CONTEXT: Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders. OBJECTIVES: To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately. DESIGN: A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders. SETTING: Identification of 7,328,100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register. PARTICIPANTS: A total of 13,428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case. Main Outcome Measure Bipolar disorder based on ICD codes at discharge from hospital treatment. RESULTS: An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (<20 years) cases, the effect of paternal age was much stronger (odds ratio, 2.63; 95% CI, 1.19-5.81), whereas no statistically significant maternal age effect was found. CONCLUSIONS: Advanced paternal age is a risk factor for BPD in the offspring. The results are consistent with the hypothesis that advancing paternal age increases the risk for de novo mutations in susceptibility genes for neurodevelopmental disorders.

CONTEXT The clinical and etiologic relation between autism spectrum disorders (ASDs) and schizophrenia is unclear. The degree to which these disorders share a basis in etiology has important implications for clinicians, researchers, and those affected by the disorders. OBJECTIVE To determine whether a family history of schizophrenia and/or bipolar disorder is a risk factor for ASD. DESIGN, SETTING, AND PARTICIPANTS We conducted a case-control evaluation of histories of schizophrenia or bipolar disorder in first-degree relatives of probands in 3 samples-population registers in Sweden, Stockholm County (in Sweden), and Israel. Probands met criteria for ASD, and affection status of parents and siblings for schizophrenia and bipolar disorder were established. RESULTS The presence of schizophrenia in parents was associated with an increased risk for ASD in a Swedish national cohort (odds ratio [OR], 2.9; 95% CI, 2.5-3.4) and a Stockholm County cohort (OR, 2.9; 95% CI, 2.0-4.1). Similarly, schizophrenia in a sibling was associated with an increased risk for ASD in a Swedish national cohort (OR, 2.6; 95% CI, 2.0-3.2) and an Israeli conscription cohort (OR, 12.1; 95% CI, 4.5-32.0). Bipolar disorder showed a similar pattern of associations but of lesser magnitude. CONCLUSIONS Findings from these 3 registers along with consistent findings from a similar study in Denmark suggest that ASD, schizophrenia, and bipolar disorder share common etiologic factors.

OBJECTIVE We conducted a meta-analysis of epidemiological studies investigating the association between maternal age and autism. METHOD Using recommended guidelines for performing meta-analyses, we systematically selected, and extracted results from, epidemiological scientific studies reported before January 2012. We calculated pooled risk estimates comparing categories of advancing maternal age with and without adjusting for possible confounding factors. We investigated the influence of gender ratio among cases, ratio of infantile autism to autism spectrum disorder (ASD), and median year of diagnosis as effect moderators in mixed-effect meta-regression. RESULTS We found 16 epidemiological papers fulfilling the a priori search criteria. The meta-analysis included 25,687 ASD cases and 8,655,576 control subjects. Comparing mothers ≥35 years with mothers 25 to 29 years old, the crude relative risk (RR) for autism in the offspring was 1.52 (95% confidence interval [CI]= 1.12-1.92). Comparing mothers ≥35 with mothers 25 to 29, the adjusted relative risk (RR) for autism in the offspring was 1.52 (95% CI = 1.12-1.92). For mothers <20 compared with mothers 25 to 29 years old, there was a statistically significant decrease in risk (RR = 0.76; 95% confidence interval = 0.60-0.97). Almost all studies showed a dose-response effect of maternal age on risk of autism. The meta-regression suggested a stronger maternal age effect in the studies with more male offspring and for children diagnosed in later years. CONCLUSIONS The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age. The association persisted after the effects of paternal age and other potential confounders had been considered, supporting an independent relation between higher maternal age and autism.

AIMS An abundance of evidence has firmly established the familial aggregation of schizophrenia. The aim of this study was to examine how age at onset, parental characteristics and season of birth modify the familiality in schizophrenia. METHODS A population-based cohort was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. Among 5,075,998 full siblings born between 1932 through to 1990, 16,346 cases of schizophrenia were identified. Familial aggregation was measured by the sibling recurrence-risk ratio, defined as the risk of schizophrenia among full siblings of schizophrenia patients compared with the risk among siblings of unaffected people. RESULTS We found a statistically significantly lower recurrence-risk ratio in siblings of later onset cases (7.2; 95% confidence interval (95% CI) 6.7-7.9) than of early onset cases (10.8; 95% CI 9.4-12.2). A lower recurrence-risk ratio was observed among offspring to fathers above 40 years (6.3; 95% CI 5.3-7.3) as compared with offspring of younger fathers (8.6; 95% CI 8.0-9.3). Further, among offspring to parents born outside Sweden the recurrence-risk ratio was statistically significantly lower (maternal immigrants 4.8; 95% CI 4.0-5.7, paternal immigrants 5.7; 95% CI 4.6-6.9) than among offspring to parents born in Sweden. CONCLUSIONS The familial aggregation of schizophrenia was reduced by higher age at onset, advancing paternal age and immigrant status of parents.

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

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The current study, based on all births in Sweden from 1983 to 1991 (N = 654,707), explored the processes underlying the association between smoking during pregnancy (SDP) and offspring school grades and mathematic proficiency at age 15. The analyses compared relatives who varied in their exposure to SDP and who varied in their genetic relatedness. Although SDP was statistically associated with academic achievement (AA) when comparing unrelated individuals, the results suggest that SDP does not cause poorer academic performance, as full siblings differentially exposed to SDP did not differ in their academic scores. The pattern of results suggests that genetic factors shared by parents and their offspring help explain why offspring exposed to SDP have lower levels of AA.

Background: Despite extensive efforts, the causes of autism remain unknown. Advancing paternal age has been associated with various neurodevelopmental disorders. We aim to investigate three unresolved questions:(a) What is the association between paternal age and autism spectrum disorders (ASD)?;(b) Does paternal age moderate the genetic and environmental etiological factors for ASD?(c) Does paternal age affect normal variation in autistic-like traits? Methods: Two nationally representative twin studies from Sweden (n = 11, 122, assessed at age 9 or 12) and the UK (n = 13, 524, assessed at age 9) were used. Categorical and continuous measures of ASD, autistic-like traits and autistic similarity were calculated and compared over paternal age categories. Results: Both cohorts showed a strong association between paternal age and the risk for ASD. A U-shaped risk association could be discerned since the offspring of both the youngest and oldest fathers showed an elevation in the risk for ASD. Autistic similarity increased with advancing paternal age in both monozygotic and dizygotic twins. Both cohorts showed significantly higher autistic-like traits in the offspring of the youngest and oldest fathers. Conclusions: Phenomena associated with paternal age are clearly involved in the trajectories leading to autistic-like traits and ASD. Mechanisms influencing the trajectories might differ between older and younger fathers. Molecular genetic studies are now needed in order to further understand the association between paternal age and ASD, as well as normal variation in social, language, and repetitive behaviors in the general population.

This study was undertaken to disentangle the maternal genetic from the fetal genetic effects for preterm birth and to study the possibility of these effects being explained by known risk factors. By cross-linking of the population-based Swedish Multigeneration and Medical Birth registers, 989,027 births between 1992 and 2004 were identified. Alternating logistic regression was applied to model the familial clustering with pairwise odds ratios (PORs), and covariates were included to evaluate if the familial aggregation was explained by exposure to shared risk factors. Generalized linear mixed models were used to estimate the contribution of genetic and environmental effects. Sisters of women who had a preterm delivery had themselves an increased odds of having a preterm delivery (POR = 1.8, 95% confidence interval: 1.5, 2.1), while there was no corresponding increase in odds in families joined by brothers (POR = 1.1, 95% confidence interval: 0.9, 1.4). Twenty-five percent of the variation in preterm birth was explained by maternal genetic factors, whereas fetal genetic factors only marginally influenced the variation in liability. The increased odds ratio between offspring of sisters was independent of maternal risk factors for preterm birth, suggesting that the relative importance of maternal effects is not explained by these well-known risk factors.

OBJECTIVES: The aim of this study was to determine the relationship between paternal age at birth and the risk of obesity in young adulthood. METHODS: Data from the medical birth register of Norway were linked with register data from the Norwegian National Conscript Service and the national statistics agency, Statistics Norway. This study used the data on 346,609 registered males who were born at term in single birth without physical anomalies during 1967-1984 and who were examined at the time of the mandatory military conscription (age 18-20 years). The relationship between paternal age at birth and the occurrence of obesity (body mass index (BMI) ≥ 30.0 kg/m(2)) at conscription was examined using a multinomial logistic regression analysis with BMI < 25.0 kg/m(2) as the reference outcome category. RESULTS: The relative risk of obesity at conscription increased linearly with increasing paternal age at birth but did not increase (P = 0.52) with maternal age at birth. Men born when their fathers were 50 years or older had a 55%(95% confidence interval (CI): 14%, 110%) higher relative risk of obesity than men born when their fathers were younger than 20 years of age, after adjustment for age at conscription, birth order, birth year, maternal age at birth, the mother's total number of children, and maternal and paternal education levels. CONCLUSIONS: The risk of obesity in young Norwegian men increases with advancing paternal age at birth but does not increase with advancing maternal age at birth. Am. J. Hum. Biol., 2012. © 2012Wiley Periodicals, Inc.

The association between advancing paternal age and increased risk of schizophrenia in the off-spring is well established. The underlying mechanisms are unknown. In order to investigate whether the psychosocial environment associated with growing up with an aged father explains the increased risk we conducted a study of all adoptive children in Sweden from 1955-1985 (n = 31 188). Their risk of developing schizophrenia or non-affective psychosis in relation to advancing age of their adoptive fathers' was examined. We found no association between risk of psychoses and advancing adoptive paternal age. There was no support of psychosocial environmental factors explaining the "paternal age effect".

BACKGROUND The incidence of non-Hodgkin lymphoma (NHL) in early life has increased in recent decades, but the relevant risk factors remain largely unknown. We examined perinatal and family risk factors for NHL in childhood through young adulthood. METHODS We conducted a national cohort study of 3 571 574 individuals born in Sweden in 1973-2008 who were followed for incidence of NHL through 2009 (ages 0-37 years). Detailed information on perinatal and family characteristics and NHL diagnoses were obtained from national birth and cancer registries. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between perinatal and family variables and NHL; P values are from two-sided tests. RESULTS There were 936 NHL case patients identified in 66.3 million person-years of follow-up. Independent risk factors for NHL included family history of NHL in either a sibling (adjusted HR = 9.84; 95% CI = 2.46 to 39.41; P =.001) or parent (adjusted HR = 2.36; 95% CI = 1.27 to 4.38; P =.007); high fetal growth (for ≥ 2 SDs relative to 0 to <1 SD from the mean: adjusted HR = 1.64; 95% CI = 1.19 to 2.25; P =.002); older maternal age (adjusted HR for each 5-year increment = 1.11; 95% CI = 1.04 to 1.19; P (trend)=.004); low birth order (adjusted HR for each increment of one birth = 0.91; 95% CI = 0.84 to 0.99; P (trend)=.02); and male sex (adjusted HR = 1.58; 95% CI = 1.38 to 1.80; P <.001). Male sex was associated with onset of NHL before 15 years of age but not with later-onset NHL, whereas the other risk factors did not vary by age at diagnosis. No association was found between gestational age at birth, twinning, paternal age, or parental education and NHL. CONCLUSION In this large national cohort study, family history of NHL, high fetal growth, older maternal age, low birth order, and male sex were independent risk factors for NHL in early life.

OBJECTIVE We conducted a meta-analysis of epidemiological studies investigating the association between maternal age and autism. METHOD Using recommended guidelines for performing meta-analyses, we systematically selected, and extracted results from, epidemiological scientific studies reported before January 2012. We calculated pooled risk estimates comparing categories of advancing maternal age with and without adjusting for possible confounding factors. We investigated the influence of gender ratio among cases, ratio of infantile autism to autism spectrum disorder (ASD), and median year of diagnosis as effect moderators in mixed-effect meta-regression. RESULTS We found 16 epidemiological papers fulfilling the a priori search criteria. The meta-analysis included 25,687 ASD cases and 8,655,576 control subjects. Comparing mothers ≥35 years with mothers 25 to 29 years old, the crude relative risk (RR) for autism in the offspring was 1.52 (95% confidence interval [CI]= 1.12-1.92). Comparing mothers ≥35 with mothers 25 to 29, the adjusted relative risk (RR) for autism in the offspring was 1.52 (95% CI = 1.12-1.92). For mothers <20 compared with mothers 25 to 29 years old, there was a statistically significant decrease in risk (RR = 0.76; 95% confidence interval = 0.60-0.97). Almost all studies showed a dose-response effect of maternal age on risk of autism. The meta-regression suggested a stronger maternal age effect in the studies with more male offspring and for children diagnosed in later years. CONCLUSIONS The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age. The association persisted after the effects of paternal age and other potential confounders had been considered, supporting an independent relation between higher maternal age and autism.

BACKGROUND As the proportions of older women giving birth increase, there is a growing body of evidence on the increased risks of poorer maternal and perinatal outcomes for this group. However, the associations are not completely understood. This study aimed to establish the prevalence of selected maternal morbidities and examine whether advanced maternal age is associated with a higher risk of morbidity for women giving birth in Victoria. METHOD Data on all births over 20 weeks‧ gestation for 2005 and 2006 were obtained from the Victorian Perinatal Data Collection. Unadjusted and adjusted analyses were undertaken using logistic regression to examine and quantify the association between advanced maternal age (35 years and older) and selected obstetric morbidities and complications. RESULTS There was evidence of an association between older maternal age and selected morbidities and complications. Older nulliparous women were at highest odds of gestational diabetes (AdjOR, 1.83; 95% CI, 1.67-2.02), placenta praevia (AdjOR, 2.02; 95% CI, 1.68-2.44), multiple birth (AdjOR, 1.80; 95% CI, 1.58-2.06) and caesarean delivery (AdjOR, 1.93; 95% CI, 1.84-2.02). Older multiparous women were at highest odds of gestational diabetes (AdjOR, 2.01; 95% CI, 1.88-2.15) and placenta praevia (AdjOR, 2.11; 95% CI, 1.83-2.44). CONCLUSIONS Older women giving birth in Victoria are at an increased risk of a range of obstetric morbidities. Delayed childbearing for an increasing number of women has societal and public health ramifications and will potentially place greater demand on healthcare services.

Using the Structured Clinical Interview for DSM-IV, patient and non-patient version (SCID-P/NP), this study investigated 351 patients with schizophrenia, 122 with obsessive-compulsive disorder (OCD), and 238 unrelated healthy volunteers in a Chinese Han population. The relative risks effected by advanced paternal age for schizophrenia and OCD in offspring were computed under logistic regression analyses and adjusted for the participant's sex, age and co-parent age at birth. Compared to the offspring with paternal age of 25-29years old, the relative risks rose from 2.660 to 10.183 in paternal age range of 30-34 and ≥35. The relative risks for OCD increased from 2.225 to 5.413 in 30-34 and ≥35. For offspring with paternal age of <25, the odds ratios of developing schizophrenia and OCD were 0.628 and 0.289 respectively, whereas, an association between increased maternal age and risk for schizophrenia/OCD was not seen. Interaction analysis showed an interaction effect between paternal age and maternal age at birth. Such a tendency of risk affected by parental age for schizophrenia and OCD existed after splitting out the data of early onset patients. Sex-specific analyses found that the relative risks for schizophrenia with paternal age of 30-34 and ≥35 in male offspring were 2.407 and 10.893, in female were 3.080 and 9.659. The relative risks for OCD with paternal age of 30-34 and ≥35 in male offspring were 3.493 and 7.373, and in female offspring 2.005 and 4.404. The mean paternal age of schizophrenia/OCD patients born before the early 1980s was much greater than that of patients who were born after then. The findings illustrated that advanced paternal age is associated with increased risk for both schizophrenia and OCD in a Chinese Han population, prominently when paternal age is over 35. Biological and non-biological mechanisms may both be involved in the effects of advanced paternal age on schizophrenia and OCD.

PURPOSE We sought to study the possible association between parental age and autism spectrum disorder (ASD) by using both a cohort design and a sibling design. METHODS Our cohort included all singleton births in Denmark from January 1, 1980, through December 31, 2003, a total of 1,311,736 children. Cases of ASDs were obtained from the Danish National Psychiatric Register using International Classification of Diseases (ICD)-8 and ICD-10. RESULTS A total of 9556 children were diagnosed with an ASD. Both maternal and paternal age were associated with a greater risk of ASD in the offspring (hazard ratios ranging from 1.21 (1.10-1.34) to 1.65 (1.09-2.48) depending on combinations of parental age categories;<35, 35-39, and 40+ years). For mothers younger than 35 years, the risk of ASD increased with increasing father's age group. For fathers younger than 35 years, the risk of ASD increased with increasing maternal age. CONCLUSIONS We found an association between parental age and ASD in the cohort study, but the combined underlying mechanisms through which paternal and maternal age impact ASD risk do not seem to act synergistically. The results of the sibling analysis suggest that the association between parental age and ASD found in the cohort study cannot be accounted for by common genetic and environmental factors.

BACKGROUND Advanced maternal age is the only well-established risk factor for trisomy 21, yet the majority of affected individuals are born to younger women. To identify factors associated with the risk of trisomy 21 in the offspring of younger and older women, we analyzed data for cases with trisomy 21 from the Texas Birth Defects Registry for 1999 to 2007. METHODS Data were analyzed separately for younger (i.e.,<35 years of age at delivery; n = 2306) and older (i.e., ≥ 35 years of age at delivery; n = 1811) women using Poisson regression. RESULTS After adjustment for maternal age and several other covariates, the prevalence of trisomy 21 in the offspring of women in both maternal age groups was higher in male than in female infants and in offspring of women who were Hispanic (compared with non-Hispanic white women) or who had at least one previous liveborn child compared to those with none. In the offspring of older women only, the prevalence of trisomy 21 was also significantly higher when the father was 20 to 24 years old (compared with 25 to 29 years old; adjusted prevalence ratio [aPR], 2.27; 95% confidence interval [CI], 1.47-3.49) and Hispanic (compared with non-Hispanic white; aPR, 1.34; 95% CI, 1.13-1.58) and among women with less than a high school education (compared with greater than high school). CONCLUSIONS This study identified several factors, in addition to maternal age, that were associated with trisomy 21 risk. In general, these factors were similar for both maternal age groups, although paternal characteristics were significantly associated with risk of trisomy 21 only in offspring of older women.

INTRODUCTION Advanced paternal age (APA) is a risk factor for nonaffective psychosis (NAP) in the offspring, although the mechanism(s) of this association are not clear. The aim of this study was to examine whether later childbearing can be explained by parental schizophrenia, and in doing so, further evaluate the "de novo mutation" hypothesis for the association between APA and NAP. METHODS Using binary logistic regression, the association between APA and parental history of schizophrenia in the offspring, considering maternal and paternal history separately, was examined in 1) all persons with NAP born in Finland between 1950 and 1969 (Finnish NAP Cohort, n = 13,712), and 2) members of the Northern Finland 1966 Birth Cohort (NFBC 1966, n = 10,224), a general population birth cohort. RESULTS In the Finnish NAP Cohort, having a mother with schizophrenia was associated with APA (Odds Ratio [OR] for linear trend = 1.20, 95% confidence interval 1.12-1.29, p < 0.01). In the NFBC 1966 sample, having a mother with schizophrenia was associated with APA at the trend level (OR = 1.14, 0.99-1.31, p = 0.07). By contrast, there was no association between having a father with schizophrenia and APA. DISCUSSION In both a general population cohort and a birth cohort of subjects with nonaffective psychosis, APA was associated with maternal, but not paternal, schizophrenia. These findings suggest that increased genetic risk from the mother may explain the association between APA and nonaffective psychosis, and argue against the "de novo mutation" hypothesis.

AIMS An abundance of evidence has firmly established the familial aggregation of schizophrenia. The aim of this study was to examine how age at onset, parental characteristics and season of birth modify the familiality in schizophrenia. METHODS A population-based cohort was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. Among 5,075,998 full siblings born between 1932 through to 1990, 16,346 cases of schizophrenia were identified. Familial aggregation was measured by the sibling recurrence-risk ratio, defined as the risk of schizophrenia among full siblings of schizophrenia patients compared with the risk among siblings of unaffected people. RESULTS We found a statistically significantly lower recurrence-risk ratio in siblings of later onset cases (7.2; 95% confidence interval (95% CI) 6.7-7.9) than of early onset cases (10.8; 95% CI 9.4-12.2). A lower recurrence-risk ratio was observed among offspring to fathers above 40 years (6.3; 95% CI 5.3-7.3) as compared with offspring of younger fathers (8.6; 95% CI 8.0-9.3). Further, among offspring to parents born outside Sweden the recurrence-risk ratio was statistically significantly lower (maternal immigrants 4.8; 95% CI 4.0-5.7, paternal immigrants 5.7; 95% CI 4.6-6.9) than among offspring to parents born in Sweden. CONCLUSIONS The familial aggregation of schizophrenia was reduced by higher age at onset, advancing paternal age and immigrant status of parents.