Schizophrenia Research 160 (2014) 131–135

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Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres

Effects of paternal age and offspring cognitive ability in early adulthood

on the risk of schizophrenia and related disorders
Holger J. Sørensen a,d,⁎, Carsten B. Pedersen b,d, Merete Nordentoft a,d, Preben B. Mortensen b,d,
Vera Ehrenstein c, Liselotte Petersen b,d
a
Mental Health Centre, Capital Region of Denmark, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark
b
National Centre for Register-Based Research, Aarhus University, Fuglesangs Allé 4, DK-8210 Aarhus V, Denmark
c
Department of Clinical Epidemiology, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark
d
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Advanced paternal age (APA) and intelligence quotient (IQ) are both associated with the risk of schizophrenia
Received 26 January 2014 spectrum disorder (SSD) in young adult offspring. We hypothesized that the offspring SSD risk gradient
Received in revised form 4 September 2014 associated with paternal age is mediated by offspring IQ. We investigated joint and separate associations of
Accepted 16 September 2014
paternal age and offspring IQ with the risk of SSD. We used IQ routinely measured at conscription in Danish
Available online 20 October 2014
males (n = 138,966) from cohorts born in 1955–84 and in 1976–1993 and followed them from a year after
Keywords:
the conscription through 2010. We used Cox regression to estimate the incidence rate ratio (IRR) of SSD. During
Schizophrenia the follow-up, 528 men developed SSD (incidence rate [IR] 5.2 and 8.6 per 10,000 person-years in the first and
Schizophrenia-spectrum disorder second cohorts, respectively). APA was associated with higher risk of SSD (IRR, 1.32; 95% CI, 1.10–1.60 per a
Paternal age ten-year increase in paternal age). A higher IQ was associated with lower SSD risk (IRR, 0.68; 95% confidence
Intelligence interval [CI], 0.63–0.74 per one SD increase). The IR of SSD was higher among persons who were draft-exempt
General cognitive ability for health reasons (b20% of the men). Overall, there was little evidence of lower premorbid IQ in APA-related
SSD (individuals who developed SSD and were also offspring of older fathers). Our results do not support the
notion that risk gradient for offspring SSD associated with paternal age is mediated by offspring IQ.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction Several studies suggest that lower IQ is associated with an increased

Studies have consistently shown associations of advanced paternal
age (APA) with an increased risk of schizophrenia (Miller et al.,
2011a) and associations with a range of other psychiatric morbidities
in offspring have also been found (D'Onofrio et al., 2014). Furthermore,
associations between APA and lower offspring general cognitive ability
(IQ) have been observed in some (Malaspina et al., 2005; Saha and
McGrath, 2012), but not all (Svensson et al., 2011; Myrskyla et al.,
2013; McGrath et al., 2013), published studies. It is uncertain whether,
and to what extent, APA, offspring IQ and offspring risk of schizophrenia
are interrelated. The association between APA and offspring psychiatric
morbidity might involve de novo mutations (Goriely et al., 2013) and if
offspring of older fathers perform worse on tests of general cognitive
ability (Malaspina et al., 2005; Saha and McGrath, 2012), then offspring
of older fathers who develop schizophrenia may display more signs of
abnormal neurodevelopment, for instance manifested by lower level
of premorbid general cognitive ability.
⁎ Corresponding author at: Mental Health Centre Copenhagen, Bispebjerg Bakke 23,
DK-2400 Copenhagen NV, Denmark.
E-mail address: holger.jelling.soerensen@regionh.dk (H.J. Sørensen).
risk of subsequent schizophrenia (Mortensen et al., 2005; Reichenberg
et al., 2006; Meier et al., 2014; Kahn and Keefe, 2013). To our knowledge,
no large-scale study on the association between APA and risk of schizo-
phrenia has previously taken IQ into account as a possible mediator.
We hypothesized that the association between APA and schizophrenia
spectrum disorders (SSD) in offspring is mediated by a lower offspring
IQ. Thus, we expected the premorbid IQ to be lower in individuals with
SSD who were also the offspring of older fathers (“APA-related SSD”)
compared with SSD patients born to younger fathers. We addressed
this hypothesis using data combined from two cohorts of Danish male
draftees (Norgaard et al., 2009; McGrath et al., 2013).
2. Materials and methods
2.1. Procedure
Denmark maintains mandatory military conscription for all men,
and they become draft-liable at age 18 years. Recently, the Danish
National Board of Health has established a nationwide Draft Board reg-
ister of everyone evaluated for by the Draft Board from 2006 onwards.
The present study was based on data from this register, which presently

http://dx.doi.org/10.1016/j.schres.2014.09.035
0920-9964/© 2014 Elsevier B.V. All rights reserved.
132 H.J. Sørensen et al. / Schizophrenia Research 160 (2014) 131–135
contains records of men born 1976–1993 who appeared before the
Draft Board in 2006–2010, combined with data from the North Jutland
birth cohort of men born 1955–1984, who appeared before the Draft
Board 1974–2002 (Sorensen et al., 1997; Norgaard et al., 2009). The
pooled data from both cohorts encompasses records of 176,454 men
who born between 1955–1984 and 1976–1993. To ensure the availabil-
ity of information of the men and their parents, we used the Danish Civil
Registration System (Pedersen, 2011) to restrict the study population to
Danish men with Danish-born parents. After this restriction, the dataset
contained 152,506 men. Men with preexisting conditions such as severe
mental retardation, asthma and extreme myopia mental health condi-
tions, musculoskeletal disorders and earlier injury/trauma are exempted
from conscription. Not all mental health problems are regarded as
disqualifiers for military service (Osler et al., 2007; Teasdale, 2009).
Exemption rates for health reasons have varied between 10 and 15%
(Norgaard et al., 2009) and about 80% of all Danish males born
1976–1993 have appeared before the Draft Board in 2006–2010.
2.2. Assessment of schizophrenia spectrum disorders in cohort members
and family members
Due to considerations regarding statistical power, we decided to ex-
amine schizophrenia spectrum disorders (SSD). Records of the cohort
members and their mothers and fathers were linked with information
from the Danish Psychiatric Central Register (Mors et al., 2011). This
register has been computerized since 1969 and contains data on all
admissions to Danish psychiatric in-patient facilities, and, from 1995 on-
wards, information on outpatient visits to psychiatric departments. To
code diagnoses, the registry used the Danish modification of the Interna-
tional Classification of Diseases, 8th revision (ICD-8) in 1969–1993
and the International Classification of Diseases, 10th revision (ICD-10)
thereafter. Schizophrenia spectrum disorder (SSD) was defined for
study population members and their parents as a psychiatric hospitaliza-
tion or an outpatient visit with a diagnosis in the schizophrenia spectrum
(ICD-8 code 295 [schizophrenia], 296.89 [schizoaffective disorder], 297,
298.39, 301.83 [schizophrenia-like]) or ICD-10 code F20–29 (including
F20 [schizophrenia], F25 [schizoaffective disorder], F21[ schizotypal per-
sonality] and other spectrum diagnoses such as F23 [acute psychoses]
and F22 [paranoid psychoses]).
2.3. Parental age, parental education, and birth order
Variables for maternal and paternal age and education at conscripts'
birth were obtained from Statistics Denmark. Variables for paternal and
maternal education were categorized, separately for fathers and
mothers, into basic, high school, vocational, medium or higher education
(corresponding to university level). Birth order was defined using mater-
nal parity.
2.4. Assessment of intelligence in early adulthood
The Danish Military Draft Board has used the Børge Prien's test
(Børge Priens Prøve [BPP]) since 1956 (Reinisch et al., 1995). The BPP
is a 45-minute 78-item group intelligence test consisting of 4 subtests
(logical, verbal, numerical, spatial reasoning). The test score is the
number of correct answers across subtests (range 0–78). The BPP
score has a correlation of 0.82 with the full-scale WAIS IQ (Mortensen
et al., 2002; Teasdale et al., 2011).
2.5. Study design and statistical analyses
We restricted our cohort to persons with available BPP data and ex-
cluded 118 men with a diagnosis within the schizophrenia spectrum
within 1 year after appearing before the Draft Board. The final analysis
dataset contained 138,966 men. The cohort members were followed
until the first diagnosis with SSD, death, emigration from Denmark, or
Dec. 31, 2011, whichever came first. Incidence rate ratios were estimated
using Cox regression in Stata 10 (Stata, College Station, Texas, United
States). The basic model was adjusted for age in the non-parametric
part of the Cox model, and for calendar time as a time dependent
variable. The periods were categorized in groups: 1970–79, 1980–89,
1990–91, 1992–93, 1994–95, 1996–97, 1998–99, 2000–03, 2004–07,
and 2008–10. The use of two-year intervals from 1990 to 1999 was due
to the change in diagnostic classification system which took place in
1993–94. The change in registration practice from 1995 to include outpa-
tient visits necessitated the use of two-year intervals up to 1999. The use
of three-year intervals from 2000 and onwards was due to a rise in the
incidence of schizophrenia and related disorders in Denmark during
this period. Year of birth was categorized to include approximately
equal number of persons: 1960–64, 1965–69, 1970–74, 1975–79,
1980–84, 1985–86, 1987, 1988, 1989, 1990, 1991, and 1992–93. Paternal
age at conscript's birth was categorized as below 24, 25–29 (ref), 30–34,
35–39, 40–44, and above 45 years, and maternal age at conscript's birth
was categorized as below 20, 20–24, 25–29 (ref), 30–34, and above
35 years as elsewhere (Pedersen and Mortensen, 2001; Sørensen et al.,
2014). We examined the effects of paternal age as a categorical as well
as a continuous variable.
For the study population, the mean BPP score was 41.7 and the
standard deviation (SD) was 10.0. In the analyses, we estimated effects
associated with 1 SD increase in BPP. We also adjusted for the degree of
urbanicity of the place of birth (capital, capital suburb, towns with
more than 100,000 inhabitants, towns with more than 10,000–100,000
inhabitants, and rural areas). Familial psychiatric history was analyzed
separately for mothers, fathers and siblings as a time-dependent variable.
Birth order was categorized as first, second, third, fourth or higher.
Cognitive performance is not measured in the men exempted before
the Draft Board evaluation. To assess the impact of a potential selection
bias, the IRs of developing SSD were calculated among the exempted in
the two cohorts and sensitivity analyses were carried out to compare
the IRs of the exempted to those of Danish men in either a provincial
rural area (the North Jutland cohort) or all Danish males of similar age
distributions.
3. Results
During a follow-up of 847,466 person-years, 528 persons were regis-
tered with a SSD, predominantly a diagnosis of schizophrenia (n = 337,
64%) or schizoaffective disorder (n = 16, 3%). The remaining 175 persons
were registered with schizotypal personality disorder, brief psychotic
disorder, or delusional disorder. The North Jutland cohort contributed
approximately 596,000 person-years and 312 SSD cases (IR = 5.23 per
10,000 person-years). The younger nationwide cohort of males who ap-
peared before the Draft Board during 2006–2010 contributed 251,000
person-years and 216 SSD cases (IR = 8.61 per 10,000 person-years).
Table 1 shows descriptive characteristics of the 138,966 Danish male
conscripts born 1955–1993 according to paternal age at conscripts'
birth. As expected, parental age directly correlated with educational
length. Compared with conscripts born to younger fathers, conscripts
born to fathers aged 40 or older had a higher proportion of schizophre-
nia spectrum disorder and psychiatric admissions among their siblings.
Schizophrenia and psychiatric admissions in general were more com-
mon in mothers than in fathers, reflecting known reproductive patterns
in people with psychosis (Laursen and Munk-Olsen, 2010). Compared
with conscripts born in the capital, conscripts born in rural areas had
greater prevalence of the youngest and the oldest fathers. Proportion
of firstborns was inversely associated with the age of the father.
3.1. Effects of IQ, parental age and parental education on the risk of SSD
Table 2 shows unadjusted and adjusted incidence rate ratios (IRR)
for developing SSD (n = 528) according to BPP score at Draft Board
assessment; paternal and maternal age, and paternal and maternal
 H.J. Sørensen et al. / Schizophrenia Research 160 (2014) 131–135 133

Table 1
Characteristics of 138,966 Danish male conscripts born 1955–1993 at baseline (1 year after Draft Board examination date) and schizophrenia spectrum disorders (SSD) during the follow-
up according to paternal age at conscripts' birth.

Paternal age at birth

12–24 years 25–29 years 30–39 years 40+ years

N = 19,241 N = 48,595 N = 61,780 N = 9350

Baseline characteristics (%)

Mother older than 30 years at birth 1.7 8.4 51 79
Mother has medium or long education 12 24 34 32
Father has medium or long education 10 22 30 27
Mean year of birth (years) 1983 1985 1985 1983
Schizophrenia spectrum disorder in mother 0.15 0.09 0.07 0.12
Schizophrenia spectrum disorder in father 0.09 0.03 0.04 0.03
Schizophrenia spectrum disorder in sibling 1.2 1.2 1.6 3.4
Psychiatric admission in mother 2.5 1.4 1.3 2.7
Psychiatric admission in father 2.1 1.2 1.1 1.4
Psychiatric admission in sibling 16 12 12 18
Born in a rural area 37 39 40 40
Born in the capital 8.0 7.9 7.7 9.1
Firstborn child 78 56 32 30
SSD during follow-up
Number of cases 93 184 198 53
Time at risk (thousand years) 144 287 345 71
Incidence rate of SSD (per 10,000 years) 6.45 6.41 5.73 7.48

education level. Covariates were urbanicity at birth, birth order and psy-
chiatric family history. We furthermore adjusted for study period and
study cohort as explained in Section 2.5. After adjusting for study period
and study cohort, higher IQ was associated with a lower risk of SSD:
IRR = 0.68 (95% CI 0.63–0.74) per 1 SD increase in IQ. Adjustment for
any other covariates did not materially affect this estimate (Table 2).
We furthermore found that the IRR for SSD was significantly associ-
ated with APA with and without adjustment for other risk factors. In the
fully adjusted model, IRR for SSD was 1.89; 95% CI, 1.13–3.17 comparing
conscripts born to fathers aged 45 year or older with those born to
fathers aged 25–29 years. There was an about 30% increase in the risk
of SSD (IRR, 1.32; 95% CI, 1.10–1.60) per 10 year increase in paternal
age at birth. Conversely, we did not observe a significant association be-
tween maternal age at birth and SSD. Offspring of mothers with high
school education level had a lower risk of SSD than the offspring of
mothers with basic education levels (IRR, 0.75; 95% CI, 0.60–0.94). No
clear effect was observed for the father's education (Table 2).
We reran all analyses with schizophrenia (ICD-10 code F20 or ICD-8
code 295.xx) as an alternative outcome. The period and cohort adjusted,
and fully adjusted effects of IQ and paternal age were of similar magni-
tude as the effects shown in Table 2. The period and cohort adjusted
effects were as follows: (IRR = 0.69 (95% CI 0.62–0.76) per SD for the
IQ variable and 1.36 (95% CI 1.07–1.73) per 10 years for paternal age.
The fully adjusted estimates were similar (data not shown).
3.2. Interactions
Table 3 shows the association between IQ and SSD according
to father's age at birth. The inverse association between individual
cognitive ability and IRR for SSD did not vary with the age of the father
(p = 0.91 for interaction). Further analyses investigating possible inter-
actions between the parents' level of education and the risk for the
offspring of developing SSD did not reach significance (p = 0.10). We
further investigated the interaction of the fathers' and mothers' level
of education in the analyses as demonstrated in Table 2. However,
including this interaction possibility did not produce altered risk
estimates between individual cognitive ability and the risk of SSD, nor
between the age of the fathers and the birth of the child and the child's
risk of SSD.
3.3. Analyses concerning generalizability of the findings
Approximately 80% of all Danish men born 1976–93 appeared before
the Draft Board between 2006 and 2010. In those 80%, the IR of develop-
ing SSD was 8.6 per 10,000 person-years. In all Danish males born 1976–
93, the IR of developing SSD was 18.7 per 10,000 person-years. The
selection was less pronounced in the North Jutland cohort where the
IR for SSD was 5.2 per 10,000 person-years for non-exempt men and
5.1 per 10,000 person-years for SSD for all Danish men born 1955–84
in a provincial or rural area. When the North Jutland cohort was ana-
lyzed separately, the linear effects of IQ (IRR, 0.69; 95% CI 0.62–0.77)
per 1 SD increase, and paternal age per 10 years' increase (IRR, 1.33;
95% CI 1.05–1.70) on the risk of developing SSD were similar to effects
in the overall study population. There was no evidence for interaction
between IQ and paternal age at birth (p = 0.75) in the North Jutland co-
hort. Similarity of the estimates argues against selection bias affecting
the observed associations.
4. Discussion
To our knowledge, this is the first large-scale study investigating the
effects of advanced paternal age and general cognitive ability on the risk
of schizophrenia spectrum disorders. Among Danish male conscripts, a
one-SD increase in IQ at conscription was associated with about a 30%
decreased risk of SSD. Both APA and IQ were associated with the risk
of SSD independently of a wide range of covariates, including parental
education. There was no evidence of interaction between offspring IQ
and paternal age on the risk of SSD.
4.1. Strengths and limitations
The prospective design and the population-based nationwide regis-
ters in Denmark ensured a relatively large study population for whom
information is recorded independently of the studied outcome and
therefore not subject to recall bias. As previously shown, reasons for
being exempt from the Draft Board evaluation for health reasons
(Norgaard et al., 2009) were many and diverse (Osler et al., 2007;
Teasdale, 2009) and it is unlikely that our results are explained by selec-
tion. The multivariate approach adjusted for a wide range of factors
including the potentially confounding effects of the educational level
134 H.J. Sørensen et al. / Schizophrenia Research 160 (2014) 131–135

Table 2
Incidence rate ratios of schizophrenia spectrum disorders in Danish men according to IQ, parental age and parental education.

Number Period and cohort IQ and parental ages IQ and parental ages and Fully
of cases adjusted mutually adjusted education mutually adjusted adjusteda

BPP score (IQ) at Draft 0.68 (0.63–0.74) 0.69 (0.63–0.75) 0.70 (0.65–0.77) 0.72 (0.66–0.78)
Board (per 1 SD increase)
Paternal age group, years
b24 93 0.95 (0.72–1.25) 0.94 (0.71–1.23) 0.93 (0.71–1.22) 0.92 (0.70–1.21)
25–29 184 1 (ref) 1 (ref) 1 (ref) 1 (ref)
30–34 128 0.99 (0.78–1.26) 0.98 (0.77–1.25) 0.98 (0.77–1.25) 0.96 (0.76–1.23)
35–39 70 1.27 (0.92–1.75) 1.24 (0.90–1.70) 1.23 (0.89–1.69) 1.19 (0.87–1.63)
40–44 31 1.41 (0.91–2.19) 1.33 (0.85–2.07) 1.30 (0.83–2.03) 1.20 (0.77–1.87)
≥45 22 2.33 (1.39–3.89) 2.13 (1.27–3.57) 2.08 (1.23–3.49) 1.89 (1.13–3.17)
Increase per 10 years 1.32 (1.10–1.60) 1.29 (1.07–1.55) 1.28 (1.06–1.54) 1.24 (1.03–1.49)
Maternal age group, years
b20 30 1.46 (0.95–2.26) 1.26 (0.82–1.95) 1.20 (0.77–1.86) 1.16 (0.74–1.82)
20–24 176 1.26 (1.00–1.58) 1.18 (0.94–1.49) 1.17 (0.93–1.47) 1.16 (0.92–1.47)
25–29 185 1 (ref) 1 (ref) 1 (ref) 1 (ref)
30–34 82 0.75 (0.56–0.99) 0.76 (0.58–1.01) 0.76 (0.58–1.01) 0.74 (0.56–0.99)
≥35 55 0.99 (0.68–1.44) 1.02 (0.70–1.49) 1.01 (0.70–1.47) 0.95 (0.65–1.40)
Paternal education
Basic 232 1 (ref) 1 (ref) 1 (ref)
High school 199 0.91 (0.74–1.11) 1.02 (0.83–1.25) 1.05 (0.86–1.29)
Vocational 12 1.01 (0.56–1.82) 1.27 (0.70–2.31) 1.22 (0.67–2.22)
Medium 67 0.95 (0.71–1.28) 1.20 (0.88–1.62) 1.22 (0.90–1.65)
Long 18 0.91 (0.74–1.11) 0.92 (0.54–1.56) 0.87 (0.51–1.49)
Maternal education
Basic 299 1 (ref) 1 (ref) 1 (ref)
High school 133 0.64 (0.52–0.80) 0.73 (0.58–0.91) 0.75 (0.60–0.94)
Vocational 7 0.40 (0.19–0.85) 0.49 (0.23–1.04) 0.49 (0.23–1.05)
Medium 82 0.64 (0.49–0.84) 0.80 (0.61–1.07) 0.82 (0.61–1.09)
Long 7 0.44 (0.20–0.99) 0.59 (0.26–1.32) 0.57 (0.25–1.28)
a
Also adjusted for urbanicity at birth, birth order and familial history of psychiatric contacts.

of the parents, number of siblings, as well as parental psychiatric
morbidity. Adjustment for parental psychiatric morbidity is potentially
important since it is possible that patients with schizophrenia have
lower IQ scores and more deviant personality traits with greater
number of childhood adversities, and adversity sub-types of abusive, ne-
glectful and dysfunctional parenting (McCabe et al., 2012). Furthermore,
parenting skills may be related to the risk of schizophrenia in the
offspring (Jones et al., 1994). A limitation of this study was availability
of only the composite measure of general cognitive ability assessed
only once at the age of conscription. Moreover, some of the youngest
cohort members had not lived through a significant proportion of the
risk period for SSD.
4.2. Effects of covariates
Maternal educational level of the mother influences the child's
neurocognitive outcome (Edwards and Roff, 2010), and low maternal
educational level was associated with an increased risk of developing
SSD in our study, corroborating the findings of an earlier cohort study
(Bao et al., 2012). We did not, however, find that a short maternal
education altered the overall association between APA and risk of SSD
or between IQ and risk of SSD. Because lower educational level influ-
ences certain health behaviors during pregnancy (Knudsen et al.,
2007), we speculate that a shorter maternal education might correlate
Table 3
Association between schizophrenia spectrum disorders and cognitive ability at Draft
Board according to paternal age at birth.
Paternal age at birth, years IRR for schizophrenia spectrum disorder
per 1 SD increase in IQ at Draft Board
b24 0.70 (0.58–0.85)
25–29 0.74 (0.64–0.85)
30–34 0.70 (0.59–0.83)
35–39 0.76 (0.61–0.94)
40–44 0.77 (0.56–1.04)
≥45 0.88 (0.60–1.29)
with conditions during pregnancy of potential relevance for the devel-
opment of SSD in the offspring (Sorensen et al., 2011).
4.3. APA and subgroups
Mechanisms related to neurodevelopment in APA-related SSD could
be different from non-APA-related SSD. Previous work on the deficit
syndrome schizophrenia (Carpenter et al., 1988) and on the classifica-
tion of endogenous psychoses by Kleist and Leonhard (Schulze, 1990;
Leonhard and Karl, 1999) suggests that mutually exclusive forms of
schizophrenia may exist (Cohen et al., 2010). APA is a candidate for ex-
ploration of the impact of etiological differences on treatment response
in schizophrenia and recent evidence suggests that APA-related
adolescent-onset schizophrenia is associated with greater treatment
response to antipsychotic medical treatment (paliperidone) (Opler
et al., 2013). We were unable to examine subgroups with respect to
treatment outcome, but it is tempting to speculate on the existence of
paternally-derived molecular-level effects on other sub-phenotypes of
SSD. Regarding clinical heterogeneity, we cannot rule out the possibility
of APA-related effects on cognitive development in schizophrenia and
related diseases. However, such potential effects might have been
counterbalanced by other effects such as the psychosocial environment.
There are known psychosocial benefits of having an older parent, e.g.
a higher likelihood of having a planned pregnancy, to have parents
with better education and socio-economic status, and a higher likeli-
hood of having nurturing, supportive and stable home environments
(McGrath et al., 2013).
4.4. Other findings
Our findings that paternal age did not affect premorbid IQ in SSD
extend previous observations by Petersen et al. of a strong association
between the age at which the father had his first child and offspring
risk of schizophrenia (Petersen et al., 2011). This “first-born effect”
could hypothetically be due to a proportion of Danish men carrying clin-
ically unexpressed genotypes that are associated with schizophrenia as
 H.J. Sørensen et al. / Schizophrenia Research 160 (2014) 131–135
well as with reproduction at a later age (Petersen et al., 2011). Following
this hypothesis, the association between APA and risk of schizophrenia
could be mediated through reduced male fertility, due to e.g. environ-
mental pollutants or infection which could also be associated with
increased schizophrenia risk in the offspring. Personality traits causing
difficulties in finding a partner could also be associated with higher
genetic risk of schizophrenia (Petersen et al., 2011), and findings from
other studies (Miller et al., 2011b) could be interpreted within such a
context. Furthermore, parental age effects may increase risk of schizo-
phrenia through social factors related to parenting or more generally,
to epigenetic mechanisms associated with the developmental environ-
ment, both in utero and postnatally (Jaffe et al., 2014). Unfortunately,
our study had insufficient number of cases to examine the impact of
birth order. Until it becomes feasible to examine these hypotheses
further, the most likely explanation for our results is that the psychoso-
cial benefits of having an older parent influence the premorbid general
cognitive ability in persons who were on the path to develop a disorder
in the schizophrenia spectrum.
Role of funding sources
The study was supported financially by: grants from The Lundbeck Foundation and
The Stanley Foundation. Neither funders had a role in the design and conduct of the
study, collection, management, analyses, and interpretation of the data, and preparation,
review, or approval of the manuscript and the decision to submit the manuscript for
publication
Contributors
Authors: L. Petersen, P. Mortensen, C. Pedersen, and V. Ehrenstein contributed to the
design of the project. H. Sørensen wrote the initial draft and M. Nordentoft contributed
to the completion of the manuscript. Drs. Petersen and Pedersen had full access to all of
the data in the study and take responsibility for the integrity of the data and the accuracy
of the data analysis. All authors approved the final version of the manuscript
Conflicts of interest
None
Acknowledgments
The study was supported financially by: grants from The Lundbeck Foundation and
The Stanley Foundation. Neither funders had a role in the design and conduct of the
study, collection, management, analyses, and interpretation of the data, and preparation,
review, or approval of the manuscript and the decision to submit the manuscript for
publication. Drs. Petersen and Pedersen had full access to all of the data in the study and
take responsibility for the integrity of the data and the accuracy of the data analysis.
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