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Objective: To examine whether ancestry influenced sex ratios of offspring in a birth cohort before parental antenatal sex selection influenced offspring sex., Methods: We measured the sex ratio as the percent of males according to countries of birth of paternal and maternal grandfathers in 91,459 live births from 1964 to 1976 in the Jerusalem Perinatal Study. Confidence limits (CI) were computed based on an expected sex ratio of 1.05, which is 51.4% male., Results: Of all live births recorded, 51.4% were male. Relative to Jewish ancestry (51.4% males), significantly more males (1,761) were born to Muslim ancestry (54.5, 95% CI = 52.1-56.8, P = 0.01). Among the former, sex ratios were not significantly associated with paternal or maternal age, education, or offspring's birth order. Consistent with a preference for male offspring, the sex ratio decreased despite increasing numbers of births over the 13-year period. Sex ratios were not affected by maternal or paternal origins in North Africa or Europe. However, the offspring whose paternal grandfathers were born in Western Asia included fewer males than expected (50.7, 50.1-51.3, P = 0.02), whether the father was born abroad (50.7) or in Israel (50.8). This was observed for descendents of paternal grandfathers born in Lebanon (47.6), Turkey (49.9), Yemen & Aden (50.2), Iraq (50.5), Afghanistan (50.5), Syria (50.6), and Cyprus (50.7); but not for those from India (51.5) or Iran (51.9). The West Asian group showed the strongest decline in sex ratios with increasing paternal family size., Conclusions: A decreased sex ratio associated with ancestry in Western Asia is consistent with reduced ability to bear sons by a subset of Jewish men in the Jerusalem cohort. Lower sex ratios may be because of pregnancy stress, which may be higher in this subgroup. Alternatively, a degrading Y chromosome haplogroup or other genetic or epigenetic differences on male germ lines could affect birth ratios, such as differential exposure to an environmental agent, dietary differences, or stress. Differential stopping behaviors that favor additional pregnancies following the birth of a daughter might exacerbate these lower sex ratios., (© 2016 Wiley Periodicals, Inc.)

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Pregnant women exposed to an acute traumatic event are thought to produce offspring with an increased incidence of affective disorders. It is not known whether there are specific times in pregnancy which confer increased vulnerability, or if psychosocial stress alone can increase the incidence of affective disorders in offspring. We examined the relationship of the timing of an acute psychosocial threat during pregnancy to the incidence of affective disorders in offspring using data from a large birth cohort., Methods: Using data on 90079 offspring born in Jerusalem in 1964-1976 and linked to Israel's psychiatric registry, we constructed proportional hazards models to evaluate the link between gestational age during the Arab-Israeli war of June 1967 and incidence of mood disorders., Results: Those in their first trimester of fetal development during the war were more likely to be admitted to hospitals for any mood disorders [relative risk (RR) = 3.01, 95% confidence interval (CI): 1.68-5.39, p = 0.0002]; for bipolar disorder the risk was doubled (RR = 2.44, 95% CI: 0.996-5.99, p = 0.054) and for all 'other' mood disorders the risk was tripled (RR = 3.61, 95% CI: 1.68-7.80, p = 0.001). Mood disorders were also increased in offspring whose mothers had been in the third month of pregnancy in June of 1967 (RR = 5.54, 95% CI: 2.73-11.24, p < 0.0001)., Conclusions: A time-limited exposure to a severe threat during early gestation may be associated with an increased incidence of affective disorders in offspring. The third month of fetal development was a moment of special vulnerability., (© 2012 John Wiley and Sons A/S.)

The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers ≥35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations.

Schizophrenia has been linked to advanced paternal age, but the explanation is unknown. We questioned whether the incidence of schizophrenia would be related to male reproductive capacity, as reflected in the time taken to conceive. We measured the incidence of schizophrenia in relation to time to conception in a sub-group of 12,269 in the Jerusalem cohort whose mothers, interviewed post-partum, reported that the pregnancy had been intended. Compared with those conceived in less than 3 months, the unadjusted relative risks (RR) of schizophrenia associated with conception-waits of 3-5, 6-11 and 12+ months were 1.10 (95% confidence interval, 0.62-1.94), 1.41 (0.79-2.52) and 1.88 (1.05-3.37) with p for trend=0.035. This trend was attenuated somewhat by adjusting for paternal age, and was observed more strongly in offspring of fathers aged 30+ (p=.010). These findings suggest that factors associated with fecundability, either male or female, may contribute to the risk of schizophrenia., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Some forms of epigenetic abnormalities transmitted to offspring are manifested in differences in disease incidence that depend on parent-of-origin. To explore whether such phenomena might operate in schizophrenia spectrum disorders, we estimated the relative incidence of these conditions in relation to parent-of-origin by considering the two grandfathers' countries of birth. In a prospective cohort of 88,829 offspring, born in Jerusalem in 1964-76 we identified 637 cases through Israel's psychiatric registry. Relative risks (RR) were estimated for paternal and maternal grandfathers' countries of birth using proportional hazards methods, controlling for parents' ages, low social class and duration of marriage. After adjusting for multiple observations, we found no significant differences between descendants of maternal or paternal grandfathers born in Iraq, Iran, Turkey, Syria, Yemen, Morocco, Algeria, Tunisia, Libya/Egypt, Poland, USSR, Czechoslovakia, Germany or the USA. Those with paternal grandfathers from Romania (RR=1.9, 95% CI=1.3-2.8) or Hungary (1.6, 1.0-2.6) showed an increased incidence; however, those with maternal grandfathers from these countries experienced reduced incidence (RR=0.5, 0.3-0.8 and 0.4, 0.2-0.8). In post-hoc analyses we found that results were similar whether the comparison groups were restricted to descendants of other Europeans or included those from Western Asia and North Africa; and effects of paternal grandfathers from Romania/Hungary were more pronounced in females, while effects of maternal grandfathers from these countries were similar in males and females. These post-hoc "hypothesis-generating" findings lead one to question whether some families with ancestors in Romania or Hungary might carry a variant or mutation at a parentally imprinted locus that is altering susceptibility to schizophrenia. Such a locus, if it exists, might involve the X chromosome.

Objective: Increased incidence of schizophrenia is observed among some immigrant groups in Europe, with the offspring of immigrants, ie "second-generation" immigrants particularly vulnerable. Few contemporary studies have evaluated the risk of schizophrenia among second-generation immigrants in other parts of the world., Methods: We studied the incidence of schizophrenia in relation to parental immigrant status in a population-based cohort of 88 829 offspring born in Jerusalem in 1964-1976. Parental countries of birth were obtained from birth certificates and grouped together as (1) Israel, (2) Other West Asia, (3) North Africa, and (4) Europe and industrialized countries. Cox proportional hazards methods were used in adjusting for sex, parents' ages, maternal education, social class, and birth order., Results: Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. Incidence of schizophrenia was not increased among second-generation immigrants in this birth cohort, neither overall nor by specific group., Conclusions: The difference in risk of schizophrenia among second-generation immigrants in Europe and in this Israeli birth cohort suggests that the nature of the immigration experience may be relevant to risk, including reasons for migration, the nature of entry, and subsequent position in the host country for immigrants and their offspring. Minority status may be of importance as, in later studies, immigrants to Israel from Ethiopia had increased risk of schizophrenia.

Although it is known that schizophrenia is associated with social class, controversy exists as to the nature of this association. The authors studied the incidence of schizophrenia in relation to social class at birth in a population-based cohort of 88,829 offspring born in Jerusalem in 1964-1976. They constructed a six-point scale to index social class, based on paternal occupation at the time of birth, with each of 108 occupations being ranked by mean education. Cox proportional hazards methods were used in adjusting for sex, parents' ages, duration of marriage and birth order. Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. There was no gradient of risk for schizophrenia associated with social class at birth; however, offspring of fathers in the lowest social class showed a modest increase in risk (adjusted Relative Risk = 1.4; 95% Confidence interval = 1.1-1.8, P = 0.002). These data suggest that in contrast to many other health outcomes, there is not a continuous gradient for increasing schizophrenia with decreasing social class of origin. Instead, a modest increase in risk for schizophrenia was observed only for those born at the bottom of the social ladder.

Objective: To investigate whether incidence of twin deliveries is related to father's age, independently of mother's age, and whether it differs for same-sex or opposite-sex twin sets., Study Design: In a program of research on effects of paternal age, this study used data from a prospective cohort of 92,408 offspring born in Jerusalem from 1964 to 1976. Of the 91,253 deliveries in the Jerusalem Perinatal Study, 1115 were twin deliveries. The data were analyzed with General Estimate Equations to inform unconditional logistic regression., Results: After controlling for maternal age, odds ratios (ORs) and 95% confidence intervals (95% CI) associated with father's ages 25-34 and 35+ were 1.3 (1.1, 1.7) and 1.5 (1.2, 2.1) respectively, compared with fathers <25 years old. The effect of maternal age was partly explained by paternal age. The ORs for opposite-sex twin sets and male-male twin sets increased slightly with paternal age, while the OR for same-sex and female-female twin decreased., Conclusion: Studies of twins are used to estimate effects of genes and environment in a variety of diseases. Our findings highlight the need to consider paternal as well as maternal age when analyzing data on twins to explore etiology of diseases.

Background: Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced father's age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study., Methods: Subjects were 403486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parent's age, parental socioeconomic status, birth order, and year of draft board assessment., Results: Compared with offspring of parents aged 25-29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08-1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43-1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07-1.24) times more likely to have poor social functioning., Conclusions: These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.

Background: Twins are exposed to intrauterine environments that differ significantly from those of singletons. These diverse environments might alter the risk for schizophrenia in twins and make it difficult to generalize from findings in twins when studying the risk of schizophrenia in the general population. Previous studies report contradictory findings on the risk for schizophrenia in twins., Methods: We studied the incidence of schizophrenia spectrum disorders, ascertained from Israel's National Psychiatric Registry, in a cohort of 2124 twins and 87,955 singletons. These offspring were followed from their birth in 1964-76 in the Jerusalem Perinatal study. Cox proportional hazards methods were used to compare outcomes over 28-41 years, adjusting for ages of parents., Results: Twins showed a relative risk [RR] of .84 relative to singletons, with a 95% confidence interval [CI] of (.51-1.4). RRs and CIs for males and females were .68 [.34-1.4] and 1.1 [.55-2.2] respectively. Twins in male-male, female-female or opposite-sex sets showed no significant variation in RRs; furthermore, first- or second-born twins did not differ significantly from each other. Siblings of twins had the same risk of schizophrenia as siblings of singletons., Conclusion: Twins have the same risk for schizophrenia as the general population.

Unlabelled: Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offspring's sex., Method: In a pilot study linking birth records to Israel's Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964-76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for father's age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison., Results: There was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1-4.7), seen more in females (4.3, 1.7-10.7) than in males (1.2, 0.4-3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2-5.2), also seen more in females (3.6, 1.3-9.7) than males (1.8, 0.6-5.2)., Conclusion: These findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.

The Jerusalem Perinatal Study recorded information on population-based cohorts of 92 408 live- and stillbirths in 1964-76, and their parents, with active surveillance of infant deaths and birth defects. Data on maternal conditions, obstetric complications and interventions during labour and delivery were recorded for 92% of the births. Subsets were surveyed with antenatal interviews in 1965-68 (n = 11 467), paediatric admissions to hospital (n = 17 782) and postpartum interviews in 1975-76 (n = 16 912). Data from some offspring were linked to records of a health examination at age 17. The offspring, mothers and fathers have been traced recently, their vital status assessed, and the data linked to Israel's Cancer Registry and Psychiatric Registry. This paper describes the different types of data available, their sources, and some potential biases. Characteristics of this unique population are shown. Findings from the study are reviewed and a list of references is provided. The cohorts provide a unique source of data for a wide variety of studies.

Tetrachloroethylene is a solvent used in dry cleaning with reported neurotoxic effects. Using proportional hazard methods, we examined the relationship between parental occupation as a dry cleaner and risk for schizophrenia in a prospective population-based cohort of 88,829 offspring born in Jerusalem from 1964 through 1976, followed from birth to age 21-33 years. Of 144 offspring whose parents were dry cleaners, 4 developed schizophrenia. We observed an increased incidence of schizophrenia in offspring of parents who were dry cleaners (RR=3.4, 95% CI, 1.3-9.2, p=0.01). Tetrachloroethylene exposure warrants further investigation as a risk factor for schizophrenia.

Context: Maternal and paternal ages are associated with neurodevelopmental disorders., Objective: To examine the relationship between advancing paternal age at birth of offspring and their risk of autism spectrum disorder (ASD)., Design: Historical population-based cohort study., Setting: Identification of ASD cases from the Israeli draft board medical registry., Participants: We conducted a study of Jewish persons born in Israel during 6 consecutive years. Virtually all men and about three quarters of women in this cohort underwent draft board assessment at age 17 years. Paternal age at birth was obtained for most of the cohort; maternal age was obtained for a smaller subset. We used the smaller subset (n = 132 271) with data on both paternal and maternal age for the primary analysis and the larger subset (n = 318 506) with data on paternal but not maternal age for sensitivity analyses., Main Outcome Measures: Information on persons coded as having International Classification of Diseases, 10th Revision ASD was obtained from the registry. The registry identified 110 cases of ASD (incidence, 8.3 cases per 10 000 persons), mainly autism, in the smaller subset with complete parental age data., Results: There was a significant monotonic association between advancing paternal age and risk of ASD. Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46; P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on maternal age., Conclusions: Advanced paternal age was associated with increased risk of ASD. Possible biological mechanisms include de novo mutations associated with advancing age or alterations in genetic imprinting.

Background: Animal models of schizophrenia suggest a link between maternal crowding during pregnancy and increased risk of the offspring to develop physiological, developmental, and behavioral abnormalities that are comparable to those observed in schizophrenia. We tested the hypothesis that a similar link is present in humans., Method: We investigated whether prenatal exposure to household crowding was associated with the risk of schizophrenia in a sub-cohort of the Jerusalem Perinatal Study (JPS) consisting 11,015 individuals born between 1964 and 1976. During these years mothers participated in face to face interviews in early pregnancy. The prenatal and birth data, including the number of rooms and individuals living in the mothers' household, was cross-linked with the Israel Psychiatric Registry by ministry personnel., Results: 104 schizophrenia cases were identified in the cohort. Offspring who, while in utero, their mother resided in a household with five or more individuals had RR of 1.47 (95% CI: 0.99-2.16, p=0.05) to develop schizophrenia, compared to those whose mother resided with four or fewer individuals. However, when adjusted for paternal age, the RR was reduced to 1.18 (95% CI: 0.76-1.84, p=0.46). The number of rooms in the household and the household crowding during pregnancy did not significantly impact the offspring's risk to develop schizophrenia., Conclusion: The link between maternal household crowding during pregnancy and the offspring's risk of schizophrenia was explained primarily by the impact of paternal age. The authors discuss the results in view of findings from animal and human studies.

Objective: To evaluate the influence of paternal age upon spontaneous abortion., Methods: This case-control study of 13,865 women draws on data from women's antenatal or postpartum interviews in the Jerusalem Perinatal Study, a population-based cohort derived from 92,408 births in 1964-1976. Case women (n=1,506) reported spontaneous abortion in the pregnancy preceding the interview; they were compared with women reporting live births in their previous pregnancy (n=12,359). Logistic regression was used to adjust for maternal age, maternal diabetes, maternal smoking, history of spontaneous abortions before the index pregnancy, parity at interview, and interval between the index pregnancy and the interview., Results: The adjusted odds ratio for spontaneous abortion was 0.59 (95% confidence interval 0.45-0.76, P< .0001) for pregnancies conceived from fathers aged younger than 25 years compared with those from fathers aged 25-29 years. For fathers age 40 years or older the odds ratio for spontaneous abortion was 1.6 (95% confidence interval 1.2-2.0, P=.0003) when compared with the same reference group., Conclusion: Increasing paternal age is significantly associated with spontaneous abortion, independent of maternal age and multiple other factors.

Pre-eclampsia has been described as a 'disease of first pregnancies' and many believe that its occurrence in a later pregnancy signals a fundamentally different entity. We sought to compare risk factors in first and subsequent pregnancies. We studied 1319 cases of pre-eclampsia recorded in a historical cohort of 82,436 deliveries in Jerusalem in 1964-76. Logistic regression was used to control for covariates. The adjusted odds ratio (OR) for pre-eclampsia in first births was 2.58 (95% confidence interval[CI] 2.23, 2.97), compared with all later birth order groups, between which there were no detectable differences in risk. Other risk factors included increasing maternal age, diabetes (OR 5.64, 95% CI 4.33, 7.35), multiple gestations (OR 3.38, 95% CI 2.54, 4.49), fetal haemolytic disease (OR 2.24, 95% CI 1.43, 3.50) and lower maternal education. The risk of pre-eclampsia was not associated with the mother's employment outside the home and did not differ between immigrants vs. Israeli-born mothers or between groups of women whose fathers had been born in Western Asia, North Africa or Europe. Effects of each risk factor were similar within first and subsequent births. These results lend no support to the hypothesis that there is a fundamental difference between pre-eclampsia in a first pregnancy compared with that occurring in a later pregnancy; conclusions may be moderated, however, by the knowledge that the incidence of pre-eclampsia was low in this historical cohort.

Objective: The Israeli National Psychiatric Hospitalization Registry is a nationwide list of all psychiatric hospitalizations in the country and has been widely used as a source of data for psychiatric research. This study assessed the sensitivity of the diagnosis of psychotic disorders ( International Statistical Classification of Diseases, 10th Revision [ ICD-10 ] F20.0-F29.9) and schizophrenia ( ICD-10 F20.0-F20.9) in the Registry., Method: Registry discharge diagnoses of psychotic disorders ( ICD-10 F20.0-F29.9) and schizophrenia ( ICD-10 F20.0-F20.9) were compared with research diagnoses derived from best-estimate procedures based on Research Diagnostic Criteria (RDC) using structured clinical research interviews, hospital records, and family information., Results: Out of 169 patients meeting RDC for psychotic disorder, 150 also had a diagnosis of psychotic disorders in the Registry, yielding a sensitivity of 0.89. Re-running this analysis for the narrow definition of schizophrenia identified 94 patients who were diagnosed with schizophrenia using RDC; 82 of those patients also had a diagnosis of schizophrenia in the Registry, yielding a sensitivity of 0.87., Conclusion: In 87% to 89% of cases with psychotic disorders or with schizophrenia, Registry diagnoses agreed with RDC diagnoses, a rate of agreement comparable with those of other, similar registries. Because a large number of analyses derived from this and similar national registries will be published in the coming years, this constitutes relevant information.

Background: Paternal aging is associated with premeiotic damage to spermatogonia, a mechanism by which new point mutations are introduced into the gene pool. We hypothesized that paternal age might contribute to preeclampsia., Methods: We studied the incidence of preeclampsia in 81,213 deliveries surveyed in 1964-1976 in the Jerusalem Perinatal Study. We controlled for maternal age, parity and other risk factors using logistic regression., Results: Preeclampsia was reported in 1303 deliveries (1.6%). Compared with fathers age 25-34 years, the odds ratios (ORs) for preeclampsia were 1.24 (95% confidence interval = 1.05-1.46) for age 35-44 and 1.80 (1.40-2.31) for age 45+. For fathers age <25, the OR was 1.25 (1.04-1.51). Although weaker than maternal age effects, paternal effects were consistent within subgroups of other variables., Conclusions: These findings support the hypothesis that a modest proportion of preeclampsia might be explained by new mutations acquired from fathers and add to a growing body of evidence for paternal age effects in birth defects, neuropsychiatric disease and neoplasia.

Background: A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines., Method: We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry., Results: Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age., Conclusions: These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.