AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS
Leslie B. Raschka, MD: "The age of the father is an important determinant of the health of future generations. Children conceived by fathers older than 34 years of age are at increased risk for genetic illness due to recent mutation in the male germ cell.
The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations."
Scientists reveal dangers of older fathers By Laura Donnelly, Health Correspondent Last Updated: 10:18PM BST 31/05/2008 Children are almost twice as likely to die before adulthood if they have a father over 45, research has shown. A mass study found that deaths of children fathered by over-45s occurred at almost twice the rate of those fathered by men aged between 25 and 30.
Scientists believe that children of older fathers are more likely to suffer particular congenital defects as well as autism, schizophrenia and epilepsy. The study was the first of its kind of such magnitude in the West, and researchers believe the findings are linked to the declining quality of sperm as men age.
A total of 100,000 children born between 1980 and 1996 were examined, of whom 830 have so far died before they reached 18, the majority when they were less than a year old.
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The deaths of many of the children of the older fathers were related to congenital defects such as problems of the heart and spine, which increase the risk of infant mortality. But there were also higher rates of accidental death, which the researchers believe might be explained by the increased likelihood of suffering from autism, epilepsy or schizophrenia.
Most research into older parents has, until now, focused on the risks passed on by older mothers. But the new study, published in the European Journal of Epidemiology, was adjusted to take account of maternal age and socio-economic differences.
The research also found higher death rates among children of the youngest fathers, especially those below the age of 19. However, the study said these differences were explained by the risks of teenage motherhood and poorer diet and lifestyle.
Previous research using the same data found that older men were four times as likely to father a child with Down's syndrome, while other studies have found that the genetic quality of sperm deteriorates as men age.
More than 75,000 babies in Britain are born to fathers aged 40 and over each year, or more than one in 10 of all births. This includes more than 6,000 born to fathers aged 50 or over. The average age of fathering a child in this country is 32.
Dr Allan Pacey, senior lecturer in andrology – the medical specialty dealing with male reproduction – at the University of Sheffield, said: "A lot of people know that there are risks for the child that come from having an older mother, but children of older fathers also carry an increased risk. These sorts of results provide another good reason to have children early, when possible."
Dr Pacey, who is secretary of the British Fertility Society, said scientists were unsure exactly what impact the ageing process had on the quality of sperm, making it impossible to detect defects before conception.
Dr Jin Liang Zhu, from the Danish Epidemiology Science Centre, which carried out the research, said: "The risks of older fatherhood can be very profound, and it is not something that people are always aware of."
The mother's age still has the bigger impact on child health, however. About one in 900 babies born to women under 30 have Down's syndrome – a figure which reaches one in 100 by the age of 40. The number of over-40s giving birth in Britain each year has doubled in the past decade to 16,000. The risk of miscarriage rises sharply with age.
Schizophrenia Risk and the Paternal Germ Line By Dolores Malaspina
Dolores Malaspina Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the
fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.
Seminal findings We initially examined the relationship between paternal age and the risk for schizophrenia because it is well established that paternal age is the major source of de novo mutations in the human population, and most schizophrenia cases have no family history of psychosis. In 2001, we demonstrated a monotonic increase in the risk of schizophrenia as paternal age advanced in the rich database of the Jerusalem Perinatal Cohort. Compared with the offspring of fathers aged 20-24 years, in well-controlled analyses, each decade of paternal age multiplied the risk for schizophrenia by 1.4 (95 percent confidence interval: 1.2-1.7), so that the relative risk (RR) for offspring of fathers aged 45+ was 3.0 (1.6-5.5), with 1/46 of these offspring developing schizophrenia. There were no comparable maternal age effects (Malaspina et al., 2001).
Epidemiological evidence This finding has now been replicated in numerous cohorts from diverse populations (Sipos et al., 2004; El-Saadi et al., 2004; Zammit et al., 2003; Byrne et al., 2003; Dalman and Allenbeck, 2002; Brown et al., 2002; Tsuchiya et al., 2005). By and large, each study shows a tripling of the risk for schizophrenia for the offspring of the oldest group of fathers, in comparison to the risk in a reference group of younger fathers. There is also a "dosage effect" of increasing paternal age; risk is roughly doubled for the offspring of men in their forties and is tripled for paternal age >50 years. These studies are methodologically sound, and most of them have employed prospective exposure data and validated psychiatric diagnoses. Together they demonstrate that the paternal age effect is not explained by other factors, including family history, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, and birth complications. Furthermore, the paternal age effect is specific for schizophrenia versus other adult onset psychiatric disorders. This is not the case for any other known schizophrenia risk factor, including many of the putative susceptibility genes (Craddock et al., 2006).
There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study. The data support the hypothesis that paternal age increases schizophrenia risk through a de novo genetic mechanism. The remarkable uniformity of the results across different cultures lends further coherence to the conclusion that this robust relationship is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, which is independent of regional environmental, infectious, or other routes.
Indeed, the consistency of these data is unparalleled in schizophrenia research, with the exception of the increase in risk to the relatives of schizophrenia probands (i.e., 10 percent for a sibling). Yet, while having an affected first-degree relative confers a relatively higher risk for illness than having a father >50 years (~10 percent versus ~2 percent), paternal age explains a far greater portion of the population attributable risk for schizophrenia. This is because a family history is infrequent among schizophrenia cases, whereas paternal age explained 26.6 percent of the schizophrenia cases in our Jerusalem cohort. If we had only considered the risk in the cases with paternal age >30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent.
Biological plausibility We used several approaches to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, we established a translational animal model using inbred mice. Previously it had been reported that the offspring of aged male rodents had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies (Auroux et al., 1983). Our model carefully compared behavioral performance between the progeny of 18-24-month-old sires with that of 4-month-old sires. We replicated Auroux's findings, demonstrating significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires (Bradley-Moore et al., 2002).
Next, we examined if parental age was related to intelligence in healthy adolescents. We reasoned that if de novo genetic changes can cause schizophrenia, there might be effects of later paternal age on cognitive function, since cognitive problems are intertwined with core aspects of schizophrenia. For this study, we cross-linked data from the Jerusalem birth cohort with the neuropsychological data from the Israeli draft board (Malaspina et al., 2005a). We found that maternal and paternal age had independent effects on IQ scores, each accounting for ~2 percent of the total variance. Older paternal age was exclusively associated with a decrement in nonverbal (performance) intelligence IQ, without effects on verbal ability, suggestive of a specific effect on cognitive processing. In controlled analyses, maternal age showed an inverted U-shaped association with both verbal and performance IQ, suggestive of a generalized effect.
Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.
A variant of schizophrenia A persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).
1: Nat Rev Genet. 2008 May;9(5):341-55. Links Advances in autism genetics: on the threshold of a new neurobiology.Abrahams BS, Geschwind DH. Neurology Department, and Semel Institute for Neuroscience and Behaviour, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769 USA. brett.abrahams@gmail.com
Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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