Risk of Autism and Increasing Maternal and Paternal Age in a Large North American Population

Environmental Health Investigations Branch, California Department of Public Health, Richmond, California 94804, USA.
American journal of epidemiology (Impact Factor: 5.23). 09/2009; 170(9):1118-26. DOI: 10.1093/aje/kwp247
Source: PubMed


Previous studies are inconsistent regarding whether there are independent effects of maternal and paternal age on the risk of autism. Different biologic mechanisms are suggested by maternal and paternal age effects. The study population included all California singletons born in 1989-2002 (n = 7,550,026). Children with autism (n = 23,311) were identified through the California Department of Developmental Services and compared with the remainder of the study population, with parental ages and covariates obtained from birth certificates. Adjusted odds ratios and 95% confidence intervals were used to evaluate the risk of autism associated with increasing maternal and paternal age. In adjusted models that included age of the other parent and demographic covariates, a 10-year increase in maternal age was associated with a 38% increase in the odds ratio for autism (odds ratio = 1.38, 95% confidence interval: 1.32, 1.44), and a 10-year increase in paternal age was associated with a 22% increase (odds ratio = 1.22, 95% confidence interval: 1.18, 1.26). Maternal and paternal age effects were seen in subgroups defined by race/ethnicity and other covariates and were of greater magnitude among first-born compared with later-born children. Further studies are needed to help clarify the biologic mechanisms involved in the independent association of autism risk with increasing maternal and paternal age.

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    • "In developed countries, there has been a trend for parents to have children later in life; in the UK today, more than one-third of children are born to fathers aged 35 years or over (England and Wales Birth Census data series FM1). In addition to PAE disorders , there have been numerous other associations between older paternal age and increased risk of offspring being affected by disorders such as autism (Grether et al., 2009), schizophrenia (Frans et al., 2011) and cancer (Yip et al., 2006) (reviewed in Goriely et al., 2013). However, the sperm DNA and whole testis mutation studies have been limited to a few specific genomic sites located in PAE genes, owing to the major technical challenges of detecting low-frequency mutations. "
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    ABSTRACT: Owing to a recent trend for delayed paternity, the genomic integrity of spermatozoa of older men has become a focus of increased interest. Older fathers are at higher risk for their children to be born with several monogenic conditions collectively termed paternal age effect (PAE) disorders, which include achondroplasia, Apert syndrome and Costello syndrome. These disorders are caused by specific mutations originating almost exclusively from the male germline, in genes encoding components of the tyrosine kinase receptor/RAS/MAPK signalling pathway. These particular mutations, occurring randomly during mitotic divisions of spermatogonial stem cells (SSCs), are predicted to confer a selective/growth advantage on the mutant SSC. This selective advantage leads to a clonal expansion of the mutant cells over time, which generates mutant spermatozoa at levels significantly above the background mutation rate. This phenomenon, termed selfish spermatogonial selection, is likely to occur in all men. In rare cases, probably because of additional mutational events, selfish spermatogonial selection may lead to spermatocytic seminoma. The studies that initially predicted the clonal nature of selfish spermatogonial selection were based on DNA analysis, rather than the visualization of mutant clones in intact testes. In a recent study that aimed to identify these clones directly, we stained serial sections of fixed testes for expression of melanoma antigen family A4 (MAGEA4), a marker of spermatogonia. A subset of seminiferous tubules with an appearance and distribution compatible with the predicted mutant clones were identified. In these tubules, termed 'immunopositive tubules', there is an increased density of spermatogonia positive for markers related to selfish selection (FGFR3) and SSC self-renewal (phosphorylated AKT). Here we detail the properties of the immunopositive tubules and how they relate to the predicted mutant clones, as well as discussing the utility of identifying the potential cellular source of PAE mutations.
    Andrology 12/2013; 2(3). DOI:10.1111/j.2047-2927.2013.00175.x · 2.30 Impact Factor
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    • "For example, pregnancy stress results in the section of corticotrophin-releasing hormone (CRH) from the hypothalamus, and increased plasma levels of CRH have been linked to preterm labor (Hobel et al., 1999). While some evidence suggests that such maternal risk factors can contribute to the development of ASD (Rizzo et al., 1997; Croen et al., 2002, 2007; Hultman et al., 2002; Glasson et al., 2004; Beversdorf et al., 2005; Larsson et al., 2005; Lauritsen et al., 2005; Leonard et al., 2006; Reichenberg et al., 2006; Dionne et al., 2008; Durkin et al., 2008; Grant and Soles, 2009; Grether et al., 2009; King et al., 2009; Li et al., 2009a,b; Burstyn et al., 2010; James et al., 2010; Kalkbrenner et al., 2012; Meguid et al., 2010; Roza et al., 2010; Shelton et al., 2010; Dodds et al., 2011; Lee et al., 2012; Parner et al., 2012; Rai et al., 2012; Sandin et al., 2012; Schmidt et al., 2012), results remain largely mixed and are strongest for advanced maternal age. "
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    ABSTRACT: Autism Spectrum Disorder (ASD) is the collective term for neurodevelopmental disorders characterized by qualitative impairments in social interaction, communication, and a restricted range of activities and interests. Many countries, including Australia, have reported a dramatic increase in the number of diagnoses over the past three decades, with current prevalence of ASD at 1 in every 110 individuals (~1%). The potential role for an immune-mediated mechanism in ASD has been implicated by several studies, and some evidence suggests a potential link between prenatal infection-driven inflammation and subsequent development of ASD. Furthermore, a modest number of contemporary studies have reported a markedly increased prevalence of ASD in children born preterm, who are at highest risk of exposure to perinatal inflammation. However, the mechanisms that underpin the susceptibility to infection-driven inflammation during pregnancy and risk of preterm birth, and how these intersect with the subsequent development of ASD in the offspring, is not understood. This review aims to summarize and discuss the potential mechanisms and evidence for the role of prenatal infection on the central nervous system, and how it may increase the susceptibility for ASD pathogenesis in children born preterm.
    Frontiers in Neuroscience 07/2013; 7(7):123. DOI:10.3389/fnins.2013.00123 · 3.66 Impact Factor
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    • "Several studies have demonstrated that advanced paternal age is associated with increased incidence of offspring diseases including schizophrenia (Malaspina, 2001), autism (Grether et al., 2009) and bipolar disorder (Frans et al., 2008). Although older men may have decreased pregnancy rates, DNA-damaged spermatozoa do not necessarily lose their fertilizing ability (Gandini et al., 2004). "
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    ABSTRACT: The influence of paternal age on clinical pregnancy was examined within younger patients undergoing donor insemination (DI) cycles in Western Australia. A retrospective analysis of 2142 DI cycles was carried out, including only women <40 years with no history of fertility problems. Logistic regression analysis was used to relate donor age to clinical pregnancy rate. Proportional hazards regression analysis was used to relate male age to time to pregnancy. Mediation analysis was conducted to adjust for influence of sperm concentration and motility. Analysis was controlled for female age, luteal-phase progesterone support and insemination year. There was no effect of female age on pregnancy rate or time to pregnancy. Older males (age >= 45 years) were significantly associated with a reduced pregnancy rate and longer time to pregnancy. Mediation analysis indicated that sperm concentration and motility did not fully account for the effect of male age on pregnancy. This study reveals an adverse effect of male age on clinical pregnancy in women <40 years of age that is not solely mediated by decreased sperm concentration or motility. This has implications for recruitment systems that attract older donors such as open-identity systems, which may benefit from actively recruiting younger donors. RBMOnline
    Reproductive biomedicine online 05/2013; 27(2). DOI:10.1016/j.rbmo.2013.04.015 · 3.02 Impact Factor
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