophrenia, although tests for interactions tend to lack power.
The population-attributable fraction of schizophrenia for this sample that is due to having a father aged >45 years at birth is approximately 13%. However, mean paternal age has increased over the past 20 years (Office for National Statistics, 2001), suggesting that this may be an underestimate of the true population-attributable fraction resulting from advanced paternal age. This may have important consequences for genetic studies, because recent mutations are much less amenable to detection by approaches that rely upon linkage disequilibrium with marker loci. The involvement of such mutations in conferring susceptibility can be detected only by direct association methods (Owen et al, 2000). Moreover, the inclusion of subjects who have older fathers in linkage disequilibrium studies will enrich for more recent mutations and, consequently, the power of linkage disequilibrium methods to identify susceptibility genes for schizophrenia may be reduced.
Confounding by personality
A second explanation for the association observed is that it is due to
confounding. If older fathers have personality traits that are known to be
associated with schizophrenia (such as schizoid or schizotypal traits), then
these traits are likely to be shared by their offspring as a result of both
heredity and upbringing (Coolidge et
al, 2001). Such traits could result in an increased risk of
developing schizophrenia in the offspring, and also in a later age of
parenthood in the father as a result of a reduced ability for social
integration (Granville-Grossman,
1966; Hare & Moran,
1979).
A further study by Malaspina et al found that paternal age was more likely to be advanced in sporadic cases of schizophrenia compared with those with a family history of psychosis (Malaspina et al, 2002). This suggests that family history and paternal age may be acting as independent risk factors for this disorder. Although it is possible to interpret this as evidence against confounding by personality, family history of psychosis is unlikely to be a strong marker for personality traits that predispose towards delayed parenthood.
In our analyses, adjusting for poor social integration in the conscripts reduced the odds ratio for schizophrenia only minimally, suggesting that personality traits relating to social integration do not play a substantial role in explaining the association between paternal age and schizophrenia. The absence of direct information on paternal personality means that some residual confounding is very likely and cannot be excluded as an explanation for the association. However, we would expect that if a strong effect of personality existed then this would be evident in the measures of personality in the subjects themselves.
In conclusion, our result of an association between advancing paternal age and schizophrenia was not affected by adjusting for social integration of the subjects. This supports the hypothesis that accumulating germ cell mutations may lead to an increase in genetic liability to schizophrenia in the offspring.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication September 26, 2002. Revision received June 4, 2003. Accepted for publication June 19, 2003.
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