Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence

Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence
The clock ticks for men too
Mary Cannon


Funding: MC is supported by a Clinician Scientist Award from the Health Research Board, Ireland, a Grable Independent Investigator award from NARSAD (US), and the Wellcome Trust. The funders played no role in preparing this article.

Competing Interests: The author has declared that no competing interests exist.

Citation: Cannon M (2009) Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence. PLoS Med 6(3): e1000042 doi:10.1371/journal.pmed.1000042

Published: March 10, 2009

Copyright: © 2009 Mary Cannon. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mary Cannon is in the Department of Psychiatry, Royal College of Surgeons in Ireland and Beaumont Hospital, RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland. E-mail: marycannon@rcsi.ie

Provenance: Commissioned; not externally peer reviewed


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Both maternal and paternal ages are increasing in the developed world. The average age of mothers at time of childbirth has increased from 26.4 years in 1974 to 29.3 years in 2002, while the average age of fathers has increased from 29.2 years in 1980 to 32.1 years in 2002 [1]. This increase in the average parental age is most likely due to the societal trend for couples to delay starting a family for career or financial reasons. The concept of the female “biological clock” (the effect of increasing maternal age on reducing fertility) is well known and is a source of anxiety for many women [2]. In contrast, the consequences of increasing paternal age on fertility and other adverse reproductive outcomes are rarely discussed [3].

Effects of Paternal Age on Offspring Outcomes
Evidence is accumulating that advanced paternal age may exhibit a wider range of effects on the health and development of the offspring than increased maternal age (which is largely confined to risk for Down syndrome). Advanced paternal age is a risk factor for childhood conditions such as cleft lip and palate; childhood cancers and congenital heart defects [1]; and neuropsychiatric conditions such as autism [4], schizophrenia [5,6], epilepsy [7], and bipolar disorder [8]. Advanced paternal age also appears to affect mortality, and an intriguing analysis of family history data from European nobility found that older age of fatherhood (greater than 45 years) is associated with a reduction of about two years in the life span of daughters [9].

Linked Research Article
This Perspective discusses the following new study published in PLoS Medicine:

Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, et al. (2009) Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med 6(3): e1000040. doi:10.1371/journal.pmed.1000040

Using a sample of children from the US Collaborative Perinatal Project, John McGrath and colleagues show that the offspring of older fathers exhibit subtle impairments on tests of neurocognitive ability during infancy and childhood.

Some of these associations (notably that for schizophrenia) are more extensively replicated than others, but the body of evidence implicating paternal age as a risk factor for a range of adverse offspring outcomes should not be ignored. What is the postulated mechanism for these associations?

Putative Genetic Mechanisms of Paternal Age Effect
Most commentators attribute these associations to some form of genetic effect, with the greatest consensus in favour of spontaneous mutation. Genomic studies show that sperm cells undergo more mutations than ova during the life span [10]. Thus delaying fatherhood might contribute to an increased incidence of mutations that can give rise to developmental and neuropsychiatric disorders in the population. Epigenetic mechanisms, such as hypermethylation, increase with age and may be an alternative explanation [11,12].

Intermediate Phenotypes
Rather than a direct genetic effect, paternal age could increase risk for a range of neuropsychiatric outcomes in an indirect manner by increasing the likelihood of an “at-risk” or precursor phenotype in offspring. Support for this hypothesis comes from a study by Weiser and colleagues, who analysed data from an Israeli cohort of 10,000 male conscripts and found that offspring of both very young fathers (less than 20 years) and older fathers (greater than 45 years) had impaired social function [13]. Sons of older mothers (greater than 40 years) also had poorer social function. Poor social function has been shown to be a precursor for many psychiatric disorders, such as schizophrenia [14].

Parental Age and Intelligence of Offspring
A new study by John McGrath and colleagues in this issue of PLoS Medicine examines the association between paternal and maternal age and impaired neurocognitive ability in childhood (another putative intermediate phenotype) [15]. The authors use data from the Collaborative Perinatal Project, a large birth cohort of more than 50,000 individuals born between 1959 and 1965 in 12 centres in the United States, who were followed up throughout childhood. Cognitive measures were collected at three time points: eight months, four years, and seven years. The use of a cohort from the 1960s means that the association between parental age and offspring intelligence is largely unconfounded by the possible neurocognitive effects of assisted reproductive technology (which began in 1978) or the possible psychosocial effects of complex (or blended) stepfamily structures, which have become more common over the past decade.

McGrath and colleagues show remarkable contrasting effects of paternal and maternal age on the cognitive abilities of the offspring [15]. Increasing maternal age is associated with superior performance on intelligence tests in a linear fashion whereas increasing paternal age is associated with significantly poorer performance on five out of six of the measures tested.

A second notable aspect of this study is the effect of adjustment for socio-economic factors. Controlling for parental mental health and socio-economic status, measured using a composite score that indexes maternal and paternal education as well as family income, resulted in a marked attenuation of the effect of both maternal and paternal age on the intelligence scores. For instance, the average difference in IQ between the offspring of a father aged 20 and a father aged 50 decreases from six points to three points after adjustment for socio-economic factors.

These intriguing findings give rise to two questions: (1) Why should the offspring of older fathers, but not older mothers, have poorer performance on intelligence tests? and (2) If genetic effects are responsible, then what role do social factors play?

The Role of Social Factors
Social advantage (in the form of economic security and increased education) may compensate to a certain extent for the biological risks in delaying motherhood [16]. McGrath and colleagues find that delayed fatherhood does not appear to convey this social advantage in the form of better cognitive test scores [15]. Is this due to some inherent difference in the way in which older fathers and older mothers interact with their children? Or is this due to spontaneous mutation—bearing in mind that studies in rodents show that paternal age significantly influences developmental and behavioural outcomes in offspring [12]? Of course, both effects could be operating in conjunction in humans. For instance, Reichenberg and colleagues have postulated that the incidence of genetic mutations may be influenced by age at fatherhood, which in turn may be influenced by the socio-cultural environment or by personality characteristics [4].

Conclusion
McGrath and colleagues show the importance of taking socio-economic factors into account when examining the issue of paternal age [15]. Could the paternal age effect on offspring intelligence be due to so-called residual confounding, whereby adjustment does not fully remove the effect of a confounder [17]? In other words, if we could adjust the association for every relevant socio-economic and interpersonal variable (both known and unknown) using precise measures, then perhaps we could eliminate the effect of paternal age on intelligence completely. New explanatory models are needed that can encompass socio-cultural and interpersonal factors as well as biological variables. Perhaps then we can decide when is the best time to be a mother…or father.

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Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, et al. (2006) Advancing paternal age and autism. Arch Gen Psychiatry 63: 1026–1032. Find this article online
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University of Queensland research has revealed the older a dad is the more likely his children will have reduced cognitive abilities.

University of Queensland research has revealed the older a dad is the more likely his children will have reduced cognitive abilities.

Professor John McGrath, from UQ's Queensland Brain Institute, said the study could have implications for a society that is having children later in life.

He said while recent research had shown a link between the age of a father and an increased chance of schizophrenia and autism in the children, there has been less focus on the age of father and cognition.

"The results were quite startling as it was thought that the age of the father was less of a concern compared to the age of the mother," Professor McGrath said.

"Now we are getting more evidence of the age of the father being just as important.

"The older a dad is, the worse his children tend to do in intelligence tests."

The research, published in medical journal PLoS Medicine today (Tuesday, March 10), re-analysed data from one of the largest studies of children in the United States, the Collaborative Perinatal Project.

More than 33,000 children were tested at eight months, four years and seven years on a variety of intelligence tests, and when Professor McGrath and his colleagues looked at the results against the age of the fathers a pattern soon became clear.

"Frankly, we were surprised to come up with such a clear cut finding," Professor McGrath said.

"We are concerned that older men accumulate more mutations in the developing sperm cells.

"These mistakes then pile up and increase the risks of problems in the children, and it is possible that these mistakes will carry on into the next generation."

Professor McGrath said the difference in intelligence was the exact opposite for children of older women, which made the findings even more startling.

"Offspring of older women do better in similar tests, but this is usually put down to socio-economic status of women," he said.

"But with the older dads, we wonder if the association is related to mutations in the developing sperm."

Professor McGrath and colleagues at QBI and the Queensland Institute of Medical Research are currently using mouse models in order to find the underlying genetic factors that may explain the association between advance paternal age and child development.

Source : Research Australia

James Watson co-discoverer of DNA make the connection between older paternal age (35plus) and schizophrenia in son

From The Sunday Times
March 8, 2009
Not too bright? Now the blame is on your old man
Jonathan Leake, Science Editor

CHILDREN with older fathers seem to perform worse in intelligence tests, according to a study due out this week.
They tended to obtain significantly lower scores in a variety of cognitive tests than those born to younger fathers, researchers have found.
The results could be controversial. Until recent years it had been thought that it was a mother’s age that had most impact on the health and abilities of children. The father’s age, by contrast, was thought to be much less important.
The research, led by John McGrath, of the Queensland Brain Institute at the University of Queensland in Australia, suggests such ideas need rethinking.
“The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood,” he said. “In light of the trends to delay fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.”
Other research has shown linkage between advanced paternal age (men over 35) and an increased risk of neurodevelopmental disorders, such as autism and schizophrenia, as well as dyslexia. Such findings prompted James Watson, co-discoverer of the structure of DNA, to speak of his concern. His son Rufus suffers from schizophrenia and as more is uncovered about its causes Watson has publicly questioned if he is to blame. “I worry that I was 42 with Rufus,” he says. “I read that the frequency of schizophrenia goes up with the age of both parents.”
The tests, designed to measure the ability to think and reason, also generated a second startling finding — that children with older mothers gain higher intelligence scores.
McGrath analysed data on 33,437 Americans born between 1959 and 1965. All were tested at eight months, four years and seven. The data set, despite its age, remains one of the best resources. McGrath also used advanced statistical techniques to remove environmental influences.
For McGrath one of the key questions is the underlying biological mechanisms. One idea is that as men age the cells that produce sperm suffer increasing numbers of mutations, which are passed on to an offspring.
Why, though, would children born to older mothers tend to have higher intelligence? McGrath suggests this is because women’s eggs are formed when they are still in the womb and so their DNA is protected from mutation until they are used.