Tuesday, March 31, 2009

The research of Dr. Miller, a psychotic disorders fellow at MCG, includes paternal age as a risk factor for schizophrenia and mortality in offspring.

MCG Psychiatry Department has unprecedented presence at international schizophrenia meeting
AUGUSTA, Ga. th The Medical College of Georgia Department of Psychiatry and Health Behavior will have a significant presence at the International Congress on Schizophrenia Research, a biennial gathering set for March 28-April 2 in San Diego.





(Media-Newswire.com) - AUGUSTA, Ga. – The Medical College of Georgia Department of Psychiatry and Health Behavior will have a significant presence at the International Congress on Schizophrenia Research, a biennial gathering set for March 28-April 2 in San Diego.

"We are privileged to be making significant contributions to better understanding and treating such a devastating disease," says Dr. Peter Buckley, department chair and associate dean for leadership development in the MCG School of Medicine. "We are excited about the substantial strides the department is making in all aspects of psychiatry," adds Dr. Brian Kirkpatrick, department vice chair.

Dr. Buckley is an advisory board member for the Congress where MCG faculty and staff will make 15 presentations on research findings from a potential cause for widespread central nervous system problems found in patients to the benefits of an innovative education program in which patients help in the education of psychiatry and psychology residents.

MCG's Brian Miller and Anilkumar Pillai are among 30 Young Investigator Travel Award Recipients to be honored at the meeting. The program, supported by the National Institutes of Health, is designed to stimulate research careers in the field of schizophrenia.

"The young investigator awards are highly competitive and they recognize their potential to be leaders in their field," says Dr. Buckley, a former award winner. "We are very proud of them.

" The research of Dr. Miller, a psychotic disorders fellow at MCG, includes paternal age as a risk factor for schizophrenia and mortality in offspring. He will present findings showing that having an older father is a risk factor for suicide in schizophrenia while an older mother is associated with decreased risk. Dr. Miller is a graduate of The Ohio State University College of Medicine and will serve as chief resident in psychiatry at MCG beginning in July. He is working on a doctoral thesis in psychiatric epidemiology in collaboration with Finland's University of Oulu's Department of Psychiatry.

Dr. Pillai, a neuroscientist, studies cell-nourishing tropic factors, such as brain-derived neurotrophic factor or BDNF. Dr. Pillai is collaborating with Dr. Buckley on studies to see if BDNF levels are a good predictor of the common problem of relapse in schizophrenia. At the meeting, Dr. Pillai will discuss a potential cause for down regulation of BDNF in schizophrenia and bipolar disorders. He earned his Ph.D. in biochemistry at the University of Baroda in India and completed postdoctoral fellowships at Rockefeller University in New York and MCG before joining the MCG faculty in 2006.

Also at the meeting, the MCG Department of Psychiatry and Health Behavior will host:

A presentation of the first Public Advocacy Leadership Award given to a physician scientist in recognition of broad, sustained efforts to improve care and service development for patients and families. "We want to foster great science that will improve what we can do for patients in the future but also to recognize great patient and family advocacy that is making a sustained difference in their quality of life today," Dr. Buckley says.

Science to Service: Progress in Schizophrenia Research from Around the Globe, a symposium for patients, families and other advocates to hear about the latest findings in schizophrenia.

An editorial board breakfast for Clinical Schizophrenia & Related Psychoses. Dr. Buckley is the journal's editor-in-chief and Dr. Kirkpatrick is associate editor.

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Sunday, March 29, 2009

Have Married Couples Got It Wrong?

Yesterday at 02:16 PM

Have Married Couples Got It Wrong?
by Dale Harcombe


For married couples the age of having children has gone up dramatically. These days many couples are leaving it later, till their thirties before even considering having children. In the push to have it all and make sure they buy a house and get the house all set up, before having children, as many are doing, are they doing their offspring a disservice?



Recent reports conducted in the USA and in Australia claim that children of older fathers have a lower IQ. And it seems that the older the father is, the lower his child will score in intelligence tests, at least up until the age of 7. Whether the results are the same in later years is a debatable point.

Previously, most concern has focused on the age of the mother when having children, with older women being more at risk of having children with Downs Syndrome. But now it appears that the father's age can also be a risk factor for their offspring. One theory seems to be that the sperm produced by older fathers is likely to contain more DNA errors. These are then passed on to their offspring.

Is the research conclusive? Not exactly. Like many studies there are those who will counter the argument and suggest it has more, or at least as much, to do with the couple's socio-economic state, diet, opportunities for good education and stability of family life among other things. From our own circle of acquaintances we can see those who might possible support such the research findings and those who definitely wouldn't. However it does give pause for though doesn't it?

This is especially concerning when we find out this research comes on the heels of other reports which claim that show links between older fathers and birth defects such as autism and schizophrenia.

It's something for couples to think seriously about when planning marriage and having children.

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Baby Mental Illness Chances Increases with Father’s Age

Baby Mental Illness Chances Increases with Father’s Age
There has been some recent findings that the older the father’s age gets, the higher the chances of having a newborn acquiring a mental illness at a later stage in his or her life or at birth.

The cutoff age seems to be at around 40-years-old, where the chances of autism, schizophrenia, “birth defects, cleft lip and palate, water on the brain, dwarfism, miscarriage and decreased intellectual capacity” can ensue. Quite a lot to swallow, huh?

Well the stats get more serious.

“Children born to fathers 40 or older had nearly a sixfold increase in the risk of autism as compared with kids whose fathers were younger than 30, and children of fathers older than 50 had a ninefold risk of autism,” according to an article in Scientific American Magazine.

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Monday, March 23, 2009

That said, the perfect compromise would be to try to complete your family before both partners reach the age of 35.

The TimesMarch 23, 2009

Do older men have less intelligent children?
New research suggests the older your father is when you are born, the lower your IQ, so how late is too late?Dr Mark Porter
New research suggesting that the age of your father influences your IQ - the older he was when you were born, the worse you are likely to fare when tested - is the latest addition to growing evidence that it is not just maternal age that matters when it comes to starting a family. The longer a couple delay, the poorer the outcome for all concerned. But how late is too late?

Back in the early Nineties, about a quarter of children were fathered by men over the age of 35; today it is closer to half, at least for married couples, who still account for the majority (just) of children born in the UK, with the average first-time mother and father now being aged 30 and 32 respectively.

There are lots of reasons why couples are waiting longer, but career and financial pressures feature highly - a trend likely to have been exacerbated by the current economic climate. But while there are obvious benefits to having more mature parents, these have to be offset against the medical implications - and there are many.

For women the main hurdle is declining fertility. While it is technically possible to conceive naturally right up until your last period, female fertility wanes dramatically after the age of 35, and by the time most women reach their late forties they are technically infertile.

Related Links
Biological clock strikes for men too - at 35
Children of older fathers at risk of autism
The problems of being an older mum
A healthy couple in their twenties have a 25 to 30 per cent chance of conceiving each month. This falls to between 10 and 25 per cent when the woman is in her mid-thirties, and has plummeted to less than 5 per cent by the time she is in her early forties. What's more, nearly half of those who do manage to conceive at this age will miscarry within the first three months.

Much of this decline is due to genetic damage inflicted on a woman's eggs by a combination of environmental factors, such as toxins in the diet and natural background radiation. Women are born with a finite supply of eggs, and a 40-year-old egg is harder to fertilise and nurture than a 20-year-old one.

Tradition has it that advancing years do not have such a detrimental effect on men, who, unlike women, manufacture fresh sperm throughout their lives. But they are not actually manufactured from scratch, and the basic template that matures into a fully grown sperm is, like a woman's eggs, as old as the man - so male fertility wanes, too.

The fall starts to become significant when a man reaches his early forties, meaning that it takes longer to conceive, irrespective of the age of the would-be mother. When they are successful, the woman is also more likely to miscarry if her partner is over 40.

The effect of age on the risk of congenital abnormalities appears to be shared between the parents, too. The best known example in women is the link with Down's syndrome. If a woman is in her late twenties, the risk of her child having Down's is about 1 in 1,000. By the age of 35 it increases to 1 in 270, and by 40 it is closer to 1 in 100.

But less marked genetic mutations are thought to be a problem in older fathers as well, and the implications can be just as serious. Children born to men aged over 35 are more likely to have a cleft lip or palate, congenital heart defects, and to develop some forms of cancer, including leukaemia (a 50 per cent increase) and brain tumours (25 per cent increase).

There is also evidence of a link between paternal age and the chances of a child going on to develop autism, dyslexia or schizophrenia - the link with the last of these being particularly strong. Experts estimate that the trend towards delayed fatherhood could account for as many as 10 per cent of new cases of schizophrenia diagnosed each year.

But let's not be overly pessimistic. Torture statistics enough and they will tell you anything. In fact, the vast majority of older mums and dads will have trouble-free pregnancies and perfectly healthy children. Leaving it later may increase the risk of a range of complications - but a 50 per cent increase on a tiny risk is still only a tiny risk. And the medical implications need to be offset against the social and emotional benefits of bringing up a child in a more stable environment.

That said, the perfect compromise would be to try to complete your family before both partners reach the age of 35. It's a feat that my parents managed with ease - they were just 20 and 21 when they had me, which, statistically, means that I will probably live for ever.

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Sunday, March 22, 2009

Time is not on the side of older dads (offspring)

Time is not on the side of older dads
23 Mar 2009

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 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: The University of Queensland, Australia: PLoS Medicine: March 2009.)

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Plan your family when you are young

Saturday, March 21, 2009
Plan your family when you are young!
Older the father, duller the child! On the contrary, children born to older mothers are smart and active! This inference is the outcome of the study made by London researchers.

It has come to light that men above 35 years run the risk of neurodevelopmental disorders such as autism, schizophrenia and dyslexia. With aging, the male sperm suffer genetic mutations resulting in above defects in children born to these parents.

According to scientists the ideal age for men to plan children is between 20 and 30 years. This concept goes well with the present trend in our youth to marry in their early / mid twenties.

In case both the spouses are professionals, though they get married early in their life, they tend postpone child birth beyond limits setting their priorities on professional career, buying apartments, cars and other luxuries.

These couple feel they would be better placed in rearing children once all the above infrastructures are built. Ironically, they are timed out in planning their families and get trapped in above genetic problems in their off springs.

We also hear a lot about broken families and divorces in childless families.

Children are the best entertainment for the parents and are the strongest cementing factor in their conjugal life.

Beget them when you are young and bring them up when your are healthy!
Posted by Rajagopalan at 7:27 PM

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Parental Age May Affect Children Intelligence

Parental Age May Affect Children Intelligence
Opposite Effect Of Maternal and Paternal Age
© Cecile Le Page

Mar 21, 2009

Increasing maternal age is associated with better performance on intelligence tests of children while paternal age is associated with a poorer cognitive performances.

It is already well known that increase parental age is associated with decrease fertility. Unfortunately, increasing parental age has other various negative impacts on children health and should also be of concern for the future parents. More recently, attention to health outcome of offspring of older father has been increased. Since 1996, a practice guideline on genetic counseling for advanced paternal age is public and updated in 2008 by Dr Toriello et colleagues. The report is entitled 'the state of knowledge of advanced paternal age effects on single gene mutations, chromosome anomalies, and complex traits ' (Genet Med. 2008 Jun;10(6):457-60).

Disorders Associated with Increase Paternal Age
Some of the increase risks of disorders of offspring with older fathers are:

Alzheimer disease
Dyslexia
Bipolar disorder,
Epilepsy
Schizophrenia
Autism
Fetal death
Physical deformity such as Clift lip and palate


Read more: "Parental Age May Affect Children Intelligence: Opposite Effect Of Maternal and Paternal Age" - http://humangenetics.suite101.com/article.cfm/parental_age_may_affect_children_intelligence#ixzz0AUo0o6Fr

Saturday, March 14, 2009

Shocker of a discovery for older dads

Sunday March 15, 2009
Shocker of a discovery for older dads
Insight Down Under
By JEFFREY FRANCIS


LIKE some famous movie stars and top musicians, many men in Australia and other Western nations are more inclined to marry late in life and become fathers when they are in their 40s, 50s and even 60s or 70s.

What they didn’t realise until now is that the children they fathered are at risk of being less intelligent and the performance of their brainpower leaves much to be desired in their early years.

This shocking discovery, the first ever, in a new study of researchers led by world-renowned Australian psychiatrist and brain expert Dr John McGrath, was published last week in a medical journal, PLoS Medicine.

But an interesting contrast is that children born of older women tend to score higher in the same tests designed to measure the ability to think and reason, including concentration, learning, memory, speaking and reading skills.

Whether this has anything to do with older mothers’ better socio-economic status, better health care and health literacy is not known, though Dr Grath’s research noted these conditions.

These factors do not appear to help children fathered by older men in the same way as children of older mothers, he says.

Instead, some kind of biology appears to be at work. As men age, the sperm they produce appears to acquire genetic mutations.

And while the men’s fertility declines with age, the number of damaged sperm which are still able to fertilise a woman’s egg increases.

“It was very clear: If your mother was older, you were doing better. But it went the other way for the dad,” declares Dr McGrath, who is director of Epidemiology and Developmental Neurobiology at Queensland University in Bris­bane.

The bespectacled young-looking professor has carried out various research, one of which led to him and his group discovering the importance of pre-natal vitamin D on brain development.

A winner of several national and international awards, Dr McGrath has published 110 peer-reviewed papers, three books and 13 book chapters.

Hitherto, previous studies have linked advanced paternal age to reduced fertility rate and associated problems such as increased risks of birth deformities and neuropsychiatric conditions. For example, becoming fathers at 40 or older has been linked repeatedly in the past to their offspring being at a significantly higher risk of schizophrenia, autism and a rare syndrome that causes facial or skull abnormalities.

Now, it has been discovered for the first time that children fathered by older men have an average score on the Stanford Binet Intelligence Scale of six points lower than those fathered by men who were just 20.

Yet all the children have better access to health and educational services.

Although some scientists believe that the 20s and 30s are the ideal years for fatherhood, Dr McGrath stresses that researchers could not yet predict the ideal maternal and paternal age that might result in a healthy, intelligent child.

“Future generations will still be bearing the age-related mutations their fathers, grandfathers or great-grandfathers accumulated,” he says.

Dr McGrath points out that there is no single age threshold at which the risk increases, as is the case with women and Down syndrome after 35, and a continual decline for men.

“We, as a society, need to worry about the age of fatherhood a little bit more than in the past,” he says.

“While everyone is aware of a decline in fertility as we age, maybe the general public needs to be aware that there may be something else happening. We need to work out what underlies this association.”

His group of researchers, who have studied data collected from more than 33,400 Ameri­can children and parents ranging in age from 14 to 66, has found a correlation between advanced paternal age and lower intelligence scores.

The children were tested at eight months, four years and seven years of age. They were also assessed for their sensory discrimination, hand-eye coordination, reading, spelling and arithmetic ability.

However, some researchers have suggested that children of older mothers might do better because they experience a more nurturing and attentive home environment.

If this is correct, how is it that Dr McGrath’s study did not show the same benefit among children of older fathers?

But his group found that genetics and social factors might play a role in their findings. They say that a woman’s eggs are formed before birth, so DNA may stay relatively stable.

Sperm, on the other hand, is produced over a man’s lifetime and may gain mutations as men grow older, they say.

Despite the impact Dr McGrath’s findings have caused on society, he says humbly that it is “small and preliminary”.

Jeffrey Francis is editorial consultant, Australasia-Pacific Media

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Friday, March 13, 2009

Paternal Ages Above and below 35 are associated with a different risk of schizophrenia

Paternal Ages Above and below 35 are associated with a different risk of schizophrenia

Paternal Age Above 35

Paternal Ages Above and below 35 are associated with a different risk of schizophrenia
concerned heart View Delete
1: Eur Psychiatry. 2006 Dec 1; [Epub ahead of print] Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.
INSERM U675, 16 rue Henri Huchard 75018 Paris, France; AP-HP (Paris VII), C.H.U Louis Mourier, Service de psychiatrie du Professeur Ades, 178 rue des Renouillers, 92701 Colombes Cedex, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win((R))) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.
Labels: older age of fatherhood, paternal age 35, Philip Gorwood, public health, schizophrenia

Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence

PERSPECTIVEOpen Access Everything we publish is freely available online throughout the world, for you to read, download, copy, distribute, and use (with attribution) any way you wish. No permission required. Read a detailed definition of open access.
The Perspectives section is for experts to discuss the clinical practice or public health implications of a published study that is freely available online.

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.

References
Bray I, Gunnell D, Davey Smith G (2006) Advanced paternal age: How old is too old? J Epid Comm Health 60: 851–853. Find this article online
Bewley S, Davies M, Braude P (2005) Which career first? The most secure age for childbearing remains 20–35. BMJ 331: 588–589. Find this article online
Lewis BH, Legato M, Fisch H (2006) Medical implications of the male biological clock. JAMA 296: 2369–2371. Find this article online
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
Malaspina D, Harlap S, Fennig S, Heiman D, Nachon D, et al. (2001) Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 58: 361–367. Find this article online
Zammit S, Alleback P, Dalman C, Lundberg I, Hemmingson T, et al. (2003) Paternal age and risk for schizophrenia. Br J Psychiatry 183: 405–408. Find this article online
Vestergaard M, Mork A, Madsen KM, Olsen J (2005) Paternal age and epilepsy in the offspring. Eur J Epid 20: 1003–1005. Find this article online
Frans E, Sandlin S, Reichenberg A, Lichtenstein P, Langstrom N, et al. (2008) Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 65: 1034–1040. Find this article online
Gavrilov LA, Gavrilova NS (1997) When should fatherhood stop? Science 277: 17–21. Find this article online
Buwe A, Guttenbach M, Schmid M (2005) Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111: 213–228. Find this article online
Perrin MC, Brown AS, Malaspina D (2007) Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull 33: 1270–1273. Find this article online
Garcia-Palomares S, Pertusa JF, Minarro J, Garcia-Perez MA, Hermenegildo C, et al. (2008) Long-term effects of delayed fatherhood in mice on postnatal development and behavioural traits of offspring. Biol Reprod 80: 337–342. Find this article online
Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, et al. (2008) Advanced parental age at birth is associated with poorer social functioning in adolescent males: Shedding light on a core feature of schizophrenia and autism. Schizophr Bull 34: 1042–1046. Find this article online
Cannon M, Jones PB, Gilvarry C, Rifkin L, McKenzie K, et al. (1997) Premorbid social adjustment in schizophrenia and bipolar disorder: Similarities and differences. Am J Psychiatry 154: 1544–1550. Find this article online
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: e1000040. doi:10.1371/journal.pmed.1000040. Find this article online
Stein Z, Susser M (2000) The risks of having children in later life. Social advantage may make up for biological disadvantage. BMJ 320: 1681–1682. Find this article online
Leon DA (1993) Failed or misleading adjustment for confounding. Lancet 342: 479–481. Find this article online

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Thursday, March 12, 2009

Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood

RESEARCH ARTICLEOpen Access
Everything we publish is freely available online throughout the world, for you to read, download, copy, distribute, and use (with attribution) any way you wish. No permission required. Read a detailed definition of open access.
Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood
Sukanta Saha1, Adrian G. Barnett2, Claire Foldi3, Thomas H. Burne1,3, Darryl W. Eyles1,3, Stephen L. Buka4, John J. McGrath1,3,5*
1 Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, Australia, 2 Institute of Health and Biomedical Innovation and School of Public Health, Queensland University of Technology, Kelvin Grove, Australia, 3 Queensland Brain Institute, The University of Queensland, St. Lucia, Australia, 4 Department of Community Health, Brown University, Providence, Rhode Island, United States of America, 5 Department of Psychiatry, The University of Queensland, St. Lucia, Australia
Background
Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood.
Methods and Findings
A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures.
Conclusions
The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.
Funding: The authors received no specific funding for this article.
Competing Interests: The authors have declared that no competing interests exist.
Academic Editor: Carol Brayne, University of Cambridge, United Kingdom
Citation: 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
Received: September 8, 2008; Accepted: January 15, 2009; Published: March 10, 2009
Copyright: © 2009 Saha et al. 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.
Abbreviations: APA, advanced paternal age; CI, confidence interval; CPP, Collaborative Perinatal Project; WISC, Wechsler Intelligence Scale for Children; WRAT, Wide Range Achievement Test
* To whom correspondence should be addressed. E-mail: john_mcgrath@qcmhr.uq.edu.au
These authors contributed equally to this work.
Editors' Summary
Background.
Over the last few decades, changes in society in the developed world have made it increasingly common for couples to wait until their late thirties to have children. In 1993, 25% of live births within marriage in England and Wales were to fathers aged 35–54 years, but by 2003 it was 40%. It is well known that women's fertility declines with age and that older mothers are more likely to have children with disabilities such as Down's syndrome. In contrast, many men can father children throughout their lives, and little attention has been paid to the effects of older fatherhood.
More recent evidence shows that a man's age does affect both fertility and the child's health. “Advanced paternal age” has been linked to miscarriages, birth deformities, cancer, and specific behavioral problems such as autism or schizophrenia.
Rates of autism have increased in recent decades, but the cause is unknown. Studies of twins and families have suggested there may be a complex genetic basis, and it is suspected that damage to sperm, which can accumulate over a man's lifetime, may be responsible. A woman's eggs are formed largely while she is herself in the womb, but sperm-making cells divide throughout a man's lifetime, increasing the chance of mutations in sperm.
Why Was This Study Done?
There is good evidence linking specific disorders with older fathers, but the link between a father's age and a child's more general intelligence is not as clear. A recent study suggested a link between reduced intelligence and both very young and older fathers. The authors wanted to use this large dataset to test the idea that older fathers have children who do worse on tests of intelligence. They also wanted to re-examine others' findings using this same dataset that older mothers have more intelligent children.
What Did the Researchers Do and Find?
The researchers gathered no new data but reanalyzed data on children from the US Collaborative Perinatal Project (CPP), which had used a variety of tests given to children at ages 8 months, 4 years, and 7 years, to measure cognitive ability—the ability to think and reason, including concentration, memory, learning, understanding, speaking, and reading. Some tests included assessments of “motor skills”—physical co-ordination.
The CPP dataset holds information on children of 55,908 expectant mothers who attended 12 university-affiliated hospital clinics in the United States from 1959 to 1965. The researchers excluded premature babies and multiple births and chose one pregnancy at random for each eligible woman, to keep their analysis simpler. This approach reduced the number of children in their analysis to 33,437.
The researchers analyzed the data using two models. In one, they took into account physical factors such as the parents' ages. In the other, they also took into account social factors such as the parents' level of education and income, which are linked to intelligence. In addition, the authors grouped the children by their mother's age and, within each group, looked for a link between the lowest-scoring children and the age of their father.
The researchers found that children with older fathers had lower scores on all of the measures except one measure of motor skills. In contrast, children with older mothers had higher scores. They found that the older the father, the more likely was this result found.
What Do These Findings Mean?
This study is the first to show that children of older fathers perform less well in a range of tests when young, but cannot say whether those children catch up with their peers after the age of 7 years. Results may also be biased because information was more likely to be missing for children whose father's age was not recorded.
Previous researchers had proposed that children of older mothers may perform better in tests because they experience a more nurturing home environment. If this is the case, children of older fathers do not experience the same benefit.
However, further work needs to be done to confirm these findings. Especially in newer datasets, current trends to delay parenthood mean these findings have implications for individuals, couples, and policymakers. Individuals and couples need to be aware that the ages of both partners can affect their ability to have healthy children, though the risks for individual children are small. Policymakers should consider promoting awareness of the risks of delaying parenthood or introducing policies to encourage childbearing at an optimal age.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000040.
Mothers 35+ is a UK Web site with resources and information for older mothers, mothers-to-be, and would-be mothers, including information on the health implications of fathering a child late in life
The American Society for Reproductive Medicine published a Patient Information Booklet on Age and Fertility in 2003, which is available online; it contains a small section called “Fertility in the Aging Male,” but otherwise focuses on women
The online encyclopedia Wikipedia has a short article on the “Paternal age effect” (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
In 2005, the UK Office of National Statistics published a booklet entitled “Perpetual postponers? Women's, men's and couple's fertility intentions and subsequent fertility behaviour” looking at data from the British Household Panel Survey
Introduction
In recent decades there has been increased attention to health outcomes in the offspring of older fathers. Evidence shows that advanced paternal age (APA) is associated with an increased risk of a wide range of disorders [1]. While not discounting the influence of various age-related psychosocial factors that may translate to differential health outcomes for the offspring of older fathers (e.g., higher socioeconomic status, better education), advances in genomics have refocused attention on the vulnerability of sperm from older fathers to carrying de novo mutations. The development of the germ cell differs between human males and females—there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte [2]. In the female there are 22 mitotic cell divisions that occur in utero. In contrast, after puberty, progenitor sperm stem cells undergo mitotic cell division once every 16 d. By age 20 the progenitor sperm cells have undergone approximately 150 cell divisions. By age 50 this number is 840. Thus, the chance of copy error mutations increases with age in males more dramatically than for females.
Advanced paternal age is associated with increased fetal deaths [3,4] and certain rare congenital syndromes (e.g., achondroplasia) [1,5]. In recent years evidence has accumulated linking APA with a wide range of neurological and neuropsychiatric conditions including Alzheimer's disease [6,7], bipolar disorder [8], dyslexia [9], neural tube defects [10], and epilepsy [11]. A sizeable body of evidence has accumulated linking APA with an increased risk of schizophrenia [1218]. A recent meta-analysis based on eight studies found that paternal age above 35 was associated with an increased risk of schizophrenia [19]. There is also evidence linking APA to autism spectrum disorders [2024].
The associations between APA and outcomes such as autism and schizophrenia are of particular interest, as these disorders have recently been associated with genomic structural variation [2530]. It is feasible that APA-related mechanisms may contribute to genomic structural variation (e.g., copy number variants, microdeletions) [2]. Thus, within the fields of schizophrenia and autism research, there has been an unexpected convergence between epidemiology and molecular biology.
While there is good evidence linking paternal age with several clinically distinct neurodevelopmental disorders, the evidence linking paternal age and other neurocognitive outcomes such as general intelligence is less robust. Earlier studies noted an association between APA and poorer performance on neurocognitive tests [3134]. This issue has been addressed specifically in a recent study based on male and female Israeli conscripts (age 16–17 y, n = 44,175) [35]. The study found independent effects of paternal age on offspring intelligence with the lowest scores associated with both younger and older fathers (inverted “U”-shaped association). This finding is in contrast to the association between maternal age and offspring intelligence, where most studies have reported a linear association between older maternal age and superior neurocognitive ability [3639].
The aim of the present study was to explore the association between paternal age and a range of neurocognitive measures using a large, prospective birth cohort: the US-based Collaborative Perinatal Project (CPP). Based on the literature linking increased paternal age with a range of developmental anomalies and neuropsychiatric disorders, we hypothesized that the children of older fathers would have lower scores on various tests used to measure neurocognitive ability when assessed at 8 mo, 4 y, and 7 y. While a study based on this same cohort had previously identified that the offspring of older mothers had superior performance on neurocognitive functioning [36], we also took the opportunity to re-examine this hypothesis in the current analyses.
Methods
Sample Selection
The Collaborative Perinatal Project (CPP) recruited pregnant women from 12 university-affiliated hospital clinics in the United States of America from 1959 to 1965. The selection method varied from centre to centre, with between 14% and 100% of the registered pregnant women being invited to participate. At centres with less than 100% sampling, women were selected according to various quasi-random rules (e.g., every nth woman). Of 132,560 eligible pregnancies, 55,908 pregnancies were included, which was a proportion representative of the original sampling frame [40,41].
In order to reduce the impact of prematurity on the neurocognitive outcome measures, we restricted the sample to offspring born after 37 wk gestation. In order to minimize statistical complexities arising from dependent data, we restricted the sample to (a) singleton pregnancies, and (b) one randomly chosen pregnancy for each woman enrolled in the study.
Measures of Neurocognitive Function
Study offspring were assessed at regular intervals until age 7 y. Detailed descriptions of the methods used for cognitive assessments have been published elsewhere [36,42]. At 8 mo of age the Bayley Scales for Infant Development were administered [43,44]. Two scores were available: (a) Mental Scale, which assesses aspects of development including sensory discrimination and eye-hand coordination, and (b) Motor Scale, which assessed various aspects of fine and gross motor coordination. At age 4 y the children were administered (a) the Stanford Binet Intelligence Scale, Form L-M (a measure of general intelligence in young children) [45,46], and (b) the Graham-Ernhart Block Sort Test, which assesses conceptual and perceptual motor ability. This test involves increasingly difficult tasks that range from matching simple like-shaped blocks, to sorting blocks according to one or two dimensions (e.g., colour, shape, size) [47]. At age 7 y the children were administered the widely used Wechsler Intelligence Scale for Children (WISC) [48]. Scores for Full Scale, Verbal, and Performance were available for this study. However, the two WISC subscales (Verbal and Performance) were strongly correlated with WISC Full Scale IQ (Pearson correlation = 0.90 and 0.89, respectively), thus only the WISC Full Scale IQ results are presented. The Wide Range Achievement Test (WRAT) scale was also used at the age 7 y follow-up in order to evaluate academic achievements (e.g., the ability to read words, comprehend sentences, spell, and compute solutions to math problems) [49]. Scores for WRAT Arithmetic, Reading, and Spelling were available in this study. Because the WRAT Reading, Spelling, and Arithmetic scores were all strongly correlated (Pearson correlations of 0.65 to 0.89), only the WRAT Reading is presented.
Statistical Methods
For the primary analyses, we modelled nonlinear associations between parental age and neurocognitive outcomes using a generalized additive model [50]. We used the generalized cross-validation algorithm to select the degree of nonlinearity. To verify the assumptions of the models, we examined the residuals to check (a) their normality and (b) their homoscedasticity (constant variance) against paternal age.
Each parent's age (at the birth of the child) was adjusted for the other parent's age. For the primary analyses, we examined a simple model (Model 1) adjusted for offspring sex, other parent's age, mother's race, weeks of gestation, and child's age at testing (which varied slightly at the 8 mo, 4 y, and 7 y follow-ups). In order to explore if various socioeconomic variables influenced the strength of the association, a second model (Model 2) also included additional adjustments related to maternal marital status, family socioeconomic status and parental mental health. Socioeconomic status was measured by a composite index that averaged centiles derived from maternal and paternal education and occupation, as well as family income [51].
Because maternal and paternal age were strongly correlated (Pearson correlation = 0.80), we checked the models for colinearity using the variance inflation factor [52]. The variance inflation factors were roughly three for paternal and maternal age in all models. This value is well below the suggested threshold of ten [52], and hence we modelled both ages together.
The results of the primary analyses are displayed graphically, with the nonlinear model fitted for both maternal and paternal age (and 95% confidence intervals [CIs]). The variance explained (adjusted R-squared) and the p-values for each of the primary analyses are also shown in tabular form. Nonlinear models do not lend themselves to simple quantitative descriptions (e.g., statements such as “the outcome variable falls by a certain number of units for every additional 5 years of paternal age” cannot be made for nonlinear relationships). In order to facilitate interpretation of the primary analyses, we also provided estimates (and 95% CIs) for each outcome variable at two paternal ages (20 and 50 y).
As secondary analyses, we examined the association between paternal age and offspring neurocognition according to various strata of maternal age. This removes widely diverse effects due to maternal age on neurocognitive outcomes by estimating the effect of paternal age in subgroups where mother's ages were highly comparable. We identified cohort members where maternal ages fell within roughly 5 y age strata: <20, 20–24, 25–29, 30–34, 35–39, 40+. For these secondary analyses, we also chose a more stringent test of the association between the variables of interest. For each of the neurocognitive variables, we stratified the sample by sex, age, and race and then dichotomized the sample into a low-achievers group, defined as the lowest 10% of scores in each sex, age, and race group, versus the remaining 90% of the group. We calculated the adjusted odds ratio for being in the low achievers group for a 5 y increase in paternal age using conditional logistic regression.
All p-values were two-sided and statistical significance was set at 0.05. We used the mgcv library in R to fit the generalized additive models [53] and SAS PROC PHREG for the conditional logistic regression [54].
Results
There were 55,740 singleton pregnancies. Of these, 12,297 children were excluded because of (a) missing maternal and/or paternal age (1,542), (b) having indeterminate or unspecified sex (1,050), or (c) gestational age that was missing or less than 37 wk (9,705). After randomly selecting one live-born offspring per study mother, this left a total of 33,437 study offspring (17,148 males) available for the main analyses. Of these, 51% of the mothers were white, 39% black, and the remaining 10% were Asian and other racial groups. Finally, 6,355 children were missing information about age at testing at 8 mo, while 9,930 were missing age at testing at 4 y, and 9,109 were missing age at testing at 7 y. Those with missing paternal age were significantly more likely to have missing outcome variables at 8 mo, 4 y, and 7 y (each p < 0.001).
Table 1 shows descriptive statistics for paternal and maternal age and differences in parental age. On average, fathers were 3 to 4 y older than mothers, but the differences in parental age varied widely. Concerning the primary analyses, there was a statistically significant association between advanced paternal age and inferior performance on all neurocognitive tests (all p < p =" 0.104)" href="http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.1000040#journal-pmed-1000040-t002">Table 2). Concerning the influence of maternal age, there were statistically significant associations between advanced maternal age and superior performance on all measures. Figures 1 and 2 show the mean adjusted score for paternal and maternal age for the outcome variables based on Models 1 and 2 respectively. Apart from the direction of the association between maternal and paternal age, the association between maternal age and the outcome variables at ages 4 and 7 y was curvilinear (generally steep at younger ages, then less steep at older ages), in contrast to the near-linear association with paternal age. Post-hoc analyses examining the goodness-of-fit of nonlinear versus linear models indicated that two of the variables were adequately capture by simple linear models (Bayley Mental score and Graham Ernhart Block Sort Test), but that nonlinear models were best suited for all other variables (unpublished data). Table 3 shows the estimated scores (and 95% CIs) for two paternal ages (20 and 50 y) based on the nonlinear modelling used in the primary analyses. For Model 2, the adjusted R-squared ranged from 2.4% (Bayley Motor) to 29.5% (WISC Full Scale IQ).

Table 1.
Descriptive Statistics of Maternal and Paternal Age, and Parental Age Difference (n = 33,437)

Table 2.
Primary Analyses: Summary Table for the Nonlinear Model Fits for Models 1 and 2

Figure 1. Primary Analyses: Model 1—Adjusted for Other Parent's Age, Mother's Race, Gestational Age, and Child Gender
Solid lines ranging from 15 to 45 y for maternal age, dotted lines ranging from 15 to 65 y for paternal age. Nonlinear model fit with 95% CIs.

Figure 2. Primary Analyses: Model 2—Adjusted for Other Parent's age, Mother's Race, Gestational Age, and Child Gender, Socioeconomic Index, Marital Status, and Maternal and Paternal Mental Illness
Solid lines ranging from 15 to 45 y for maternal age, dotted lines ranging from 15 to 65 y for paternal age. Nonlinear model fit with 95% CIs.

Table 3.
Primary Analyses: Estimates for Two Paternal Ages Based on the Nonlinear Model Fits for Models 1 and 2
Concerning the secondary analyses, the odds ratio (Model 2) for being in the lowest decile for each neurocognitive variable was significantly associated with elevated paternal age for three of the neurocognitive measures (Bayley Motor, Graham Ernhart Block Sort Test, WISC Full Scale IQ), with trend level association identified for the other three measures (Bayley Mental, Stanford Binet Intelligence Scale, WRAT Reading) (Table 4).

Table 4.
Secondary Analyses: Associations between Increasing Paternal Age and Neurocognitive Measures in Children, Results from Logistic Regression Analyses Using Subgroups of Women with Similar Ages
Discussion
We report, to our knowledge for the first time, that the offspring of older fathers show impairments on a range of neurocognitive tasks during infancy and childhood. The pattern of findings was relatively consistent across ages and across neurocognitive domains, with near-linear declines found in most of the measures. When the data were examined with a more stringent definition of cognitive impairment (scores in the lowest 10%), a significant relationship between APA and impaired neurocognition was found for three of the six outcome variables, with trend level associations found for the remaining three variables. These findings persisted after adjustment for a range of socioeconomic variables and for parental mental health. In striking contrast to the findings for APA, the association between advanced maternal age and performance on neurocognitive tasks was in the opposite direction.
The findings differ somewhat from those reported by Malaspina et al. [35], who reported on four different measures related to cognitive ability in teenagers (age 16–17y). In that study the offspring of both younger (<20>40 y) had impaired neurocognitive performance compared to those with fathers in the other age strata. However, differences between the Malaspina et al. study and the current study with respect to the psychometric measures and the age of the offspring make direct comparisons difficult. As expected, the current study also identified an association between advanced maternal age and superior performance on the neurocognitive tests, in keeping with some [3639] but not all studies [35].
The association between APA and reduced neurocognitive ability may have important implications for clinical outcomes previously linked to APA. While not all individuals with autistic spectrum disorders have impaired intelligence, many have specific learning disabilities and/or intellectual handicap [55]. With respect to schizophrenia, systematic reviews and meta-analyses have shown a reliable, medium-sized impairment in premorbid intelligence associated with this disorder [56,57]. For example, Woodberry et al. [57] reported that years before the onset of psychotic symptoms, individuals who later developed schizophrenia had IQ scores that, on average, were approximately one-half of a standard deviation below that of healthy comparison participants. Consistent with these findings, a systematic review of the antecedents of schizophrenia based on prospective birth cohorts [58] provided robust evidence that individuals who later develop schizophrenia show deviation during childhood on a range of cognitive measures related to intelligence, motor development, speech and language, and educational outcomes. In particular, cohort members who later developed schizophrenia, as a group, achieved lower scores on intelligence tests in childhood and adolescence than their peers [5961].
The findings from this study linking APA and impaired cognition may be best conceptualized within the notion of impaired cognitive reserve [62,63]. Just as superior cognitive capacity appears to provide a buffer against dementia [64,65], subtle APA-related impairments in neurocognitive ability may contribute to an increased risk of a diverse range of adverse neurological and neuropsychiatric health outcomes.
The study has several caveats. Nonrandom sample attrition and missing data may influence the generalisability of the findings [41]. Those with missing data on paternal age were more likely to be lost to follow-up. It will be important to examine the variables of interest in cohorts with optimal participant retention and minimal missing data. More importantly, the cohort members were born in the United States during the 1960s, thus the generalisability of the findings with respect to more contemporary cohorts needs to be examined. While it is feasible that various economic and psychosocial factors that can influence childhood developmental trajectories may have changed in recent decades, there is no reason to suspect that the putative biological processes linking APA and adverse health outcome would have varied over this time frame. Finally, it is important to note that these analyses investigated neurocognitive outcomes only until age 7 y, and it is feasible that the offspring of older fathers “catch up” during later childhood. How the subtle neurocognitive features associated with APA translate into later educational and mental health outcomes across the lifespan remains to be determined.
With respect to the mechanism of action underpinning these findings, several hypotheses warrant further scrutiny. While twin studies have demonstrated that cognitive ability and brain structure are heritable [66,67], studies based on sibships within the CPP have also confirmed that socioeconomic factors play a role in mediating the heritable aspects of intelligence [68]. With respect to paternal age, a broad range of socioeconomic factors improve with increasing age, thus most commentators believe that the offspring of older parents would have better access to health and educational services compared to the offspring of younger parents (who tend to have lower education and poorer income) [69]. For example, Fergusson and Lynsky [38] found that offspring of younger mothers tended to be born into relatively poorly educated and socially disadvantaged families. These authors commented that children born to young mothers were exposed to less nurturing and more changeable home environments. One would expect that such mechanisms would also operate with respect to paternal age. Clearly, our findings linking APA with impaired neurocognitive development cannot be readily explained by these social mechanisms.
Mechanisms related to the development of the male germline warrant consideration [70]. Each time the cell divides, the replication of the genome introduces the possibility of copy error mutations. In humans it has been confirmed that sperm from older men have significantly more mutations [2,71,72]. Levels of DNA proofreading and repair enzymes also decline as a function of APA [16] and DNA fragmentation increases [73], further compromising the integrity of gene replication. Apart from genetic changes (i.e., changes in DNA basepair sequence), APA may also involve abnormal epigenetic mechanisms [7476].
Unravelling the molecular mechanisms underlying the association between APA and adverse health outcomes will be a substantial task for the biomedical research community. The precise location and nature of these mechanisms will probably vary substantially from offspring to offspring. It is unlikely that they will “map” neatly to a few loci, nor probably to one mechanism (e.g. genetic, epigenetic). With respect to genetic mechanisms, these may include single nucleotide mutations, or various types of genomic rearrangements (e.g., microdeletions, tandem and trinucleotide repeat expansions, microduplication or higher order expansions, aneuploidy). Animal experiments based on inbred rodent strains may provide the most efficient way to explore genetic and epigenetic factors mediating APA and brain development. Comparable to “forward genetics” platforms based on chemical mutagens [77,78], rodent-based APA models could provide an age-related mutagenesis experiment that has epidemiological face validity [79].
The observation linking APA with risk of schizophrenia has led to the hypothesis that APA-related mechanisms are contributing de novo mutations, which could explain the persistence of schizophrenia in the population in spite of reduced fertility and/or fecundity associated with this disorder [80]. APA-related mechanisms could accumulate over several generations, with the full clinical phenotype “breaking through” only after a critical threshold of certain mutations have accumulated [81,82]. In light of secular trends related to delayed parenthood [83], and in light of the potential for APA-related mechanisms to accumulate over several generations, the association between APA and subtle deficits in neurocognitive outcomes warrants closer scrutiny. While most of the neurocognitive differences were small at the individual level, these could have important implications from a public health perspective [84].
Acknowledgments
Computational resources and services used in this work were provided by the High Performance Computing and Research Support Unit, Queensland University of Technology, Brisbane, Australia.
Author contributions. The overall study was designed and supervised by JJM. The dataset was prepared by SLB and the statistical analyses were conducted by SS, AGB, and JJM. All authors contributed to the interpretation of the data and writing up of the manuscript.
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