Paternal age effect

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The paternal age effect is the statistical relationship between the father's age at conception and biological effects on the child.

The genetic quality of sperm, as well as its volume and motility, may decrease with age,[5]^[6] leading the population geneticist James F. Crow to claim that the "greatest mutational health hazard to the human genome is fertile older males".^[7]

The paternal age effect was first proposed implicitly by physician Wilhelm Weinberg in 1912^[8] and explicitly by psychiatrist Lionel Penrose in 1955.^[9] DNA-based research started more recently, in 1998, in the context of paternity testing.

Health effects

Evidence for a paternal age effect has been proposed for a number of conditions, diseases and other effects. In many of these, the statistical evidence of association is weak, and the association may be related by confounding factors or behavioural differences.^[10][3] Conditions proposed to show correlation with paternal age include the following:^[11]

Single-gene disorders

Advanced paternal age may be associated with a higher risk for certain

A systematic review published in 2010 concluded that the graph of the risk of low birthweight in infants with paternal age is "saucer-shaped" (U-shaped); that is, the highest risks occur at low and at high paternal ages.^[18] Compared with a paternal age of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a paternal age of 20 and approximately 1.2 at a paternal age of 50.^[18] There was no association of paternal age with preterm births or with small for gestational age births.^[18]

Mental illness

In one study, the risk of bipolar disorder, particularly for early-onset disease, is J-shaped, with the lowest risk for children of 20- to 24-year-old fathers, a twofold risk for younger fathers and a threefold risk for fathers >50 years old. There is no similar relationship with maternal age.^[23] A second study also found a risk of schizophrenia in both fathers above age 50 and fathers below age 25. The risk in younger fathers was noted to affect only male children.^[24]

A 2010 study found the relationship between parental age and psychotic disorders to be stronger with maternal age than paternal age.^[25]

A 2016 review concluded that the mechanism behind the reported associations was still not clear, with evidence both for selection of individuals liable to psychiatric illness into late fatherhood and evidence for causative mutations. The mechanisms under discussion are not mutually exclusive.^[26]

A 2017 review concluded that the vast majority of studies supported a relationship between older paternal age and autism and schizophrenia but that there is less convincing and also inconsistent evidence for associations with other psychiatric illnesses.^[3]

Cancers

Paternal age may be associated with an increased risk of breast cancer,^[27] but the association is weak and there are confounding effects.^[11]

According to a 2017 review, there is consistent evidence of an increase in incidence of childhood

High paternal age has been suggested as a risk factor for type 1 diabetes,^[28] but research findings are inconsistent, and a clear association has not been established.^[29][30]

Down syndrome

It appears that a paternal-age effect might exist with respect to

On the other hand, later research concluded that previously reported negative associations might be explained by confounding factors, especially parental intelligence and education. A re-analysis of the 2009 study found that the paternal age effect could be explained by adjusting for maternal education and number of siblings.[36] A 2012 Scottish study found no significant association between paternal age and intelligence, after adjusting what was initially an inverse-U association for both parental education and socioeconomic status as well as number of siblings.^[37] A 2013 study of half a million Swedish men adjusted for genetic confounding by comparing brothers and found no association between paternal age and offspring IQ.^[38] Another study from 2014 found an initially positive association between paternal age and offspring IQ that disappeared when adjusting for parental IQs.^[39]

Life expectancy

A 2008 paper found a U-shaped association between paternal age and the overall mortality rate in children (i.e., mortality rate up to age 18).^[40] Although the relative mortality rates were higher, the absolute numbers were low, because of the relatively low occurrence of genetic abnormality. The study has been criticized for not adjusting for maternal health, which could have a large effect on child mortality.^[41] The researchers also found a correlation between paternal age and offspring death by injury or poisoning, indicating the need to control for social and behavioral confounding factors.^[42]

In 2012, a study showed that greater age at paternity tends to increase telomere length in offspring for up to two generations. Since telomere length has effects on health and mortality, this may have effects on health and the rate of aging in these offspring. The authors speculated that this effect may provide a mechanism by which populations have some plasticity in adapting longevity to different social and ecological contexts.^[43]

Associated social and genetic characteristics

Parents do not decide when to reproduce randomly. This implies that paternal age effects may be confounded by social and genetic predictors of reproductive timing.

A simulation study concluded that reported paternal age effects on psychiatric disorders in the epidemiological literature are too large to be explained only by mutations. They conclude that a model in which parents with a genetic liability to psychiatric illness tend to reproduce later better explains the literature.^[10]

Later age at parenthood is also associated with a more stable family environment, with older parents being less likely to divorce or change partners.^[44] Older parents also tend to occupy a higher socio-economic position and report feeling more devoted to their children and satisfied with their family.^[44] On the other hand, the risk of the father dying before the child becomes an adult increases with paternal age.^[44]

To adjust for genetic liability, some studies compare full siblings. Additionally, or alternatively, studies statistically adjust for some or all of these confounding factors. Using sibling comparisons or adjusting for more covariates frequently changes the direction or magnitude of paternal age effects. For example, one study drawing on Finnish census data concluded that increases in offspring mortality with paternal age could be explained completely by parental loss.^[45] On the other hand, a population-based cohort study drawing on 2.6 million records from Sweden found that risk of attention deficit hyperactivity disorder was only positively associated with paternal age when comparing siblings.^[46]

Mechanisms

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects.^[17][47] There are different types of genome mutations, with distinct mutation mechanisms:

• DNA length mutations of repetitive DNA (such as telomeres and microsatellites), caused by cellular copying errors
• DNA point mutations, caused by cellular copying errors and also by chemical and physical insults such as radiation
• chromosome breaks and rearrangements, which can occur in the resting cell
• epigenetic changes, i.e. methylation of the DNA, which can activate or silence certain genes, and is sometimes passed down from parent to child

Telomere length

During the past two decades evidence has accumulated that pregnancy loss as well as reduced rate of success with assisted reproductive technologies is linked to impaired sperm chromosome integrity and DNA fragmentation.^[51] Advanced paternal age was shown to be associated with a significant increase in DNA fragmentation in a recent systematic review (where 17 out of the 19 studies considered showed such an association).^[52]

Epigenetic changes

The production of sperm cells involves

A 2001 review on variation in semen quality and fertility by male age concluded that older men had lower semen volume, lower sperm motility, a decreased percent of normal sperm, as well as decreased pregnancy rates, increased time to pregnancy and increased infertility at a given point in time.^[55] When controlling for the age of the female partner, comparisons between men under 30 and men over 50 found relative decreases in pregnancy rates between 23% and 38%.^[55]

A 2014 review indicated that increasing male age is associated with declines in many semen traits, including semen volume and percentage motility. However, this review also found that sperm concentration did not decline as male age increased.^[56]

X-linked effects

Some classify the paternal age effect as one of two different types. One effect is directly related to advanced paternal age and autosomal mutations in the offspring. The other effect is an indirect effect in relation to mutations on the X chromosome which are passed to daughters who are then at risk for having sons with

Birth defects were acknowledged in the children of older men and women even in antiquity. In book six of Plato's Republic, Socrates states that men and women should have children in the "prime of their life" which is stated to be twenty in a woman and thirty in a man. He states that in his proposed society men should be forbidden to father children in their fifties and that the offspring of such unions should be considered "the offspring of darkness and strange lust." He suggests appropriate punishments be administered to the offenders and their offspring.^[58][59]

In 1912, Wilhelm Weinberg, a German physician, was the first person to hypothesize that non-inherited cases of achondroplasia could be more common in last-born children than in children born earlier to the same set of parents.^[60] Weinberg "made no distinction between paternal age, maternal age and birth order" in his hypothesis. In 1953, Krooth used the term "paternal age effect" in the context of achondroplasia, but mistakenly thought the condition represented a maternal age effect.^{[60][61]: 375} The paternal age effect for achondroplasia was described by Lionel Penrose in 1955. At a DNA level, the paternal age effect was first reported in 1998 in routine paternity tests.^[62]

Scientific interest in paternal age effects is relevant because the average paternal age increased in countries such as the United Kingdom,

Geneticist James F. Crow described mutations that have a direct visible effect on the child's health and also mutations that can be latent or have minor visible effects on the child's health; many such minor or latent mutations allow the child to reproduce, but cause more serious problems for grandchildren, great-grandchildren and later generations.^[7]

See also

• Maternal age effect
• Pregnancy over age 50

References