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Paternal age and mortality in nonaffective psychosis
Schizophrenia Research 121 (2010) 218–226
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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Paternal age and mortality in nonaffective psychosis Brian Miller a,b, Johanna Pihlajamaa c, Jari Haukka c, Mary Cannon d, Markus Henriksson c, Hannele Heilä c, Matti Huttunen c, Antti Tanskanen c, Jouko Lönnqvist c, Jaana Suvisaari c, Brian Kirkpatrick a,⁎ a b c d
Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia, United States Department of Psychiatry, University of Oulu, Oulu, Finland Department of Mental Health and Alcohol Research, National Institute for Health and Welfare, Helsinki, Finland Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
a r t i c l e
i n f o
Article history: Received 17 November 2009 Received in revised form 21 January 2010 Accepted 22 January 2010 Available online 18 February 2010 Keywords: Paternal age Mortality Schizophrenia Nonaffective psychosis Longitudinal studies Gender differences
a b s t r a c t Introduction: Advanced paternal age (APA) is associated with an increased mortality in the general population, and is a risk factor for schizophrenia. We aimed to test if APA is associated with increased mortality in people with nonaffective psychosis. Methods: Subjects with nonaffective psychosis who were born in Helsinki, Finland, between 1951 and 1960 (n = 529) were followed until June 2006 (age 46 to 55). Hazard ratios were calculated, adjusting for subject age, age of the other parent, and gender. Results: In females but not males, there was a significant increase in all-causes mortality (HR = 7.04, 95% CI 1.60–31.04, p = 0.01) and natural deaths (HR = 7.64, 95% CI 1.20–48.66, p = 0.03) in offspring of fathers age ≥ 40, after adjustment for potential confounders. In males but not females, there was a significant decrease in suicides (HR = 0.89, 95% CI 0.81–0.97, p = 0.01) with increasing maternal age (as a continuous variable). In the entire sample, there was also a trend for decreased all-cause mortality (HR = 0.96, 95% CI 0.92–1.01, p = 0.08) with increasing maternal age (as a continuous variable). Discussion: Both paternal and maternal age may affect mortality risk in offspring with psychosis. The specific disorders and pathway(s) associated with the increase in natural cause mortality remain to be determined. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Evidence is accumulating that advanced paternal age may exhibit a wide range of effects on the health and development of the offspring. Advanced paternal age is a risk factor for childhood conditions such as cleft lip and palate, cancer, congenital heart defects, and neuropsychiatric conditions such as autism, epilepsy, and bipolar disorder (Bray et al., 2006; Cannon, 2009). Advanced paternal age has also been associated with poorer intellectual performance in the offspring (Malaspina et al., 2005; Saha et al.,
⁎ Corresponding author. Department of Psychiatry and Health Behavior, Medical College of Georgia, 997 Saint Sebastian Way, Augusta, Georgia 30912, United States. Tel.: + 1 706 721 6720; fax: + 1 706 721 1793. E-mail address: [email protected] (B. Kirkpatrick). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.01.020
2009). The best replicated of these associations is that between advanced paternal age and risk of schizophrenia in offspring (Granville-Grossman, 1966; Bojanovsky and Gerylovova, 1967; Costello et al., 1968; Hare and Moran, 1979; Gillberg, 1982; Kinnell, 1983; Malama et al., 1988; Bertranpetit and Fananas, 1993; Raschka, 1998; Malaspina et al., 2001; Dalman and Allebeck, 2002; Brown et al., 2002; Byrne et al., 2003; Zammit et al., 2003; Sipos et al., 2004; El-Saadi et al., 2004; Tsuchiya et al., 2005; Laursen et al., 2007; Torrey et al., 2009; Lopez-Castroman et al., 2009). Paternal age also appears to affect offspring mortality. Gavrilov and Garvrilova (2000) found that increasing paternal age was associated with increased mortality in daughters, but not sons, in a study of genealogical and longevity data on European royal and noble families. Robine and Allard (1997)
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did not find a relationship between paternal age and mortality, but the findings may have been biased due to incomplete data. A large Danish register based study found a U-shaped association between paternal age and all-cause childhood mortality (Zhu et al., 2008). In our previous work (Miller et al., in press), we have found that increasing paternal age was associated with increased suicides and all-cause mortality in a large Finnish register study with follow-up to age 39. Findings were adjusted for subject age, maternal age, paternal social class, and maternal parity. A study of male inpatients with psychosis found that paternal age was positively correlated with completed suicides, but did not consider the relationship between paternal age and other causes of death (Axelsson and Lagerkvist-Briggs, 1992). In the present study, we tested the hypothesis that increasing paternal age is associated with increased mortality in subjects with nonaffective psychosis, from age of onset of psychosis up to age 46 to 55. The broader category of nonaffective psychosis appears to share family history and other characteristics of schizophrenia (Lichtermann et al., 2000; Niemi et al., 2004). 2. Methods 2.1. Study population and study sample The study population consisted of all individuals with nonaffective psychosis who were born in Helsinki, Finland, between January 1, 1951 and December 31, 1960. We did not have any data on subjects without nonaffective psychosis who were born during this ten-year period. Risk factors for schizophrenia in this cohort have been investigated in two previous studies (Cannon et al., 1999; Cannon et al., 2002). Individuals with a diagnosis of schizophrenia spectrum psychosis (International Classification of Diseases, Eighth Revision [ICD-8] and Ninth Revision [ICD-9] diagnostic code 295.x, including schizophrenia, schizophreniform disorder, and schizoaffective disorder), born during this ten-year period were ascertained from three nationwide healthcare registers: 1) the Finnish Hospital Discharge Register (FHDR), and two registers of the Social Insurance Institution, namely, 2) the Pension Register and 3) the Medication Reimbursement Register. The FHDR was founded in 1967 and covers all mental, general and private hospitals in Finland. It contains the unique social security number for each individual and the hospital identification code, and it lists data on date of birth, gender, admission and discharge dates, and primary plus up to three subsidiary diagnoses for each inpatient stay. For all disability pensions, the pension register includes their beginning dates and the diagnoses on which the pension was granted. The Medication Reimbursement Register includes the diagnoses of persons receiving free outpatient medication, and the type of medication the benefit concerns. All health care registers were computerized in 1968, and used the ICD-8 diagnostic criteria and codes before 1987 (WHO 1967). Between 1987 and 1995 psychiatric diagnoses were coded according to ICD-9 (WHO 1977), applying the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) diagnostic criteria (APA 1987). ICD-10 diagnostic codes and criteria have been used since 1996 (WHO 1994). The data in all registers were linked by means of each individual's unique social security number.
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Information from these registers was available for the period January 1, 1969, through December 31, 1991. In order to facilitate the case note collection, the FHDR information was later extended to cover years 1992–1998, with year 1998 being the latest available year in the FHDR at the time the case note collection was started. The search of all three registers identified 928 individuals with a diagnosis of schizophrenia-spectrum psychosis, of whom 877 (94.5%) had at least one psychiatric hospitalisation for psychosis according to FHDR. All of the available hospital case notes were collected from the archives of the hospitals (n = 834, or 95.1% of those hospitalized). Of the remaining 43 case notes, 8 had been destroyed, 27 were lost, and 8 were not given for research purposes. As described in detail elsewhere (Pihlajamaa et al., 2008), all hospital case notes were carefully examined by five experienced psychiatrists who extracted clinical information from the case notes and filled the Operational Criteria (OPCRIT) checklist. The OPCRIT-system (version 3.4) consists of checklist of 90 items and a computer program, which generates psychiatric diagnoses based on 13 different diagnostic classifications and subclassifications (McGuffin et al., 1991). In the present study, we used the DSM-IV diagnoses given by the OPCRIT program. Of those n=834 individuals with available case notes, n=679 (81.4%) met criteria for a DSM-IV nonaffective psychotic disorder (schizophrenia, schizophreniform disorder, brief psychotic disorder, delusional disorder, or psychotic disorder not otherwise specified) given by the OPCRIT program. The study was approved by the Ethics Committee of the National Public Health Institute, and the case notes were collected with permission from the Finnish Ministry of Social Affairs and Health. The study was also overseen by the Human Assurance Committee of the Medical College of Georgia.
2.2. Information on parents Parents and their dates of birth were identified from the Population Register Centre. Maternal information was found for all n = 679 persons with nonaffective psychosis, while information on father was missing for n = 150 subjects (22.1% of the study sample). Family information was linked into the register at the beginning of the 1970s for persons alive at that time. Missing paternal information means that the father had died before 1970, or that the father's identity was unknown.
2.3. Information on socioeconomic status Information on the socioeconomic status (SES) of the family of origin, based on paternal occupation, was obtained from either obstetric (n = 435) or school (n = 76) records. These data were missing for n = 168 subjects (24.7% of the study sample). We coded SES according to the Rauhala scale. This classification results from sociological studies in Finland at the time of the study (Rauhala, 1966), and was formed on the basis of education, occupation, industrial status, and industry groupings (Central Statistical Office of Finland, 1974). The Rauhala scale is coded from 1 to 9, with 1 being the highest. In the analyses, we trichotomized SES into high (Rauhala scale scores 1–3), middle (4–6), and low (7–9).
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2.4. Information on causes of death
2.5. Statistical analysis
The Register of Causes of Death, kept by Statistics Finland, provided data on causes of death until June 2006 (ages 46 to 55). Statistics Finland has stored death certificates since 1936, but the data are available as a combined electronic file only from 1969 and onward. Therefore, subjects who developed nonaffective psychosis and died before 1969 would be missing. Our primary outcome measure was all-causes mortality. In secondary analyses, for descriptive purposes and blind to parental age, we stratified causes of death into natural and unnatural deaths. As schizophrenia is associated with an increased risk of suicide, including schizophrenia we further stratified unnatural deaths into suicides and other unnatural deaths (e.g., accidents and homicides). Deaths in the cohort were not further stratified by more specific causes due to small numbers at this level of analysis.
Of the n = 679 subjects with an OPCRIT diagnosis of nonaffective psychosis, information on both parents was available for n = 529 subjects. The final study sample for the present study consisted on these n = 529 individuals with nonaffective psychosis and data on parental ages, and was followed from birth until time of death or the end of followup (June 2006), whichever came first. Thus, those individuals still alive at the end of follow-up were age 46 to 55. A flow chart summarizing the selection of the study sample is presented in Fig. 1. We initially stratified paternal and maternal ages into eight age groups: ≤19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, and ≥50. However, because the upper and lower ends of this distribution led to small cells sizes, we combined the ≤19 and 20–24 groups into a b25 age group, and combined the 40–44,
Fig. 1. Flow chart of the selection of the study sample.
B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
45–49 and ≥50 groups in a ≥40 age group. We used the 25–29 age group as the reference group, its hazard ratio being set to 1.00. We first investigated the effect of parental age (as a categorical variable) on offspring mortality in Cox models adjusted only for subject age. The results were expressed as hazard ratios (HRs) with 95% confidence intervals (95% CIs). We then investigated the effect of parental age (as a categorical variable) on offspring mortality in multivariate Cox models, adjusting for the effects of subject age and age of the other parent (as a continuous variable). Next, we investigated the effect of parental age (categorical) on offspring mortality in multivariate Cox models, adjusting for the effects of subject age, age of the other parent (continuous), and gender. Lastly, we investigated the effect of parental age (as a categorical variable) on offspring mortality in multivariate Cox models, adjusting for the effects of subject age, age of the other parent (continuous), gender, and SES, for those n = 431 subjects with complete data on all variables (Fig. 1). As the inclusion of SES did not change the results and reduced the sample size considerably, it was eliminated from the models. We also tested for a linear association between parental age (continuous) and offspring mortality in multivariate Cox models, adjusting for the effects of subject age, age of the other parent (continuous), and gender. In a secondary analysis, we examined the association between paternal age (categorical) and mortality for males and females separately in multivariate Cox models, adjusting for maternal age (continuous) and subject age. All survival analyses were performed in SPSS version 17.0. 3. Results The final study sample (n=529) consisted of 311 males (60.1%) and 218 females (39.9%). The majority of persons (n=428, 80.9%) had schizophrenia. Other diagnoses in the study sample included psychotic disorder not otherwise specified (n=99, 18.7%), and delusional disorder (n=2, 0.4%). There were 107 deaths (20.2% of the study sample) – 78 (25.1%) males and 29 (13.3%) females – during the follow-up period. The causes of death included 39 suicides (5.7% of the study sample), 24 “other unnatural” deaths (4.5%), and 34 natural deaths (6.4%). Information on the cause of death was missing for 10 subjects (1.9%). There was no difference in the percentage of subjects who died during the follow-up period between subjects with unknown versus known fathers (n=150 subjects, 35 deaths [23.3%] versus n=529 subjects, 111 deaths [21.0%], respectively, p=0.66, Fisher's exact test, two-sided). Table 1 and Fig. 2 present hazard ratios (HRs) for mortality with 95% confidence intervals (CIs) by categorical parental age groups. In the analyses adjusted for subject age, maternal age (continuous), and gender (Model 3), compared to the paternal age 25–29 group, there was a trend for increased allcauses mortality (HR = 1.89, 95% CI 0.95–3.77, p = 0.07) in offspring of fathers age ≥40. Otherwise, there were no significant associations between mortality and categorical paternal age groups. By contrast, compared to the maternal age 25–29 group, there was a trend for increased suicides (HR = 1.96, 95% CI 0.91–4.20, p = 0.09) and decreased other unnatural deaths (HR = 0.30, 95% CI 0.08–1.08, p = 0.07) in offspring of mothers b25. Furthermore, in the fully-adjusted model (Model 3), increasing maternal age (continuous), was
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associated with a decreased risk of suicide (HR = 0.91, 95% CI 0.84–0.98, p = 0.01). There was also a trend for a decreased risk of all-causes mortality (HR = 0.96, 95% CI 0.92–1.01, p = 0.08) with increasing maternal age (continuous). Table 2 presents HRs for mortality with 95% CIs by categorical paternal age groups for males and females separately. After adjusting for subject age and maternal age, there was a significant increase in all-causes mortality (HR=7.04, 95% CI 1.60–31.04, p=0.01) and natural deaths (HR=7.64, 95% CI 1.20–48.66, p=0.03) in female but not male offspring of fathers age≥40. There was also a significant increase in all-causes mortality (HR=7.45, 95% CI 1.78–31.34, pb 0.01) in female offspring of fathers age 35–39, compared to the age 25–29 group. By contrast, increasing maternal age (continuous) was associated with significantly decreased risk of suicide mortality (HR=0.89, 95% CI 0.81–0.97, p=0.01) in males but not females. There was also a trend for a decrease in all-causes mortality (HR=0.95, 95% CI 0.90–1.00, p=0.07) in males but not females with increasing maternal age (continuous). 4. Discussion We found that after adjusting for potential confounders, in the entire sample of patients with nonaffective psychosis, there was a trend for increased all-causes mortality in offspring of fathers age ≥40. By contrast, increasing maternal age was associated with a significant decreased risk of suicide, and a trend for decreased all-causes mortality in the entire sample. We also found a significant increased risk of all-causes mortality in female but not male offspring of fathers age ≥40. By contrast, increasing maternal age was associated with significantly decreased risk of suicide, and a trend for decreased all-causes mortality in males but not females with nonaffective psychosis. We also found a high overall mortality rate (21.5%) in a relatively young cohort of patients with nonaffective psychosis. This result is consistent with previous reports of increased premature mortality in patients with schizophrenia compared to the average life expectancy in the general population from the same geographic area (Brown et al., 2000; Capasso et al., 2008; Tiihonen et al., 2009). To our knowledge, this is the first study to examine the association between parental age and mortality in nonaffective psychosis. The strengths of our study were two-fold. First of all, the subjects with nonaffective psychosis used in this study were drawn from a birth cohort with register-based diagnoses, thus reducing bias in the selection of cases. Secondly, the determination of causes of deaths in Finland is considered extremely reliable (Lahti and Penttilä, 2001). In every case of violent, sudden, or unexpected death in Finland, the possibility of suicide must be assessed by detailed police and medical-legal investigations involving autopsy and forensic examinations (Öhberg and Lönnqvist, 1998; Henriksson et al., 1993; Heilä et al., 1997). This procedure reduces bias due to the potential misclassification of the underlying cause of death. We emphasize the preliminary nature of our secondary analyses stratified by more specific causes of death and gender. One limitation of our findings is that we did not correct for multiple comparisons in these exploratory analyses. Our results warrant replication in larger cohorts, in which multiple comparisons should be considered.
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Table 1 Effects of parental age on risk of death. Cause of death
Variable
All-causes
Paternal age, y b 25 17 25–29 33 30–34 23 35–39 15 ≥40 17 Total 105 Maternal age, y b 25 42 25–29 49 30–34 22 35–39 11 ≥40 8 Total 132 Paternal age, y b 25 5 25–29 16 30–34 6 35–39 5 ≥40 5 Total 37 Maternal age, y b 25 18 25–29 17 30–34 4 35–39 3 ≥40 3 Total 45 Paternal age, y b 25 6 25–29 6 30–34 5 35–39 4 ≥40 3 Total 24 Maternal age, y b 25 3 25–29 13 30–34 6 35–39 4 ≥40 2 Total 28 Paternal age, y b 25 6 25–29 10 30–34 9 35–39 3 ≥40 6 Total 34 Maternal age, y b 25 20 25–29 16 30–34 8 35–39 4 ≥40 1 Total 49
Suicides
Other Unnatural Deaths
Natural Deaths
Deaths (n)
Alive (N)
Model 1 a
Model 2 b
Model 3 c
RR
95% CI
p-value
RR
95% CI
p-value
RR
95% CI
p-value
68 147 97 53 56 421
1.17 1.00 1.08 1.22 1.19
0.65–2.11 Reference 0.63–1.84 0.66–2.26 0.66–2.15
0.60
1.05 1.00 1.27 1.59 1.71
0.58–1.92 Reference 0.72–2.23 0.81–3.11 0.85–3.42
0.87
1.10 1.00 1.24 1.69 1.89 1.02
0.61–2.01 Reference 0.71–2.17 0.86–3.31 0.95–3.77 0.99–1.06
0.75
150 174 112 66 26 528
1.00 1.00 0.71 0.61 0.94
0.66–1.52 Reference 0.43–1.18 0.32–1.17 0.45–1.99
0.99
1.03 1.00 0.63 0.52 0.81
0.63–1.68 Reference 0.35–1.13 0.23–1.15 0.33–2.00
0.91
1.10 1.00 0.62 0.55 0.79 0.96
0.68–1.79 Reference 0.34–1.13 0.25–1.23 0.32–1.95 0.92–1.01
0.70
68 147 97 53 56 421
0.67 1.00 0.55 0.83 0.77
0.25–1.84 Reference 0.22–1.41 0.31–2.27 0.28–2.10
0.44
0.54 1.00 0.76 1.37 1.51
0.20–1.51 Reference 0.29–2.02 0.46–4.07 0.49–4.66
0.24
0.57 1.00 0.72 1.49 1.67 1.03
0.20–1.57 Reference 0.27–1.90 0.50–4.39 0.55–5.08 0.97–1.09
0.27
150 174 112 66 26 528
1.25 1.00 0.38 0.50 1.12
0.64–2.42 0.13–1.12 0.13–1.12 0.15–1.69 0.33–3.81
0.51
1.84 1.00 0.50 0.40 0.73
0.85–3.98 Reference 0.16–1.58 0.09–1.90 0.14–3.80
0.12
1.96 1.00 0.49 0.44 0.70 0.91
0.91–4.20 Reference 0.16–1.54 0.09–2.06 0.14–3.68 0.84–0.98
0.09
68 147 97 53 56 421
2.19 1.00 1.24 1.74 1.19
0.71–6.79 Reference 0.38–4.07 0.49–6.15 0.30–4.78
0.18
2.60 1.00 0.93 1.07 0.61
0.82–8.28 Reference 0.26–3.27 0.25–4.59 0.97–1.17
0.11
2.58 1.00 0.95 1.15 0.70 0.96
0.82–8.15 Reference 0.27–3.31 0.27–4.95 0.13–3.82 0.88–1.04
0.11
150 174 112 66 26 528
0.28 1.00 0.73 0.85 0.94
0.08–0.97 Reference 0.28–1.92 0.28–2.59 0.21–4.17
0.04
0.27 1.00 0.50 1.49 1.99
0.07–0.97 Reference 0.14–1.81 0.41–5.42 0.33–12.14
0.05
0.30 1.00 0.50 0.16 1.98 1.07
0.08–1.08 Reference 0.14–1.85 0.44–5.76 0.30–12.96 0.97–1.17
0.07
68 147 97 53 56 421
1.51 1.00 1.53 0.86 1.36
0.54–4.23 Reference 0.61–3.86 0.23–3.17 0.48–3.86
0.44
1.30 1.00 1.93 1.24 2.23
0.45–3.72 Reference 0.73–5.13 0.31–5.00 0.66–7.57
0.63
1.30 1.00 1.93 1.24 2.24 1.02
0.45–3.74 Reference 0.73–5.12 0.31–5.02 0.66–7.63 0.96–1.08
0.63
150 174 112 66 26 528
1.44 1.00 0.79 0.65 0.33
0.73–2.83 Reference 0.34–1.84 0.22–1.94 0.04–2.51
0.29
1.15 1.00 0.72 0.37 0.29
0.48–2.71 Reference 0.27–1.92 0.08–1.70 0.04–2.48
0.75
1.15 1.00 0.72 0.37 0.29 0.96
0.49–2.74 Reference 0.27–1.92 0.08–1.71 0.03–2.47 0.89–1.04
0.75
0.79 0.52 0.56
0.19 0.13 0.88
0.21 0.72 0.61
0.08 0.26 0.86
0.72 0.39 0.80
0.53 0.77 0.94
0.37 0.82 0.56
0.58 0.44 0.29
0.41 0.18 0.13
0.12 0.11 0.65
0.58 0.57 0.48
0.24 0.25 0.71
0.91 0.92 0.57
0.29 0.54 0.46
0.19 0.76 0.20
0.51 0.20 0.26
0.45 0.13 0.07 0.26
0.12 0.15 0.60 0.08
0.51 0.47 0.37 0.33
0.22 0.29 0.68 0.01
0.94 0.85 0.68 0.31
0.30 0.48 0.47 0.19
0.19 0.76 0.20 0.61
0.51 0.20 0.26 0.29
HR = Hazard Ratio. 95% CI = 95% Confidence Interval. a Adjusted for subject age. b Adjusted for subject age and age of the other parent (continuous). c Adjusted for subject age, age of the other parent (continuous), and gender.
Another important limitation of the study was that paternal age data were missing for 22% of the study sample (n = 150 subjects). For these subjects, it was not possible to differentiate between fathers who died before 1970 (which would be biased
towards older fathers) and unknown fathers. It is reassuring that there was no difference in the percentage of subjects who died during the follow-up period between subjects with unknown versus known fathers. Furthermore, an association
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Fig. 2. Paternal age and mortality risk by cause of death. Hazard ratios (HR) for categorical paternal age groups (reference group = 25–29) are adjusted for maternal age, gender, and socio-economic status. 95% confidence intervals are shown for all-cause mortality.
between advanced paternal age and increased mortality in other general population studies (Zhu et al., 2008; Miller et al., in press) supports the plausibility of our findings, and that the observed associations were not due to Type 1 error. We did not have any data on subjects without nonaffective psychosis, in order to make comparisons to the general population from which these cases of nonaffective psychosis were identified. Furthermore, subjects who developed nonaffective psychosis and died before 1969 were missing. This is likely to be a very small number of cases. The relationship between paternal age and earlier age of onset cases of nonaffective psychosis is unknown. However, for each subject who was initially identified from the health care registers with nonaffective psychosis, the follow-up information regarding mortality is complete. Taken together, it is not expected that these missing data would substantially change our results. Another limitation of the present study is that the relatively small number of deaths may have limited the statistical power of our analyses. Our previous study (Miller et al., in press) found that increasing paternal age was associated with increased allcauses mortality and suicides in females in the general population. We observed an increase in all-causes mortality with increasing paternal age in females, though the association was not significant (HR = 1.05, 95% CI 0.99–1.11, p = 0.12). It is possible that there is an association between paternal age and increased suicide mortality in females with psychosis, which our study did not have the statistical power to detect, as the female group was 32% smaller than the male group. We were
also unable to further stratify natural deaths by more specific causes due to small numbers. Our results, therefore, should be interpreted with caution, and warrant replication in larger cohorts. We did not use parity as a covariate due to incomplete data on siblings in the Finnish population register for persons born in the 1950s, although one study found parity of the mother was a significant predictor of mortality in the offspring (Modin, 2002). In that study, the parity effect was partly mediated by adult social class, education and income, and we adjusted for SES in this paper. Moreover, another study did not find evidence that birth order was associated with adult mortality in the offspring (O'Leary et al., 1996). Parity is also strongly correlated with maternal and paternal age. In our previous study, we did not find an association between paternal age and natural cause mortality in the general population (Miller et al., in press). However, subjects in that study were followed to age 39, compared to age 46 to 55 in the present study. A possible explanation for the absence of an association in our general population study is that there are significant differences in leading causes of death in these two age groups. Since the risk of natural cause mortality increases with increasing age, the difference may also have been due to a Type II error, as a result of a shorter length of follow-up. On the other hand, schizophrenia and related disorders are also associated with increased premature mortality from natural deaths (Brown, 1997; Saha et al., 2007), and it is possible that the paternal age effect on natural cause mortality is restricted to
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Table 2 Hazard ratios for paternal age by cause of death and gender. Males a
Cause of death
Variable
All-causes
Paternal age, y b 25 14 25–29 29 30–34 17 35–39 8 ≥40 9 Total 77 Maternal age, y b 25 29 25–29 38 30–34 13 35–39 5 ≥40 7 Total 92 Paternal age, y b 25 5 25–29 15 30–34 5 35–39 2 ≥40 4 Total 31 Maternal age, y b 25 16 25–29 12 30–34 3 35–39 1 ≥40 3 Total 35 Paternal age, y b 25 5 25–29 6 30–34 4 35–39 3 ≥40 1 Total 19 Maternal age, y b 25 3 25–29 11 30–34 3 35–39 1 ≥40 2 Total 20 Paternal age, y b 25 4 25–29 7 30–34 5 35–39 1 ≥40 1 Total 18 Maternal age, y b 25 10 25–29 12 30–34 4 35–39 3 ≥40 0 Total 29
Deaths (n)
Suicides
Other Unnatural Deaths
Natural Deaths
Females a Alive (N)
RR
95% CI
p-value
Deaths (n)
Alive (N)
35 80 58 29 30 232
1.08 1.00 0.97 1.08 1.27 1.01
0.56–2.06 Reference 0.52–1.81 0.46–2.52 0.53–3.00 0.96–1.05
0.83
3 4 6 7 8 28
33 67 39 24 26 189
1.65 1.00 4.12 7.45 7.04 1.05
0.33–8.34 Reference 0.97–17.43 1.78–31.34 1.60–31.04 0.99–1.11
78 100 70 37 14 299
1.08 1.00 0.53 0.35 1.14 0.95
0.63–1.87 Reference 0.25–1.10 0.10–1.20 0.39–3.34 0.90–1.00
0.78
13 11 9 6 1 40
72 74 42 29 12 229
1.34 1.00 1.16 0.93 0.35 0.98
0.45–4.00 Reference 0.40–3.33 0.30–2.96 0.04–2.97 0.91–1.06
35 80 58 29 30 232
0.61 1.00 0.64 0.69 1.58 1.02
0.22–1.71 Reference 0.23–1.82 0.15–3.24 0.47–5.33 0.96–1.09
0.35
0 1 1 3 1 6
33 67 39 24 26 189
0.00 1.00 2.10 10.32 3.53 1.05
78 100 70 37 14 299
2.33 1.00 0.50 0.34 1.07 0.89
1.00–5.45 Reference 0.13–1.92 0.04–2.86 0.18–6.23 0.81–0.97
0.05
2 5 1 2 0 10
72 74 42 29 12 229
0.93 1.00 0.52 0.57 0.00 0.97
0.14–6.20 Reference 0.05–5.02 0.06–5.93
0.93
0.82–1.12
0.71
35 80 58 29 30 232
2.08 1.00 0.82 1.03 0.31 0.95
0.62–0.94 Reference 0.22–3.07 0.21–5.21 0.03–3.37 0.85–1.05
0.23
1 0 1 1 2 5
33 67 39 24 26 189
1.00 0.00 0.24 0.32 0.34 0.98
Reference
78 100 70 37 14 299
0.34 1.00 0.40 0.54 3.07 1.05
0.09–1.25 Reference 0.08–1.90 0.06–4.78 0.35–27.32 0.93–1.16
0.11
0 2 3 3 0 8
72 74 42 29 12 229
0.00 1.00 1.79 8.22 0.00 1.15
35 80 58 29 30 232
1.47 1.00 1.20 0.56 0.58 0.96
0.42–5.24 Reference 0.36–4.02 0.06–5.26 0.06–6.00 0.86–1.07
0.55
2 3 4 2 5 16
33 67 39 24 26 189
78 100 70 37 14 299
1.01 1.00 0.43 0.52 0.00 0.96
0.35–2.92 Reference 0.09–2.11 0.06–4.51
0.99
0.86–1.07
0.49
10 4 4 1 1 20
72 74 42 29 12 229
0.93 0.87 0.59 0.81
0.09 0.10 0.81 0.07
0.40 0.64 0.46 0.53
0.31 0.32 0.94 0.01
0.76 0.97 0.33 0.29
0.25 0.58 0.32 0.52
0.70 0.61 0.65 0.49
0.30 0.55
RR
95% CI
Reference 0.12–37.06 0.88–120.69 0.17–75.82 0.93–1.18
p-value 0.54 0.05 b 0.01 0.01 0.11 0.60 0.79 0.91 0.33 0.67
0.61 0.06 0.42 0.41
0.57 0.64
0.01–7.37 0.01–11.40 0.01–14.47 0.84–1.15
0.41 0.53 0.57 0.84
Reference 0.11–29.27 0.60–112.77
0.69 0.12
0.96–1.38
0.14
1.46 1.00 0.04 3.82 7.64 1.05
0.20–10.67 Reference 0.83–29.40 0.49–29.97 1.20–48.66 0.98–1.13
0.71
1.82 1.00 1.56 0.33 0.52 0.96
0.39–8.53 Reference 0.39–6.29 0.04–3.03 0.05–5.17 0.87–1.06
0.45
0.08 0.20 0.03 0.17
0.53 0.33 0.57 0.42
HR = Hazard Ratio. 95% CI = 95% Confidence Interval. a Adjusted for subject age, age of the other parent (continuous).
patients with nonaffective psychosis. Furthermore, causes of death that are prevalent in subjects beyond middle age are not represented here, and if subjects in this study were followed past age 55, our findings may have been different. Our data provide little basis for postulating a mechanism of this effect, which may be mediated by biological factors,
psychosocial factors, or both. Several biological mechanisms have been proposed for the adverse health effects of increasing paternal age. There is evidence for an increased rate of de novo mutations with advanced paternal age (Crow, 1997). The possibility of epigenetic changes, such as imprinting, DNA methylation, or histone acetylation, has also been proposed, but
B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
this mechanism has not been thoroughly investigated (Perrin et al., 2007). Several disorders that have been related to advanced paternal age are also associated with increased natural cause mortality, including diabetes and other components of the metabolic syndrome (Osmond and Barker, 2000) and some cancers (Kaijse et al., 2003), and it is possible that both mutations and epigenetic changes contribute. However, one could also postulate non-genetic explanations for this association. One possibility is that advanced paternal age is associated with an adverse psychosocial environment during prenatal development. Exposure to prenatal stress in pregnancy appears to confer on the offspring an increased risk of developing schizophrenia later in life (Malaspina et al., 2008; Susser et al., 1996). Prenatal stress and developmental problems have also become an increasingly important area of research in diabetes and other aspects of the metabolic syndrome (Osmond and Barker, 2000; Ravelli et al., 1998), thereby increasing risk of natural death. Potential stressors during gestation that may be associated with older fathers include loss of the father due to death or divorce, paternal psychiatric disorders, or other adverse health and personality factors related to aging. Further examination of the social consequences of advancing paternal age would be desirable. Although the primary focus of our paper was paternal age, we also found that increasing maternal age was associated with a significant decreased risk of suicide in males but not females. To our knowledge, this is the first study to report an association between maternal age and suicide mortality in nonaffective psychosis. In the general population, younger maternal age is a replicated risk factor for suicide (Riordan et al., 2006; Ekéus et al., 2006; Mittendorfer-Rutz et al., 2004). Our data provide little basis for postulating whether the maternal age effect is mediated by biological factors, psychosocial factors, or both. This finding should be also explored in larger cohorts. An understanding of this risk factor has substantial public health potential, as average paternal ages are increasing (Bray et al., 2006). Older paternal age is becoming more common, has widespread effects, and it might be possible to elucidate the mechanism of this association with animal studies. Accounting for the paternal age effect as a potential confounding factor may increase the signal-to-noise ratio in other epidemiological and genetic analyses in future mortality research both in samples of patients with nonaffective psychosis and the general population. Role of the funding source Dr. Miller receives grant support from the University of Oulu, Finland, and Oy H. Lundbeck Ab. Dr. Cannon received grant support from the Health Research Board (Ireland) and NARSAD. Dr. Suvisaari received grant support from the Academy of Finland. Dr. Kirkpatrick was provided in part by grant R01 DK069265 from the National Institute of Diabetes and Digestive and Kidney Diseases. The University of Oulu, Oy H. Lundbeck Ab, the Health Research board, NARSAD, the Academy of Finland, and the NIDDK had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Drs. Miller, Suvisaari, and Kirkpatrick designed the study. Dr. Miller managed the literature searches. Dr. Haukka managed the analyses. Drs. Miller, Cannon, Suvisaari, and Kirkpatrick wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest Dr. Miller has no conflicts of interest to disclose. Dr. Pihlajamaa has no conflicts of interest to disclose.
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Dr. Haukka has no conflicts of interest to disclose. Dr. Cannon has no conflicts of interest to disclose. Dr. Henriksson has no conflicts of interest to disclose. Dr. Heilä has no conflicts of interest to disclose. Dr. Huttunen has no conflicts of interest to disclose. Dr. Tanskanen has no conflicts of interest to disclose. Dr. Lönnqvist has no conflicts of interest to disclose. Dr. Suvisaari has no conflicts of interest to disclose. Dr. Kirkpatrick received consulting and/or speaking fees from Pfizer, Organon, AstraZeneca, Wyeth, Bristol Myers Squibb, Solvay, and Cephalon.
Acknowledgements The authors would like to acknowledge Kirsi Niinistö, Johanna Koskela, MD, and Elisa Karjalainen, MD, PhD for assistance. The sample collection was funded by the Theodore and Vada Stanley Foundation and the Wellcome Trust through grants to Mary Cannon.
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O'Leary, S.R., Wingard, D.L., Edelstein, S.L., et al., 1996. Is birth order associated with adult mortality. Ann. Epidemiol. 6, 34–40. Osmond, C., Barker, D., 2000. Fetal, infant, and childhood growth are predictors of coronary heart disease, diabetes, and hypertension in adult men and women. Environ. Health Perspect. 108, 545–553. 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. Pihlajamaa, J., Suvisaari, J., Henriksson, M., Heilä, H., Karjalainen, E., Koskela, J., et al., 2008. The validity of schizophrenia diagnosis in the Finnish Hospital Discharge Register: findings from a 10-year birth cohort sample. Nord. J. Psychiatry 62, 198–203. Raschka, L.B., 1998. Parental age and schizophrenia. Magyar Andrologica 47–50. Rauhala, U., 1966. Social Review. No. 6. Helsinki: Ministry of Social Affairs and Health. Social structures of the Finnish society. Ravelli, A.C., van der Meulen, J.H., Michels, R.P., Osmond, C., Barker, D.J., Hales, C.N., et al., 1998. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351, 173–177. Riordan, D.V., Selvaraj, S., Stark, C., Gilbert, J.S., 2006. Perinatal circumstances and risk of offspring suicide. Birth cohort study. Br. J. Psychiatry 189, 502–507. Robine, J.-M., Allard, M., 1997. Towards a genealogical epidemiology of longevity. In: Robine, J.M., Vaupel, J.W., Jeune, B., Allard, M. (Eds.), Longevity: to the limits and beyond. Springer-Verlag, Berlin, Heidelberg, pp. 121–129. Saha, S., Chant, D., McGrath, J., 2007. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch. Gen. Psychiatry 64, 1123–1131. Saha, S., Barnett, A.G., Foldi, C., Burne, T.H., Eyles, D.W., Buka, S.L., et al., 2009. Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med. 6, e40. Sipos, A., Rasmussen, F., Harrison, G., Tynelius, P., Lewis, G., Leon, D.A., et al., 2004. Paternal age and schizophrenia: a population based cohort study. BMJ 329, 1070. Susser, E., Neugebauer, R., Hoek, H., Brown, A., Lin, S., Labovitz, D., 1996. Schizophrenia after prenatal famine. Further evidence. Arch. Gen. Psychiatry 53, 25–31. Tiihonen, J., Lönnqvist, J., Wahlbeck, K., Klaukka, T., Niskanen, L., Tanskanen, A., et al., 2009. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study. Lancet 374, 620–627. Torrey, E.F., Buka, S., Cannon, T.D., Goldstein, J.M., Seidman, L.J., Liu, T., et al., 2009. Paternal age as a risk factor for schizophrenia: how important is it? Schizophr. Res. 114, 1–5. Tsuchiya, K.J., Takagai, S., Kawai, M., Matsumoto, H., Nakamura, K., Minabe, Y., et al., 2005. Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophr. Res. 76, 337–342. Zammit, S., Allebeck, P., Dalman, C., Lundberg, I., Hemmingson, T., Owen, M.J., et al., 2003. Paternal age and risk for schizophrenia. Br. J. Psychiatry 183, 405–408. Zhu, J.L., Vestergaard, M., Madsen, K.M., Olsen, J., 2008. Paternal age and mortality in children. Eur. J. Epidemiol. 23, 443–447.
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Paternal age and mortality in nonaffective psychosis Brian Miller a,b, Johanna Pihlajamaa c, Jari Haukka c, Mary Cannon d, Markus Henriksson c, Hannele Heilä c, Matti Huttunen c, Antti Tanskanen c, Jouko Lönnqvist c, Jaana Suvisaari c, Brian Kirkpatrick a,⁎ a b c d
Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia, United States Department of Psychiatry, University of Oulu, Oulu, Finland Department of Mental Health and Alcohol Research, National Institute for Health and Welfare, Helsinki, Finland Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
a r t i c l e
i n f o
Article history: Received 17 November 2009 Received in revised form 21 January 2010 Accepted 22 January 2010 Available online 18 February 2010 Keywords: Paternal age Mortality Schizophrenia Nonaffective psychosis Longitudinal studies Gender differences
a b s t r a c t Introduction: Advanced paternal age (APA) is associated with an increased mortality in the general population, and is a risk factor for schizophrenia. We aimed to test if APA is associated with increased mortality in people with nonaffective psychosis. Methods: Subjects with nonaffective psychosis who were born in Helsinki, Finland, between 1951 and 1960 (n = 529) were followed until June 2006 (age 46 to 55). Hazard ratios were calculated, adjusting for subject age, age of the other parent, and gender. Results: In females but not males, there was a significant increase in all-causes mortality (HR = 7.04, 95% CI 1.60–31.04, p = 0.01) and natural deaths (HR = 7.64, 95% CI 1.20–48.66, p = 0.03) in offspring of fathers age ≥ 40, after adjustment for potential confounders. In males but not females, there was a significant decrease in suicides (HR = 0.89, 95% CI 0.81–0.97, p = 0.01) with increasing maternal age (as a continuous variable). In the entire sample, there was also a trend for decreased all-cause mortality (HR = 0.96, 95% CI 0.92–1.01, p = 0.08) with increasing maternal age (as a continuous variable). Discussion: Both paternal and maternal age may affect mortality risk in offspring with psychosis. The specific disorders and pathway(s) associated with the increase in natural cause mortality remain to be determined. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Evidence is accumulating that advanced paternal age may exhibit a wide range of effects on the health and development of the offspring. Advanced paternal age is a risk factor for childhood conditions such as cleft lip and palate, cancer, congenital heart defects, and neuropsychiatric conditions such as autism, epilepsy, and bipolar disorder (Bray et al., 2006; Cannon, 2009). Advanced paternal age has also been associated with poorer intellectual performance in the offspring (Malaspina et al., 2005; Saha et al.,
⁎ Corresponding author. Department of Psychiatry and Health Behavior, Medical College of Georgia, 997 Saint Sebastian Way, Augusta, Georgia 30912, United States. Tel.: + 1 706 721 6720; fax: + 1 706 721 1793. E-mail address: [email protected] (B. Kirkpatrick). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.01.020
2009). The best replicated of these associations is that between advanced paternal age and risk of schizophrenia in offspring (Granville-Grossman, 1966; Bojanovsky and Gerylovova, 1967; Costello et al., 1968; Hare and Moran, 1979; Gillberg, 1982; Kinnell, 1983; Malama et al., 1988; Bertranpetit and Fananas, 1993; Raschka, 1998; Malaspina et al., 2001; Dalman and Allebeck, 2002; Brown et al., 2002; Byrne et al., 2003; Zammit et al., 2003; Sipos et al., 2004; El-Saadi et al., 2004; Tsuchiya et al., 2005; Laursen et al., 2007; Torrey et al., 2009; Lopez-Castroman et al., 2009). Paternal age also appears to affect offspring mortality. Gavrilov and Garvrilova (2000) found that increasing paternal age was associated with increased mortality in daughters, but not sons, in a study of genealogical and longevity data on European royal and noble families. Robine and Allard (1997)
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did not find a relationship between paternal age and mortality, but the findings may have been biased due to incomplete data. A large Danish register based study found a U-shaped association between paternal age and all-cause childhood mortality (Zhu et al., 2008). In our previous work (Miller et al., in press), we have found that increasing paternal age was associated with increased suicides and all-cause mortality in a large Finnish register study with follow-up to age 39. Findings were adjusted for subject age, maternal age, paternal social class, and maternal parity. A study of male inpatients with psychosis found that paternal age was positively correlated with completed suicides, but did not consider the relationship between paternal age and other causes of death (Axelsson and Lagerkvist-Briggs, 1992). In the present study, we tested the hypothesis that increasing paternal age is associated with increased mortality in subjects with nonaffective psychosis, from age of onset of psychosis up to age 46 to 55. The broader category of nonaffective psychosis appears to share family history and other characteristics of schizophrenia (Lichtermann et al., 2000; Niemi et al., 2004). 2. Methods 2.1. Study population and study sample The study population consisted of all individuals with nonaffective psychosis who were born in Helsinki, Finland, between January 1, 1951 and December 31, 1960. We did not have any data on subjects without nonaffective psychosis who were born during this ten-year period. Risk factors for schizophrenia in this cohort have been investigated in two previous studies (Cannon et al., 1999; Cannon et al., 2002). Individuals with a diagnosis of schizophrenia spectrum psychosis (International Classification of Diseases, Eighth Revision [ICD-8] and Ninth Revision [ICD-9] diagnostic code 295.x, including schizophrenia, schizophreniform disorder, and schizoaffective disorder), born during this ten-year period were ascertained from three nationwide healthcare registers: 1) the Finnish Hospital Discharge Register (FHDR), and two registers of the Social Insurance Institution, namely, 2) the Pension Register and 3) the Medication Reimbursement Register. The FHDR was founded in 1967 and covers all mental, general and private hospitals in Finland. It contains the unique social security number for each individual and the hospital identification code, and it lists data on date of birth, gender, admission and discharge dates, and primary plus up to three subsidiary diagnoses for each inpatient stay. For all disability pensions, the pension register includes their beginning dates and the diagnoses on which the pension was granted. The Medication Reimbursement Register includes the diagnoses of persons receiving free outpatient medication, and the type of medication the benefit concerns. All health care registers were computerized in 1968, and used the ICD-8 diagnostic criteria and codes before 1987 (WHO 1967). Between 1987 and 1995 psychiatric diagnoses were coded according to ICD-9 (WHO 1977), applying the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) diagnostic criteria (APA 1987). ICD-10 diagnostic codes and criteria have been used since 1996 (WHO 1994). The data in all registers were linked by means of each individual's unique social security number.
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Information from these registers was available for the period January 1, 1969, through December 31, 1991. In order to facilitate the case note collection, the FHDR information was later extended to cover years 1992–1998, with year 1998 being the latest available year in the FHDR at the time the case note collection was started. The search of all three registers identified 928 individuals with a diagnosis of schizophrenia-spectrum psychosis, of whom 877 (94.5%) had at least one psychiatric hospitalisation for psychosis according to FHDR. All of the available hospital case notes were collected from the archives of the hospitals (n = 834, or 95.1% of those hospitalized). Of the remaining 43 case notes, 8 had been destroyed, 27 were lost, and 8 were not given for research purposes. As described in detail elsewhere (Pihlajamaa et al., 2008), all hospital case notes were carefully examined by five experienced psychiatrists who extracted clinical information from the case notes and filled the Operational Criteria (OPCRIT) checklist. The OPCRIT-system (version 3.4) consists of checklist of 90 items and a computer program, which generates psychiatric diagnoses based on 13 different diagnostic classifications and subclassifications (McGuffin et al., 1991). In the present study, we used the DSM-IV diagnoses given by the OPCRIT program. Of those n=834 individuals with available case notes, n=679 (81.4%) met criteria for a DSM-IV nonaffective psychotic disorder (schizophrenia, schizophreniform disorder, brief psychotic disorder, delusional disorder, or psychotic disorder not otherwise specified) given by the OPCRIT program. The study was approved by the Ethics Committee of the National Public Health Institute, and the case notes were collected with permission from the Finnish Ministry of Social Affairs and Health. The study was also overseen by the Human Assurance Committee of the Medical College of Georgia.
2.2. Information on parents Parents and their dates of birth were identified from the Population Register Centre. Maternal information was found for all n = 679 persons with nonaffective psychosis, while information on father was missing for n = 150 subjects (22.1% of the study sample). Family information was linked into the register at the beginning of the 1970s for persons alive at that time. Missing paternal information means that the father had died before 1970, or that the father's identity was unknown.
2.3. Information on socioeconomic status Information on the socioeconomic status (SES) of the family of origin, based on paternal occupation, was obtained from either obstetric (n = 435) or school (n = 76) records. These data were missing for n = 168 subjects (24.7% of the study sample). We coded SES according to the Rauhala scale. This classification results from sociological studies in Finland at the time of the study (Rauhala, 1966), and was formed on the basis of education, occupation, industrial status, and industry groupings (Central Statistical Office of Finland, 1974). The Rauhala scale is coded from 1 to 9, with 1 being the highest. In the analyses, we trichotomized SES into high (Rauhala scale scores 1–3), middle (4–6), and low (7–9).
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2.4. Information on causes of death
2.5. Statistical analysis
The Register of Causes of Death, kept by Statistics Finland, provided data on causes of death until June 2006 (ages 46 to 55). Statistics Finland has stored death certificates since 1936, but the data are available as a combined electronic file only from 1969 and onward. Therefore, subjects who developed nonaffective psychosis and died before 1969 would be missing. Our primary outcome measure was all-causes mortality. In secondary analyses, for descriptive purposes and blind to parental age, we stratified causes of death into natural and unnatural deaths. As schizophrenia is associated with an increased risk of suicide, including schizophrenia we further stratified unnatural deaths into suicides and other unnatural deaths (e.g., accidents and homicides). Deaths in the cohort were not further stratified by more specific causes due to small numbers at this level of analysis.
Of the n = 679 subjects with an OPCRIT diagnosis of nonaffective psychosis, information on both parents was available for n = 529 subjects. The final study sample for the present study consisted on these n = 529 individuals with nonaffective psychosis and data on parental ages, and was followed from birth until time of death or the end of followup (June 2006), whichever came first. Thus, those individuals still alive at the end of follow-up were age 46 to 55. A flow chart summarizing the selection of the study sample is presented in Fig. 1. We initially stratified paternal and maternal ages into eight age groups: ≤19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, and ≥50. However, because the upper and lower ends of this distribution led to small cells sizes, we combined the ≤19 and 20–24 groups into a b25 age group, and combined the 40–44,
Fig. 1. Flow chart of the selection of the study sample.
B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
45–49 and ≥50 groups in a ≥40 age group. We used the 25–29 age group as the reference group, its hazard ratio being set to 1.00. We first investigated the effect of parental age (as a categorical variable) on offspring mortality in Cox models adjusted only for subject age. The results were expressed as hazard ratios (HRs) with 95% confidence intervals (95% CIs). We then investigated the effect of parental age (as a categorical variable) on offspring mortality in multivariate Cox models, adjusting for the effects of subject age and age of the other parent (as a continuous variable). Next, we investigated the effect of parental age (categorical) on offspring mortality in multivariate Cox models, adjusting for the effects of subject age, age of the other parent (continuous), and gender. Lastly, we investigated the effect of parental age (as a categorical variable) on offspring mortality in multivariate Cox models, adjusting for the effects of subject age, age of the other parent (continuous), gender, and SES, for those n = 431 subjects with complete data on all variables (Fig. 1). As the inclusion of SES did not change the results and reduced the sample size considerably, it was eliminated from the models. We also tested for a linear association between parental age (continuous) and offspring mortality in multivariate Cox models, adjusting for the effects of subject age, age of the other parent (continuous), and gender. In a secondary analysis, we examined the association between paternal age (categorical) and mortality for males and females separately in multivariate Cox models, adjusting for maternal age (continuous) and subject age. All survival analyses were performed in SPSS version 17.0. 3. Results The final study sample (n=529) consisted of 311 males (60.1%) and 218 females (39.9%). The majority of persons (n=428, 80.9%) had schizophrenia. Other diagnoses in the study sample included psychotic disorder not otherwise specified (n=99, 18.7%), and delusional disorder (n=2, 0.4%). There were 107 deaths (20.2% of the study sample) – 78 (25.1%) males and 29 (13.3%) females – during the follow-up period. The causes of death included 39 suicides (5.7% of the study sample), 24 “other unnatural” deaths (4.5%), and 34 natural deaths (6.4%). Information on the cause of death was missing for 10 subjects (1.9%). There was no difference in the percentage of subjects who died during the follow-up period between subjects with unknown versus known fathers (n=150 subjects, 35 deaths [23.3%] versus n=529 subjects, 111 deaths [21.0%], respectively, p=0.66, Fisher's exact test, two-sided). Table 1 and Fig. 2 present hazard ratios (HRs) for mortality with 95% confidence intervals (CIs) by categorical parental age groups. In the analyses adjusted for subject age, maternal age (continuous), and gender (Model 3), compared to the paternal age 25–29 group, there was a trend for increased allcauses mortality (HR = 1.89, 95% CI 0.95–3.77, p = 0.07) in offspring of fathers age ≥40. Otherwise, there were no significant associations between mortality and categorical paternal age groups. By contrast, compared to the maternal age 25–29 group, there was a trend for increased suicides (HR = 1.96, 95% CI 0.91–4.20, p = 0.09) and decreased other unnatural deaths (HR = 0.30, 95% CI 0.08–1.08, p = 0.07) in offspring of mothers b25. Furthermore, in the fully-adjusted model (Model 3), increasing maternal age (continuous), was
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associated with a decreased risk of suicide (HR = 0.91, 95% CI 0.84–0.98, p = 0.01). There was also a trend for a decreased risk of all-causes mortality (HR = 0.96, 95% CI 0.92–1.01, p = 0.08) with increasing maternal age (continuous). Table 2 presents HRs for mortality with 95% CIs by categorical paternal age groups for males and females separately. After adjusting for subject age and maternal age, there was a significant increase in all-causes mortality (HR=7.04, 95% CI 1.60–31.04, p=0.01) and natural deaths (HR=7.64, 95% CI 1.20–48.66, p=0.03) in female but not male offspring of fathers age≥40. There was also a significant increase in all-causes mortality (HR=7.45, 95% CI 1.78–31.34, pb 0.01) in female offspring of fathers age 35–39, compared to the age 25–29 group. By contrast, increasing maternal age (continuous) was associated with significantly decreased risk of suicide mortality (HR=0.89, 95% CI 0.81–0.97, p=0.01) in males but not females. There was also a trend for a decrease in all-causes mortality (HR=0.95, 95% CI 0.90–1.00, p=0.07) in males but not females with increasing maternal age (continuous). 4. Discussion We found that after adjusting for potential confounders, in the entire sample of patients with nonaffective psychosis, there was a trend for increased all-causes mortality in offspring of fathers age ≥40. By contrast, increasing maternal age was associated with a significant decreased risk of suicide, and a trend for decreased all-causes mortality in the entire sample. We also found a significant increased risk of all-causes mortality in female but not male offspring of fathers age ≥40. By contrast, increasing maternal age was associated with significantly decreased risk of suicide, and a trend for decreased all-causes mortality in males but not females with nonaffective psychosis. We also found a high overall mortality rate (21.5%) in a relatively young cohort of patients with nonaffective psychosis. This result is consistent with previous reports of increased premature mortality in patients with schizophrenia compared to the average life expectancy in the general population from the same geographic area (Brown et al., 2000; Capasso et al., 2008; Tiihonen et al., 2009). To our knowledge, this is the first study to examine the association between parental age and mortality in nonaffective psychosis. The strengths of our study were two-fold. First of all, the subjects with nonaffective psychosis used in this study were drawn from a birth cohort with register-based diagnoses, thus reducing bias in the selection of cases. Secondly, the determination of causes of deaths in Finland is considered extremely reliable (Lahti and Penttilä, 2001). In every case of violent, sudden, or unexpected death in Finland, the possibility of suicide must be assessed by detailed police and medical-legal investigations involving autopsy and forensic examinations (Öhberg and Lönnqvist, 1998; Henriksson et al., 1993; Heilä et al., 1997). This procedure reduces bias due to the potential misclassification of the underlying cause of death. We emphasize the preliminary nature of our secondary analyses stratified by more specific causes of death and gender. One limitation of our findings is that we did not correct for multiple comparisons in these exploratory analyses. Our results warrant replication in larger cohorts, in which multiple comparisons should be considered.
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B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
Table 1 Effects of parental age on risk of death. Cause of death
Variable
All-causes
Paternal age, y b 25 17 25–29 33 30–34 23 35–39 15 ≥40 17 Total 105 Maternal age, y b 25 42 25–29 49 30–34 22 35–39 11 ≥40 8 Total 132 Paternal age, y b 25 5 25–29 16 30–34 6 35–39 5 ≥40 5 Total 37 Maternal age, y b 25 18 25–29 17 30–34 4 35–39 3 ≥40 3 Total 45 Paternal age, y b 25 6 25–29 6 30–34 5 35–39 4 ≥40 3 Total 24 Maternal age, y b 25 3 25–29 13 30–34 6 35–39 4 ≥40 2 Total 28 Paternal age, y b 25 6 25–29 10 30–34 9 35–39 3 ≥40 6 Total 34 Maternal age, y b 25 20 25–29 16 30–34 8 35–39 4 ≥40 1 Total 49
Suicides
Other Unnatural Deaths
Natural Deaths
Deaths (n)
Alive (N)
Model 1 a
Model 2 b
Model 3 c
RR
95% CI
p-value
RR
95% CI
p-value
RR
95% CI
p-value
68 147 97 53 56 421
1.17 1.00 1.08 1.22 1.19
0.65–2.11 Reference 0.63–1.84 0.66–2.26 0.66–2.15
0.60
1.05 1.00 1.27 1.59 1.71
0.58–1.92 Reference 0.72–2.23 0.81–3.11 0.85–3.42
0.87
1.10 1.00 1.24 1.69 1.89 1.02
0.61–2.01 Reference 0.71–2.17 0.86–3.31 0.95–3.77 0.99–1.06
0.75
150 174 112 66 26 528
1.00 1.00 0.71 0.61 0.94
0.66–1.52 Reference 0.43–1.18 0.32–1.17 0.45–1.99
0.99
1.03 1.00 0.63 0.52 0.81
0.63–1.68 Reference 0.35–1.13 0.23–1.15 0.33–2.00
0.91
1.10 1.00 0.62 0.55 0.79 0.96
0.68–1.79 Reference 0.34–1.13 0.25–1.23 0.32–1.95 0.92–1.01
0.70
68 147 97 53 56 421
0.67 1.00 0.55 0.83 0.77
0.25–1.84 Reference 0.22–1.41 0.31–2.27 0.28–2.10
0.44
0.54 1.00 0.76 1.37 1.51
0.20–1.51 Reference 0.29–2.02 0.46–4.07 0.49–4.66
0.24
0.57 1.00 0.72 1.49 1.67 1.03
0.20–1.57 Reference 0.27–1.90 0.50–4.39 0.55–5.08 0.97–1.09
0.27
150 174 112 66 26 528
1.25 1.00 0.38 0.50 1.12
0.64–2.42 0.13–1.12 0.13–1.12 0.15–1.69 0.33–3.81
0.51
1.84 1.00 0.50 0.40 0.73
0.85–3.98 Reference 0.16–1.58 0.09–1.90 0.14–3.80
0.12
1.96 1.00 0.49 0.44 0.70 0.91
0.91–4.20 Reference 0.16–1.54 0.09–2.06 0.14–3.68 0.84–0.98
0.09
68 147 97 53 56 421
2.19 1.00 1.24 1.74 1.19
0.71–6.79 Reference 0.38–4.07 0.49–6.15 0.30–4.78
0.18
2.60 1.00 0.93 1.07 0.61
0.82–8.28 Reference 0.26–3.27 0.25–4.59 0.97–1.17
0.11
2.58 1.00 0.95 1.15 0.70 0.96
0.82–8.15 Reference 0.27–3.31 0.27–4.95 0.13–3.82 0.88–1.04
0.11
150 174 112 66 26 528
0.28 1.00 0.73 0.85 0.94
0.08–0.97 Reference 0.28–1.92 0.28–2.59 0.21–4.17
0.04
0.27 1.00 0.50 1.49 1.99
0.07–0.97 Reference 0.14–1.81 0.41–5.42 0.33–12.14
0.05
0.30 1.00 0.50 0.16 1.98 1.07
0.08–1.08 Reference 0.14–1.85 0.44–5.76 0.30–12.96 0.97–1.17
0.07
68 147 97 53 56 421
1.51 1.00 1.53 0.86 1.36
0.54–4.23 Reference 0.61–3.86 0.23–3.17 0.48–3.86
0.44
1.30 1.00 1.93 1.24 2.23
0.45–3.72 Reference 0.73–5.13 0.31–5.00 0.66–7.57
0.63
1.30 1.00 1.93 1.24 2.24 1.02
0.45–3.74 Reference 0.73–5.12 0.31–5.02 0.66–7.63 0.96–1.08
0.63
150 174 112 66 26 528
1.44 1.00 0.79 0.65 0.33
0.73–2.83 Reference 0.34–1.84 0.22–1.94 0.04–2.51
0.29
1.15 1.00 0.72 0.37 0.29
0.48–2.71 Reference 0.27–1.92 0.08–1.70 0.04–2.48
0.75
1.15 1.00 0.72 0.37 0.29 0.96
0.49–2.74 Reference 0.27–1.92 0.08–1.71 0.03–2.47 0.89–1.04
0.75
0.79 0.52 0.56
0.19 0.13 0.88
0.21 0.72 0.61
0.08 0.26 0.86
0.72 0.39 0.80
0.53 0.77 0.94
0.37 0.82 0.56
0.58 0.44 0.29
0.41 0.18 0.13
0.12 0.11 0.65
0.58 0.57 0.48
0.24 0.25 0.71
0.91 0.92 0.57
0.29 0.54 0.46
0.19 0.76 0.20
0.51 0.20 0.26
0.45 0.13 0.07 0.26
0.12 0.15 0.60 0.08
0.51 0.47 0.37 0.33
0.22 0.29 0.68 0.01
0.94 0.85 0.68 0.31
0.30 0.48 0.47 0.19
0.19 0.76 0.20 0.61
0.51 0.20 0.26 0.29
HR = Hazard Ratio. 95% CI = 95% Confidence Interval. a Adjusted for subject age. b Adjusted for subject age and age of the other parent (continuous). c Adjusted for subject age, age of the other parent (continuous), and gender.
Another important limitation of the study was that paternal age data were missing for 22% of the study sample (n = 150 subjects). For these subjects, it was not possible to differentiate between fathers who died before 1970 (which would be biased
towards older fathers) and unknown fathers. It is reassuring that there was no difference in the percentage of subjects who died during the follow-up period between subjects with unknown versus known fathers. Furthermore, an association
B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
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Fig. 2. Paternal age and mortality risk by cause of death. Hazard ratios (HR) for categorical paternal age groups (reference group = 25–29) are adjusted for maternal age, gender, and socio-economic status. 95% confidence intervals are shown for all-cause mortality.
between advanced paternal age and increased mortality in other general population studies (Zhu et al., 2008; Miller et al., in press) supports the plausibility of our findings, and that the observed associations were not due to Type 1 error. We did not have any data on subjects without nonaffective psychosis, in order to make comparisons to the general population from which these cases of nonaffective psychosis were identified. Furthermore, subjects who developed nonaffective psychosis and died before 1969 were missing. This is likely to be a very small number of cases. The relationship between paternal age and earlier age of onset cases of nonaffective psychosis is unknown. However, for each subject who was initially identified from the health care registers with nonaffective psychosis, the follow-up information regarding mortality is complete. Taken together, it is not expected that these missing data would substantially change our results. Another limitation of the present study is that the relatively small number of deaths may have limited the statistical power of our analyses. Our previous study (Miller et al., in press) found that increasing paternal age was associated with increased allcauses mortality and suicides in females in the general population. We observed an increase in all-causes mortality with increasing paternal age in females, though the association was not significant (HR = 1.05, 95% CI 0.99–1.11, p = 0.12). It is possible that there is an association between paternal age and increased suicide mortality in females with psychosis, which our study did not have the statistical power to detect, as the female group was 32% smaller than the male group. We were
also unable to further stratify natural deaths by more specific causes due to small numbers. Our results, therefore, should be interpreted with caution, and warrant replication in larger cohorts. We did not use parity as a covariate due to incomplete data on siblings in the Finnish population register for persons born in the 1950s, although one study found parity of the mother was a significant predictor of mortality in the offspring (Modin, 2002). In that study, the parity effect was partly mediated by adult social class, education and income, and we adjusted for SES in this paper. Moreover, another study did not find evidence that birth order was associated with adult mortality in the offspring (O'Leary et al., 1996). Parity is also strongly correlated with maternal and paternal age. In our previous study, we did not find an association between paternal age and natural cause mortality in the general population (Miller et al., in press). However, subjects in that study were followed to age 39, compared to age 46 to 55 in the present study. A possible explanation for the absence of an association in our general population study is that there are significant differences in leading causes of death in these two age groups. Since the risk of natural cause mortality increases with increasing age, the difference may also have been due to a Type II error, as a result of a shorter length of follow-up. On the other hand, schizophrenia and related disorders are also associated with increased premature mortality from natural deaths (Brown, 1997; Saha et al., 2007), and it is possible that the paternal age effect on natural cause mortality is restricted to
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B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
Table 2 Hazard ratios for paternal age by cause of death and gender. Males a
Cause of death
Variable
All-causes
Paternal age, y b 25 14 25–29 29 30–34 17 35–39 8 ≥40 9 Total 77 Maternal age, y b 25 29 25–29 38 30–34 13 35–39 5 ≥40 7 Total 92 Paternal age, y b 25 5 25–29 15 30–34 5 35–39 2 ≥40 4 Total 31 Maternal age, y b 25 16 25–29 12 30–34 3 35–39 1 ≥40 3 Total 35 Paternal age, y b 25 5 25–29 6 30–34 4 35–39 3 ≥40 1 Total 19 Maternal age, y b 25 3 25–29 11 30–34 3 35–39 1 ≥40 2 Total 20 Paternal age, y b 25 4 25–29 7 30–34 5 35–39 1 ≥40 1 Total 18 Maternal age, y b 25 10 25–29 12 30–34 4 35–39 3 ≥40 0 Total 29
Deaths (n)
Suicides
Other Unnatural Deaths
Natural Deaths
Females a Alive (N)
RR
95% CI
p-value
Deaths (n)
Alive (N)
35 80 58 29 30 232
1.08 1.00 0.97 1.08 1.27 1.01
0.56–2.06 Reference 0.52–1.81 0.46–2.52 0.53–3.00 0.96–1.05
0.83
3 4 6 7 8 28
33 67 39 24 26 189
1.65 1.00 4.12 7.45 7.04 1.05
0.33–8.34 Reference 0.97–17.43 1.78–31.34 1.60–31.04 0.99–1.11
78 100 70 37 14 299
1.08 1.00 0.53 0.35 1.14 0.95
0.63–1.87 Reference 0.25–1.10 0.10–1.20 0.39–3.34 0.90–1.00
0.78
13 11 9 6 1 40
72 74 42 29 12 229
1.34 1.00 1.16 0.93 0.35 0.98
0.45–4.00 Reference 0.40–3.33 0.30–2.96 0.04–2.97 0.91–1.06
35 80 58 29 30 232
0.61 1.00 0.64 0.69 1.58 1.02
0.22–1.71 Reference 0.23–1.82 0.15–3.24 0.47–5.33 0.96–1.09
0.35
0 1 1 3 1 6
33 67 39 24 26 189
0.00 1.00 2.10 10.32 3.53 1.05
78 100 70 37 14 299
2.33 1.00 0.50 0.34 1.07 0.89
1.00–5.45 Reference 0.13–1.92 0.04–2.86 0.18–6.23 0.81–0.97
0.05
2 5 1 2 0 10
72 74 42 29 12 229
0.93 1.00 0.52 0.57 0.00 0.97
0.14–6.20 Reference 0.05–5.02 0.06–5.93
0.93
0.82–1.12
0.71
35 80 58 29 30 232
2.08 1.00 0.82 1.03 0.31 0.95
0.62–0.94 Reference 0.22–3.07 0.21–5.21 0.03–3.37 0.85–1.05
0.23
1 0 1 1 2 5
33 67 39 24 26 189
1.00 0.00 0.24 0.32 0.34 0.98
Reference
78 100 70 37 14 299
0.34 1.00 0.40 0.54 3.07 1.05
0.09–1.25 Reference 0.08–1.90 0.06–4.78 0.35–27.32 0.93–1.16
0.11
0 2 3 3 0 8
72 74 42 29 12 229
0.00 1.00 1.79 8.22 0.00 1.15
35 80 58 29 30 232
1.47 1.00 1.20 0.56 0.58 0.96
0.42–5.24 Reference 0.36–4.02 0.06–5.26 0.06–6.00 0.86–1.07
0.55
2 3 4 2 5 16
33 67 39 24 26 189
78 100 70 37 14 299
1.01 1.00 0.43 0.52 0.00 0.96
0.35–2.92 Reference 0.09–2.11 0.06–4.51
0.99
0.86–1.07
0.49
10 4 4 1 1 20
72 74 42 29 12 229
0.93 0.87 0.59 0.81
0.09 0.10 0.81 0.07
0.40 0.64 0.46 0.53
0.31 0.32 0.94 0.01
0.76 0.97 0.33 0.29
0.25 0.58 0.32 0.52
0.70 0.61 0.65 0.49
0.30 0.55
RR
95% CI
Reference 0.12–37.06 0.88–120.69 0.17–75.82 0.93–1.18
p-value 0.54 0.05 b 0.01 0.01 0.11 0.60 0.79 0.91 0.33 0.67
0.61 0.06 0.42 0.41
0.57 0.64
0.01–7.37 0.01–11.40 0.01–14.47 0.84–1.15
0.41 0.53 0.57 0.84
Reference 0.11–29.27 0.60–112.77
0.69 0.12
0.96–1.38
0.14
1.46 1.00 0.04 3.82 7.64 1.05
0.20–10.67 Reference 0.83–29.40 0.49–29.97 1.20–48.66 0.98–1.13
0.71
1.82 1.00 1.56 0.33 0.52 0.96
0.39–8.53 Reference 0.39–6.29 0.04–3.03 0.05–5.17 0.87–1.06
0.45
0.08 0.20 0.03 0.17
0.53 0.33 0.57 0.42
HR = Hazard Ratio. 95% CI = 95% Confidence Interval. a Adjusted for subject age, age of the other parent (continuous).
patients with nonaffective psychosis. Furthermore, causes of death that are prevalent in subjects beyond middle age are not represented here, and if subjects in this study were followed past age 55, our findings may have been different. Our data provide little basis for postulating a mechanism of this effect, which may be mediated by biological factors,
psychosocial factors, or both. Several biological mechanisms have been proposed for the adverse health effects of increasing paternal age. There is evidence for an increased rate of de novo mutations with advanced paternal age (Crow, 1997). The possibility of epigenetic changes, such as imprinting, DNA methylation, or histone acetylation, has also been proposed, but
B. Miller et al. / Schizophrenia Research 121 (2010) 218–226
this mechanism has not been thoroughly investigated (Perrin et al., 2007). Several disorders that have been related to advanced paternal age are also associated with increased natural cause mortality, including diabetes and other components of the metabolic syndrome (Osmond and Barker, 2000) and some cancers (Kaijse et al., 2003), and it is possible that both mutations and epigenetic changes contribute. However, one could also postulate non-genetic explanations for this association. One possibility is that advanced paternal age is associated with an adverse psychosocial environment during prenatal development. Exposure to prenatal stress in pregnancy appears to confer on the offspring an increased risk of developing schizophrenia later in life (Malaspina et al., 2008; Susser et al., 1996). Prenatal stress and developmental problems have also become an increasingly important area of research in diabetes and other aspects of the metabolic syndrome (Osmond and Barker, 2000; Ravelli et al., 1998), thereby increasing risk of natural death. Potential stressors during gestation that may be associated with older fathers include loss of the father due to death or divorce, paternal psychiatric disorders, or other adverse health and personality factors related to aging. Further examination of the social consequences of advancing paternal age would be desirable. Although the primary focus of our paper was paternal age, we also found that increasing maternal age was associated with a significant decreased risk of suicide in males but not females. To our knowledge, this is the first study to report an association between maternal age and suicide mortality in nonaffective psychosis. In the general population, younger maternal age is a replicated risk factor for suicide (Riordan et al., 2006; Ekéus et al., 2006; Mittendorfer-Rutz et al., 2004). Our data provide little basis for postulating whether the maternal age effect is mediated by biological factors, psychosocial factors, or both. This finding should be also explored in larger cohorts. An understanding of this risk factor has substantial public health potential, as average paternal ages are increasing (Bray et al., 2006). Older paternal age is becoming more common, has widespread effects, and it might be possible to elucidate the mechanism of this association with animal studies. Accounting for the paternal age effect as a potential confounding factor may increase the signal-to-noise ratio in other epidemiological and genetic analyses in future mortality research both in samples of patients with nonaffective psychosis and the general population. Role of the funding source Dr. Miller receives grant support from the University of Oulu, Finland, and Oy H. Lundbeck Ab. Dr. Cannon received grant support from the Health Research Board (Ireland) and NARSAD. Dr. Suvisaari received grant support from the Academy of Finland. Dr. Kirkpatrick was provided in part by grant R01 DK069265 from the National Institute of Diabetes and Digestive and Kidney Diseases. The University of Oulu, Oy H. Lundbeck Ab, the Health Research board, NARSAD, the Academy of Finland, and the NIDDK had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Drs. Miller, Suvisaari, and Kirkpatrick designed the study. Dr. Miller managed the literature searches. Dr. Haukka managed the analyses. Drs. Miller, Cannon, Suvisaari, and Kirkpatrick wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest Dr. Miller has no conflicts of interest to disclose. Dr. Pihlajamaa has no conflicts of interest to disclose.
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Dr. Haukka has no conflicts of interest to disclose. Dr. Cannon has no conflicts of interest to disclose. Dr. Henriksson has no conflicts of interest to disclose. Dr. Heilä has no conflicts of interest to disclose. Dr. Huttunen has no conflicts of interest to disclose. Dr. Tanskanen has no conflicts of interest to disclose. Dr. Lönnqvist has no conflicts of interest to disclose. Dr. Suvisaari has no conflicts of interest to disclose. Dr. Kirkpatrick received consulting and/or speaking fees from Pfizer, Organon, AstraZeneca, Wyeth, Bristol Myers Squibb, Solvay, and Cephalon.
Acknowledgements The authors would like to acknowledge Kirsi Niinistö, Johanna Koskela, MD, and Elisa Karjalainen, MD, PhD for assistance. The sample collection was funded by the Theodore and Vada Stanley Foundation and the Wellcome Trust through grants to Mary Cannon.
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