Paternal age and schizophrenia: a population based cohort study
http://www.100md.com
《英国医生杂志》
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
Correspondence to: F Rasmussen finn.rasmussen@phs.ki.se
Abstract
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 cancer8 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 (26.6%) 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 However, studies to date have been too small to explore fully interactions with other risk factors or have not fully assessed the range of confounding factors that may contribute to the observed associations.1 3 6
Using a large Swedish record linkage database, we investigated the association between paternal age and schizophrenia in offspring, in particular the extent to which observed associations may be confounded by birth related exposures, socioeconomic factors, family history of psychosis, and early parental death. 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
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-affective non-schizophrenic 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.
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 changed hardly at all when we also controlled for risk factors related to birth, parental death before the subject reached the age of 18 years, and family history of schizophrenia, though there was a modest reduction in models after we controlled for the three socioeconomic variables. The variable mostly responsible for this drop was highest annual parental income.
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. Just as with schizophrenia we found an increased risk in the offspring of younger men (< 21 years) with some evidence for a non-linear association (P = 0.01, quadratic).
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)
When we combined cases of narrowly defined schizophrenia and non-schizophrenic non-affective psychosis into one category the hazard ratio associated with each 10 year increase in paternal age was 1.31 (1.17 to 1.47) when we controlled for sex, age, and maternal age and 1.23 (1.10 to 1.37) in the fully controlled model.
Maternal age showed a weak association with schizophrenia in the unadjusted model (hazard ratio per 10 year increase in maternal age 1.21, 1.02 to 1.43), 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 (crude hazard ratio per 10 year increase in maternal age was 1.10 (0.98 to 1.23) and 0.94 (0.79 to 1.12) when we controlled for sex, age, and paternal age
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). Hazard ratios increased by 1.65 (1.32 to 2.06) for men and by 1.40 (1.03 to 1.89) for women for every 10 years of paternal age.
We found no evidence for any marked difference in associations in those with high and low 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). Similar but weaker effects (P = 0.16 for interaction) were seen with Apgar scores at five minutes. We found no marked change in the strength of association between paternal age and schizophrenia when we restricted the proportional hazards model to the first or the second half of the follow up period.
Discussion
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.
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.
Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry 2002;159: 1591-2.
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.
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.
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.
Crow JF. The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A 1997;94: 8380-6.
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.
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.
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.
Crow JF. Development. There's something curious about paternal-age effects. Science 2003;301: 606-7.
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.
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.
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.
Pearlson GD. Neurobiology of schizophrenia. Ann Neurol 2000;48: 556-66.
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.
Harrison G, Fouskakis D, Rasmussen F, Tynelius P, Sipos A, Gunnell D. Association between psychotic disorder and urban place of birth is not mediated by obstetric complications or childhood socio-economic position: a cohort study. Psychol Med 2003;33: 723-31.
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.
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.
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.
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.
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.(Attila Sipos, honorary se)
Correspondence to: F Rasmussen finn.rasmussen@phs.ki.se
Abstract
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 cancer8 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 (26.6%) 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 However, studies to date have been too small to explore fully interactions with other risk factors or have not fully assessed the range of confounding factors that may contribute to the observed associations.1 3 6
Using a large Swedish record linkage database, we investigated the association between paternal age and schizophrenia in offspring, in particular the extent to which observed associations may be confounded by birth related exposures, socioeconomic factors, family history of psychosis, and early parental death. 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
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-affective non-schizophrenic 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.
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 changed hardly at all when we also controlled for risk factors related to birth, parental death before the subject reached the age of 18 years, and family history of schizophrenia, though there was a modest reduction in models after we controlled for the three socioeconomic variables. The variable mostly responsible for this drop was highest annual parental income.
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. Just as with schizophrenia we found an increased risk in the offspring of younger men (< 21 years) with some evidence for a non-linear association (P = 0.01, quadratic).
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)
When we combined cases of narrowly defined schizophrenia and non-schizophrenic non-affective psychosis into one category the hazard ratio associated with each 10 year increase in paternal age was 1.31 (1.17 to 1.47) when we controlled for sex, age, and maternal age and 1.23 (1.10 to 1.37) in the fully controlled model.
Maternal age showed a weak association with schizophrenia in the unadjusted model (hazard ratio per 10 year increase in maternal age 1.21, 1.02 to 1.43), 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 (crude hazard ratio per 10 year increase in maternal age was 1.10 (0.98 to 1.23) and 0.94 (0.79 to 1.12) when we controlled for sex, age, and paternal age
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). Hazard ratios increased by 1.65 (1.32 to 2.06) for men and by 1.40 (1.03 to 1.89) for women for every 10 years of paternal age.
We found no evidence for any marked difference in associations in those with high and low 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). Similar but weaker effects (P = 0.16 for interaction) were seen with Apgar scores at five minutes. We found no marked change in the strength of association between paternal age and schizophrenia when we restricted the proportional hazards model to the first or the second half of the follow up period.
Discussion
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.
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.
Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry 2002;159: 1591-2.
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.
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.
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.
Crow JF. The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A 1997;94: 8380-6.
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.
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.
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.
Crow JF. Development. There's something curious about paternal-age effects. Science 2003;301: 606-7.
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.
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.
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.
Pearlson GD. Neurobiology of schizophrenia. Ann Neurol 2000;48: 556-66.
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.
Harrison G, Fouskakis D, Rasmussen F, Tynelius P, Sipos A, Gunnell D. Association between psychotic disorder and urban place of birth is not mediated by obstetric complications or childhood socio-economic position: a cohort study. Psychol Med 2003;33: 723-31.
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.
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.
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.
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.
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.(Attila Sipos, honorary se)