BMJ  2004;329:1070 (6 November), doi:10.1136/bmj.38243.672396.55 (published 22 October 2004)

Paper

Paternal age and schizophrenia: a population based cohort study

¹ Academic Unit of Psychiatry, Cotham House, University of Bristol BS6 6JL, ² Department of Public Health Sciences, Karolinska Institute, Norrbacka, SE-17176 Stockholm, Sweden, ³ Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, ⁴ Department of Social Medicine, Canynge Hall, Bristol BS8 2PR

Abstract

Objective To investigate the association of paternal age at conception with the risk of offspring developing schizophrenia.

Design A population based cohort study.

Setting Sweden.

Subjects 754 330 people born in Sweden between 1973 and 1980 and still alive and resident in Sweden at age 16 years.

Main outcome measures Hospital admission with schizophrenia or non-schizophrenic non-affective psychosis.

Results After adjustment for birth related exposures, socioeconomic factors, family history of psychosis, and early parental death the overall hazard ratio for each 10 year increase in paternal age was 1.47 (95% confidence interval 1.23 to 1.76) for schizophrenia and 1.12 (0.98 to 1.29) for non-schizophrenic non-affective psychosis. This association between paternal age and schizophrenia was present in those with no family history of the disorder (hazard ratio for each 10 year increase in paternal age 1.60, 1.32 to 1.92), but not in those with a family history (0.91, 0.44 to 1.89) (P = 0.04 for interaction).

Conclusions Advancing paternal age is an important independent risk factor for schizophrenia. The stronger association between paternal age and schizophrenia in people without a family history provides further evidence that accumulation of de novo mutations in paternal sperm contributes to the overall risk of schizophrenia.

Introduction

There is growing evidence that factors operating at different points in life contribute to an individual's risk of developing schizophrenia. Recent research interest has focused on the influence of paternal age at conception.^1-6 Advancing paternal age is known to be associated with several other disorders,⁷ including cancer^{8 9} and achondroplasia,¹⁰ and is thought to be due to the age associated increase in sporadic de novo mutations in male germ cells.¹¹ One study estimated that about a quarter of cases of schizophrenia could be attributed to paternal age.⁵ It has been suggested that if this association between paternal age and schizophrenia was due to accumulating de novo mutations, sporadic cases of schizophrenia should show a stronger association with increased paternal age compared with cases in people with a known family history of the disorder.¹² Using a large Swedish record linkage database, we investigated the association between paternal age and schizophrenia in offspring. We also investigated whether any associations differed in relation to family history, sex, birth weight, and Apgar score. We investigated the latter two because they have been identified as possible environmental risk factors,^{13 14} and it has been hypothesised that in the presence of genetic predisposition, exposure to such factors may lead to the clinical manifestation of schizophrenia.^{15 16}

Method

Sample
Our cohort comprised 754 330 people born in Sweden between 1973 and 1980 and still alive and resident in Sweden at the age of 16 years. Information on the study sample was obtained from linkage between Sweden's medical birth registry, its population and housing census of 1990, its inpatient discharge register (up to 31 December 2001), and its cause of death and emigration registers (up to 31 December 2001). Our analysis was based on records of people admitted to hospital between 1989 and 2001 with a diagnosis of schizophrenia (international classification of diseases, 10th revision, ICD-10: F20; ninth revision, ICD-9, Swedish version: all 295 except 295F and 295H) or other non-affective psychosis (ICD-10: F21-29; ICD-9 Swedish version: 295F, 295H, 297-8) (see table A on bmj.com).

Overall, 42 316 (5.6%) people were excluded from the main analysis because of missing data, or because they developed schizophrenia (68 cases) or other non-affective psychosis (141 cases) before the age of 16 years.

Variables examined
We examined the influence of seven possible confounding factors on the associations with paternal age. We controlled for: sex; calendar year; maternal age; place of birth; obstetric complications and fetal growth; family history of psychosis; and socio-economic position. For details of the variables used see bmj.com.

Data analysis
All statistical analysis was performed with Stata Release 8.0 (StataCorp, College Station, TX). We used Cox's proportional hazards models to assess the influence of paternal age on psychosis. People were censored at the time of first admission for schizophrenia, non-schizophrenic non-affective psychosis, death, or emigration. We used the cluster option in Stata to adjust standard errors for clustering of cases within families. We controlled all reported hazard ratios for sex, age, and maternal age, unless otherwise specified or stratified by sex. We tested the validity of the proportional hazards assumption graphically and used Wald tests to investigate interaction effects.

Results

Parental age
Subjects were followed up for a mean of nine years after the age of 16 years. During this follow up period 639 (0.09%) were admitted with a diagnosis of schizophrenia and 1311 (0.18%) with a diagnosis of non-schizophrenic non-affective psychosis. The estimated annual incidence rates were 0.10 and 0.21 per 1000 person years, respectively.

Table 1 shows the characteristics of subjects in relation to the age of their father. People with older fathers tended also to have older mothers and mothers who had had more pregnancies. People with older fathers were more likely to lose their parents before they reached the age of 18 years; they were more likely to have a family history of psychosis; and their parents were more likely to come from extreme ends of the distribution of the various measures of socioeconomic position.

View this table: [in this window] [in a new window]   Table 1 Characteristics of subjects according to paternal age groups. Figures are number (percentage) unless stated otherwise

 

Table 2 shows the hazard ratios for successive five year paternal age groups. In the basic model, adjusted for sex, age, and maternal age, there is a clear increase in the risk of schizophrenia with increasing paternal age. There is a suggestion that the offspring of younger fathers (< 21 years) are also at somewhat greater risk than those with fathers aged 21-24 years (hazard ratio 1.34, 95% confidence interval 0.74 to 2.43), but there was no evidence of a non-linear association between paternal age and schizophrenia (P = 0.39, quadratic). The strength of the association between paternal age and schizophrenia was only modestly reduced when controlled for possible confounding factors. The variable mostly responsible for this reduction was highest annual parental income.

View this table: [in this window] [in a new window]   Table 2 Hazard ratios (with 95% confidence intervals) of schizophrenia in relation to paternal age (n=639 cases of schizophrenia)

 

Table 3 shows the results for the same series of models for non-schizophrenic non-affective psychosis. Overall, we found a much weaker association.

View this table: [in this window] [in a new window]   Table 3 Hazard ratios (with 95% confidence intervals) of non-schizophrenic non-affective psychosis in relation to paternal age (n=1311 cases of non-schizophrenic non-affective psychosis)

 

Maternal age showed a weak association with schizophrenia in the unadjusted model, but this association disappeared as soon as we controlled for paternal age, sex, and age (0.83, 0.64 to 1.07) (see table B on bmj.com). We found a similar pattern for non-schizophrenic non-affective psychosis. We calculated that the population attributable fraction of schizophrenia in this sample due to having a father aged > 30 years at birth was 15.5%.

Association with family history, sex, birth weight, Apgar scores, and age of onset
Associations with paternal age differed in those with and without a family history of schizophrenia (P = 0.04 for interaction). The hazard ratio for every 10 years of paternal age was 1.60 (1.32 to 1.92) in those with no family history of schizophrenia and 0.91 (0.44 to 1.89) in those with an affected first degree relative.

We found no strong evidence for any marked difference in the association between paternal age and schizophrenia by sex (P = 0.20 for interaction) or by birth weight (P = 0.15 for interaction). The association of paternal age with schizophrenia, however, differed in relation to the subjects' Apgar score at birth (P = 0.02 for interaction). In those with normal Apgar scores (7-10) at one minute hazard ratios increased by 1.60 for every 10 years of paternal age (1.33 to 1.92) but not in those with Apgar scores suggestive of the need for resuscitation (hazard ratios decreased by 0.92, 0.31 to 2.76).

Discussion

Our findings confirm an association between increased paternal age and schizophrenia in offspring, which remained even after we controlled for a wide range of potential confounding factors. The association seems to be relatively specific to schizophrenia compared with non-schizophrenic non-affective psychosis and was stronger in those with no family history of the disorder and those with normal Apgar scores at birth.

Strengths and weaknesses of study
We used routinely recorded data on variables related to birth, parents, and adulthood collected before the onset of disease. Furthermore, as cases were ascertained from a national inpatient register the possibility of selection bias was reduced. The large number of cases gives us statistical power to control for a wide range of important confounding factors and investigate whether the associations differ in relation to family history of psychosis or environmental risk factors.

The main limitation of our analysis is that case ascertainment was based on people admitted to hospital only with diagnoses recorded on an administrative database. Though we will have missed people who were not admitted to hospital, studies in the United Kingdom indicate that in the first three years after presentation over 80% of patients are admitted, even in areas with community oriented services.¹⁷ Furthermore, analyses of diagnoses recorded on the Swedish inpatient discharge register indicate that schizophrenia is diagnosed with reasonable accuracy.^{18 19} Another limitation is that a family history of admission with schizophrenia is only a marker for and not the equivalent of genetic vulnerability.

Comparison of findings with earlier research
In comparing our findings with those of earlier studies^{1-3 5 6} it is important to bear in mind that we were able to distinguish between narrowly defined schizophrenia (ICD-10 F20) and other non-schizophrenic non-affective psychosis (ICD-10 F21-29). One previous study¹ also reported a stronger association with paternal age in relation to narrowly defined schizophrenia.

We found a pattern of association across the categories of paternal age that suggested a J shaped rather than a linear association, in line with the initial unadjusted findings of Byrne et al.² In our study this pattern remained even after we controlled for possible confounders. Two other studies also investigated the possibility that family history may modify the risk associated with paternal age. Malaspina et al showed that paternal age was significantly higher for people with schizophrenia without a family history in a small study that compared 35 familial cases with 68 sporadic cases.¹² Zammit et al found no evidence for such effects, but their study lacked statistical power.⁶

What is already known on this topic Increased paternal age is associated with several diseases, possibly due to the age associated increase in sporadic de novo mutations in male germ cells Several studies have reported an association between paternal age at conception and their offspring's risk of schizophrenia If this association was due to de novo mutations one would expect to find a stronger association between paternal age and schizophrenia in cases with no family history of the disorder What this study adds There is a strong positive association between paternal age and schizophrenia that is not due to sociodemographic, birth related, or socioeconomic factors or family history or early parental death Paternal age is only weakly associated with other non-schizophrenic non-affective psychosis This association is stronger in those with no family history of schizophrenia, supporting the hypothesis that accumulating de novo mutations in the germ lines of older fathers could play an important part in the aetiology of schizophrenia

Conclusions
Our findings confirm advancing paternal age as a strong independent risk factor for schizophrenia and indicate that 15.5% of cases of schizophrenia in our cohort could be due to the patient having a father who was aged > 30 years at birth. We found a stronger association in subjects without a family history of schizophrenia, providing further evidence to support the theory that accumulating de novo mutations in the germ cells of older fathers might contribute to an increased risk of schizophrenia in their offspring.

In England and Wales the average paternal age has increased from 29.2 years in 1980 to 32.1 in 2002.²⁰ Assuming a background annual incidence rate for schizophrenia of 10/100 000²¹ and that the association is causal, our results suggest that the increase in paternal age since 1980 could account for 710 out of the 6633 new cases of schizophrenia diagnosed in the United Kingdom in 2002.

---

This is the abridged version of an article that was posted on bmj.com on 22 October 2004: http://bmj.com/cgi/doi/10.1136/bmj.38243.672396.55

Two extra tables of data can be found on bmj.com

We thank Christina Dalman, Peter Allebeck, and Susanne Wicks for their helpful comments, Stan Zammit for his help with accessing all the relevant literature, and Geoff Adams for statistical/database support.

Contributors: See bmj.com

Funding: Stanley Medical Research Institute.

Competing interests: None declared.

Ethical approval: The ethics committee at the Karolinska Institute, Stockholm, Sweden, approved this study.

References

1. Brown AS, Schaefer CA, Wyatt RJ, Begg MD, Goetz R, Bresnahan MA, et al. Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry 2002;159: 1528-33.[Abstract/Free Full Text]
2. Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry 2003;60: 673-8.[Abstract/Free Full Text]
3. Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry 2002;159: 1591-2.[Abstract/Free Full Text]
4. El Saadi O, Pedersen CB, McNeil TF, Saha S, Welham J, O'Callaghan E, et al. Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia. Schizophr Res 2004;67: 227-36.[CrossRef][Web of Science][Medline]
5. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, et al. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58: 361-7.[Abstract/Free Full Text]
6. Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, et al. Paternal age and risk for schizophrenia. Br J Psychiatry 2003;183: 405-8.[Abstract/Free Full Text]
7. Crow JF. The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 1997;94: 8380-6.[Abstract/Free Full Text]
8. Zhang Y, Kreger BE, Dorgan JF, Cupples LA, Myers RH, Splansky GL, et al. Parental age at child's birth and son's risk of prostate cancer. The Framingham study. Am J Epidemiol 1999;150: 1208-12.[Abstract/Free Full Text]
9. Hemminki K, Kyyronen P. Parental age and risk of sporadic and familial cancer in offspring: implications for germ cell mutagenesis. Epidemiology 1999;10: 747-51.[CrossRef][Web of Science][Medline]
10. Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, et al. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet 1998;63: 711-6.[CrossRef][Web of Science][Medline]
11. Crow JF. Development. There's something curious about paternal-age effects. Science 2003;301: 606-7.[Abstract/Free Full Text]
12. Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, et al. Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet 2002;114: 299-303.[CrossRef][Web of Science][Medline]
13. Dalman C, Thomas HV, David AS, Gentz J, Lewis G, Allebeck P. Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study. Br J Psychiatry 2001;179: 403-8.[Abstract/Free Full Text]
14. Gunnell D, Rasmussen F, Fouskakis D, Tynelius P, Harrison G. Patterns of fetal and childhood growth and the development of psychosis in young males: a cohort study. Am J Epidemiol 2003;158: 291-300.[Abstract/Free Full Text]
15. Pearlson GD. Neurobiology of schizophrenia. Ann Neurol 2000;48: 556-66.[CrossRef][Web of Science][Medline]
16. Velakoulis D, Wood SJ, McGorry PD, Pantelis C. Evidence for progression of brain structural abnormalities in schizophrenia: beyond the neurodevelopmental model. Aust N Z J Psychiatry 2000;34 suppl: S113-26.
17. Sipos A, Harrison G, Gunnell D, Amin S, Singh SP. Patterns and predictors of hospitalisation in first-episode psychosis. Prospective cohort study. Br J Psychiatry 2001;178: 518-23.[Abstract/Free Full Text]
18. Dalman C, Broms J, Cullberg J, Allebeck P. Young cases of schizophrenia identified in a national inpatient register—are the diagnoses valid? Soc Psychiatry Psychiatr Epidemiol 2002;37: 527-31.[CrossRef][Web of Science][Medline]
19. David AS, Malmberg A, Brandt L, Allebeck P, Lewis G. IQ and risk for schizophrenia: a population-based cohort study. Psychol Med 1997;27: 1311-23.[CrossRef][Web of Science][Medline]
20. Office of National Statistics. Birth statistics: review of the registrar general on births and family building patterns in England and Wales—FM1. London: Stationery Office, 2002.
21. Brewin J, Cantwell R, Dalkin T, Fox R, Medley I, Glazebrook C, et al. Incidence of schizophrenia in Nottingham. A comparison of two cohorts, 1978-80 and 1992-94. Br J Psychiatry 1997;171: 140-4.[Abstract/Free Full Text]

(Accepted 4 August 2004)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Paternal age and schizophrenia: One swallow does not make a summer

Marco Procopio
BMJ 2005 330: 147-148. [Extract] [Full Text]

Paternal aging raises risk of schizophrenia
BMJ 2004 329: 0. [Full Text]

This article has been cited by other articles:

• Rutten, B. P. F., Mill, J. (2009). Epigenetic Mediation of Environmental Influences in Major Psychotic Disorders. Schizophr Bull 35: 1045-1056 [Abstract] [Full text]  
• Grether, J. K., Anderson, M. C., Croen, L. A., Smith, D., Windham, G. C. (2009). Risk of Autism and Increasing Maternal and Paternal Age in a Large North American Population. Am J Epidemiol 170: 1118-1126 [Abstract] [Full text]  
• De Iuliis, G. N., Thomson, L. K., Mitchell, L. A., Finnie, J. M., Koppers, A. J., Hedges, A., Nixon, B., Aitken, R. J. (2009). DNA Damage in Human Spermatozoa Is Highly Correlated with the Efficiency of Chromatin Remodeling and the Formation of 8-Hydroxy-2'-Deoxyguanosine, a Marker of Oxidative Stress. Biol. Reprod. 81: 517-524 [Abstract] [Full text]  
• Olsen, J., Zhu, J. L. (2009). RE: "ADVANCED PARENTAL AGE AND THE RISK OF AUTISM SPECTRUM DISORDER". Am J Epidemiol 169: 1406-1406 [Full text]  
• March, D., Hatch, S. L., Morgan, C., Kirkbride, J. B., Bresnahan, M., Fearon, P., Susser, E. (2008). Psychosis and Place. Epidemiol Rev 30: 84-100 [Abstract] [Full text]  
• Kirkpatrick, B., Messias, E., Harvey, P. D., Fernandez-Egea, E., Bowie, C. R. (2008). Is Schizophrenia a Syndrome of Accelerated Aging?. Schizophr Bull 34: 1024-1032 [Abstract] [Full text]  
• van Os, J., Rutten, B. P., Poulton, R. (2008). Gene-Environment Interactions in Schizophrenia: Review of Epidemiological Findings and Future Directions. Schizophr Bull 34: 1066-1082 [Abstract] [Full text]  
• Weiser, M., Reichenberg, A., Werbeloff, N., Kleinhaus, K., Lubin, G., Shmushkevitch, M., Caspi, A., Malaspina, D., Davidson, M. (2008). Advanced Parental Age at Birth Is Associated With Poorer Social Functioning in Adolescent Males: Shedding Light on a Core Symptom of Schizophrenia and Autism. Schizophr Bull 34: 1042-1046 [Abstract] [Full text]  
• Tsuchiya, K. J., Matsumoto, K., Miyachi, T., Tsujii, M., Nakamura, K., Takagai, S., Kawai, M., Yagi, A., Iwaki, K., Suda, S., Sugihara, G., Iwata, Y., Matsuzaki, H., Sekine, Y., Suzuki, K., Sugiyama, T., Mori, N., Takei, N. (2008). Paternal age at birth and high-functioning autistic-spectrum disorder in offspring. Br. J. Psychiatry 193: 316-321 [Abstract] [Full text]  
• Perrin, M. C., Brown, A. S., Malaspina, D. (2007). Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia. Schizophr Bull 33: 1270-1273 [Abstract] [Full text]  
• Zammit, S., Lewis, S., Gunnell, D., Smith, G. D. (2007). Schizophrenia and Neural Tube Defects: Comparisons From an Epidemiological Perspective. Schizophr Bull 33: 853-858 [Abstract] [Full text]  
• Croen, L. A., Najjar, D. V., Fireman, B., Grether, J. K. (2007). Maternal and Paternal Age and Risk of Autism Spectrum Disorders. Arch Pediatr Adolesc Med 161: 334-340 [Abstract] [Full text]  
• McClellan, J. M., Susser, E., King, M.-C. (2007). Schizophrenia: a common disease caused by multiple rare alleles. Br. J. Psychiatry 190: 194-199 [Abstract] [Full text]  
• McGrath, J. J. (2007). The Surprisingly Rich Contours of Schizophrenia Epidemiology. Arch Gen Psychiatry 64: 14-16 [Full text]  
• Deighton, C., Criswell, L. A., Lum, R. F., Silman, A. (2007). Ages of onset suggestive of genetic anticipation in rheumatoid arthritis multicase sibships can be explained by observational bias. Rheumatology (Oxford) 46: 120-123 [Abstract] [Full text]  
• Rasmussen, F. (2006). Paternal age, size at birth, and size in young adulthood - risk factors for schizophrenia. Eur J Endocrinol 155: S65-S69 [Abstract] [Full text]  
• Bray, I., Gunnell, D., Davey Smith, G. (2006). Advanced paternal age: How old is too old?. J. Epidemiol. Community Health 60: 851-853 [Abstract] [Full text]  
• Wyrobek, A. J., Eskenazi, B., Young, S., Arnheim, N., Tiemann-Boege, I., Jabs, E. W., Glaser, R. L., Pearson, F. S., Evenson, D. (2006). Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc. Natl. Acad. Sci. USA 103: 9601-9606 [Abstract] [Full text]  
• Clarke, M. C., Harley, M., Cannon, M. (2006). The Role of Obstetric Events in Schizophrenia. Schizophr Bull 32: 3-8 [Full text]  
• Procopio, M. (2005). Paternal age and schizophrenia: One swallow does not make a summer. BMJ 330: 147-148 [Full text]  

Rapid Responses:

Read all Rapid Responses

This could be due to low DHEA...

James M. Howard
bmj.com, 24 Oct 2004 [Full text]

Mistheory? Re: This could be due to low DHEA...

Adrian S. Blaj
bmj.com, 25 Oct 2004 [Full text]

Yin, yang and yin-yang.

Richard G Fiddian-Green
bmj.com, 25 Oct 2004 [Full text]

Re: Mistheory? Re: This could be due to low DHEA...

James M. Howard
bmj.com, 25 Oct 2004 [Full text]

It is my hypothesis that...

Adrian S. Blaj
bmj.com, 26 Oct 2004 [Full text]

One swallow does not make a summer

Marco Procopio
bmj.com, 2 Nov 2004 [Full text]

Online poll

Find out more >>