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. [1] Such effects can relate to birthweight, congenital disorders, life expectancy, and psychological outcomes. [2] A 2017 review found that while severe health effects are associated with higher paternal age, the total increase in problems caused by paternal age is low. [3] Average paternal age at birth reached a low point between 1960 and 1980 in many countries and has been increasing since then, but has not reached historically unprecedented levels. [4] The rise in paternal age is not seen as a major public health concern. [3]

Contents

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

The paternal age effect was first proposed implicitly by physician Wilhelm Weinberg in 1912 [7] and explicitly by psychiatrist Lionel Penrose in 1955. [8] 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. [9] [3] Conditions proposed to show correlation with paternal age include the following: [10]

Single-gene disorders

Advanced paternal age may be associated with a higher risk for certain single-gene disorders caused by mutations of the FGFR2 , FGFR3 and RET genes. [11] These conditions are Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, achondroplasia, thanatophoric dysplasia, multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2b. [11] The most significant effect concerns achondroplasia (a form of dwarfism), which might occur in about 1 in 1,875 children fathered by men over 50, compared to 1 in 15,000 in the general population. [12] However, the risk for achondroplasia is still considered clinically negligible. [13] The FGFR genes may be particularly prone to a paternal age effect due to selfish spermatogonial selection, whereby the influence of spermatogonial mutations in older men is enhanced because cells with certain mutations have a selective advantage over other cells (see § DNA mutations). [14]

Pregnancy effects

Several studies have reported that advanced paternal age is associated with an increased risk of miscarriage. [15] The strength of the association differs between studies. [16] It has been suggested that these miscarriages are caused by chromosome abnormalities in the sperm of aging men. [15] An increased risk for stillbirth has also been suggested for pregnancies fathered by men over 45. [16]

Birth outcomes

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. [17] 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. [17] There was no association of paternal age with preterm births or with small for gestational age births. [17]

Mental illness

Schizophrenia is associated with advanced paternal age. [18] [19] [20] Some studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated an association between the two, although there also appears to be an increase with maternal age. [21]

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. [22] 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. [23]

A 2010 study found the relationship between parental age and psychotic disorders to be stronger with maternal age than paternal age. [24]

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. [25]

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, [26] but the association is weak and there are confounding effects. [10]

According to a 2017 review, there is consistent evidence of an increase in incidence of childhood acute lymphoblastic leukemia with paternal age. Results for associations with other childhood cancers are more mixed (e.g. retinoblastoma) or generally negative. [3]

Diabetes mellitus

High paternal age has been suggested as a risk factor for type 1 diabetes, [27] but research findings are inconsistent, and a clear association has not been established. [28] [29]

Down syndrome

It appears that a paternal-age effect might exist with respect to Down syndrome, but it is very small in comparison to the maternal-age effect. [30] [31]

Intelligence

A review in 2005 found a U-shaped relationship between paternal age and low intelligence quotients (IQs). [32] The highest IQ was found at paternal ages of 25–29; fathers younger than 25 and older than 29 tended to have children with lower IQs. [32] It also found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence." [32] A 2009 study examined children at 8 months, 4 years and 7 years and found that higher paternal age was associated with poorer scores in almost all neurocognitive tests used but that higher maternal age was associated with better scores on the same tests; [33] this was a reverse effect to that observed in the 2005 review, which found that maternal age began to correlate with lower intelligence at a younger age than paternal age, [32] however two other past studies were in agreement with the 2009 study's results. [24] An editorial accompanying the 2009 paper emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence. [34] A 2010 study from Spain also found an association between advanced paternal age and intellectual disability. [24]

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. [35] 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. [36] 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. [37] Another study from 2014 found an initially positive association between paternal age and offspring IQ that disappeared when adjusting for parental IQs. [38]

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). [39] 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. [40] 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. [41]

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. [42]

Associated social and genetic characteristics

Father's age versus father's risk of death
(among French population) [43]
Father's age
at birth		Risk of father's death
before child's 18th birthday
201.5%
252.2%
303.3%
355.4%
408.3%
4512.1%

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. [9]

Later age at parenthood is also associated with a more stable family environment, with older parents being less likely to divorce or change partners. [43] Older parents also tend to occupy a higher socio-economic position and report feeling more devoted to their children and satisfied with their family. [43] On the other hand, the risk of the father dying before the child becomes an adult increases with paternal age. [43]

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. [44] 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. [45]

Mechanisms

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects. [16] [46] There are different types of genome mutations, with distinct mutation mechanisms:

Telomere and microsatellite length

Telomeres are repetitive genetic sequences at both ends of each chromosome that protect the structure of the chromosome. [47] As men age, most telomeres shorten, but sperm telomeres increase in length. [16] The offspring of older fathers have longer telomeres in both their sperm and white blood cells. [16] [47] A large study showed a positive paternal, but no independent maternal age effect on telomere length. Because the study used twins, it could not compare siblings who were discordant for paternal age. It found that telomere length was 70% heritable. [48] Regarding the mutation of microsatellite DNA, also known as short tandem repeat (STR) DNA, a survey of over 12,000 paternity-tested families shows that the microsatellite DNA mutation rate in both very young teenage fathers and in middle-aged fathers is elevated, while the mother's age has no effect. [49]

DNA point mutations

In contrast to oogenesis, the production of sperm cells is a lifelong process. [16] Each year after puberty, spermatogonia (precursors of the spermatozoa) divide meiotically about 23 times. [46] By the age of 40, the spermatogonia will have undergone about 660 such divisions, compared to 200 at age 20. [46] Copying errors might sometimes happen during the DNA replication preceding these cell divisions, which may lead to new (de novo) mutations in the sperm DNA. [14]

The selfish spermatogonial selection hypothesis proposes that the influence of spermatogonial mutations in older men is further enhanced because cells with certain mutations have a selective advantage over other cells. [46] [50] Such an advantage would allow the mutated cells to increase in number through clonal expansion. [46] [50] In particular, mutations that affect the RAS pathway, which regulates spermatogonial proliferation, appear to offer a competitive advantage to spermatogonial cells, while also leading to diseases associated with paternal age. [50]

DNA fragmentation

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

DNA methylation DNA methylation.jpg
DNA methylation

The production of sperm cells involves DNA methylation, an epigenetic process that regulates the expression of genes. [46] Improper genomic imprinting and other errors sometimes occur during this process, which can affect the expression of genes related to certain disorders, increasing the offspring's susceptibility. The frequency of these errors appears to increase with age. This could explain the association between paternal age and schizophrenia.; [53] Paternal age affects offspring's behavior, possibly via an epigenetic mechanism recruiting a transcriptional repressor REST. [54]

Semen

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 X-linked diseases. [57]

History

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, [63] Australia [64] and Germany, [65] and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States. [66] Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage. [65] Despite recent increases in average paternal age, however, the oldest father documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the Journal of the American Medical Association stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96. [65] [67] [68]

Medical assessment

The American College of Medical Genetics recommends obstetric ultrasonography at 18–20 weeks gestation in cases of advanced paternal age to evaluate fetal development, but it notes that this procedure "is unlikely to detect many of the conditions of interest." They also note that there is no standard definition of advanced paternal age; [11] it is commonly defined as age 40 or above, but the effect increases linearly with paternal age, rather than appearing at any particular age. [69] According to a 2006 review, any adverse effects of advanced paternal age "should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security." [63]

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. [6]

See also

Related Research Articles

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the female or male parent. Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. In 2014, there were about 150 imprinted genes known in mice and about half that in humans. As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.

<span class="mw-page-title-main">Infertility</span> Inability to reproduce by natural means

Infertility is the inability of a couple to reproduce by natural means. It is usually not the natural state of a healthy adult. Exceptions include children who have not undergone puberty, which is the body's start of reproductive capacity. It is also a normal state in women after menopause.

Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate is the average number of children born during an individual's lifetime. In medicine, fertility refers to the ability to have children, and infertility refers to difficulty in reproducing naturally. In general, infertility or subfertility in humans is defined as not being able to conceive a child after one year of unprotected sex. The antithesis of fertility is infertility, while the antithesis of fecundity is sterility.

<span class="mw-page-title-main">Birth defect</span> Condition present at birth regardless of cause

A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders.

A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and genotype of its mother. In genetics, maternal effects occur when an organism shows the phenotype expected from the genotype of the mother, irrespective of its own genotype, often due to the mother supplying messenger RNA or proteins to the egg. Maternal effects can also be caused by the maternal environment independent of genotype, sometimes controlling the size, sex, or behaviour of the offspring. These adaptive maternal effects lead to phenotypes of offspring that increase their fitness. Further, it introduces the concept of phenotypic plasticity, an important evolutionary concept. It has been proposed that maternal effects are important for the evolution of adaptive responses to environmental heterogeneity.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

Recurrent miscarriage or recurrent pregnancy loss (RPL) is the spontaneous loss of 2-3 pregnancies that is estimated to affect up to 5% of women. The exact number of pregnancy losses and gestational weeks used to define RPL differs among medical societies. In the majority of cases, the exact cause of pregnancy loss is unexplained despite genetic testing and a thorough evaluation. When a cause for RPL is identified, almost half are attributed to a chromosomal abnormality. RPL has been associated with several risk factors including parental and genetic factors, congenital and acquired anatomical conditions, lifestyle factors, endocrine disorders, thrombophila, immunological factors, and infections. The American Society of Reproductive Medicine recommends a thorough evaluation after 2 consecutive pregnancy losses; however, this can differ from recommendations by other medical societies. RPL evaluation can be evaluated by numerous tests and imaging studies depending on the risk factors. These range from cytogenetic studies, blood tests for clotting disorders, hormone levels, diabetes screening, thyroid function tests, sperm analysis, antibody testing, and imaging studies. Treatment is typically tailored to the relevant risk factors and test findings. RPL can have a significant impact on the psychological well-being of couples and has been associated with higher levels of depression, anxiety, and stress. Therefore, it is recommended that appropriate screening and management be considered by medical providers.  

<span class="mw-page-title-main">Virility</span> Traits of masculinity viewed in a positive light

Virility refers to any of a wide range of masculine characteristics viewed positively. Virile means "marked by strength or force". Virility is commonly associated with vigour, health, sturdiness, and constitution, especially in the fathering of children. In this last sense, virility is to men as fertility is to women. Virile has become obsolete in referring to a "nubile" young woman, or "a maid that is Marriageable or ripe for a Husband, or Virill".

Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans, it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.

Advanced maternal age, in a broad sense, is the instance of a woman being of an older age at a stage of reproduction, although there are various definitions of specific age and stage of reproduction. The variability in definitions is in part explained by the effects of increasing age occurring as a continuum rather than as a threshold effect.

Schizophrenia is a neurodevelopmental disorder with no precise or single cause. Schizophrenia is thought to arise from multiple mechanisms and complex gene–environment interactions with vulnerability factors. Risk factors of schizophrenia have been identified and include genetic factors, environmental factors such as experiences in life and exposures in a person's environment, and also the function of a person's brain as it develops. The interactions of these risk factors are intricate, as numerous and diverse medical insults from conception to adulthood can be involved. Many theories have been proposed including the combination of genetic and environmental factors may lead to deficits in the neural circuits that affect sensory input and cognitive functions.

Metabolic imprinting refers to the long-term physiological and metabolic effects that an offspring's prenatal and postnatal environments have on them. Perinatal nutrition has been identified as a significant factor in determining an offspring's likelihood of it being predisposed to developing cardiovascular disease, obesity, and type 2 diabetes amongst other conditions.

Prenatal stress, also known as prenatal maternal stress, occurs when an expectant mother is exposed to psychosocial or physical stress. This can be brought on by daily events or environmental hardships.[1] [2] According to the Developmental Origins of Health and Disease (DOHaD), a wide range of environmental factors a woman may experience during the perinatal period can contribute to biological impacts and changes in the fetus that then cause health risks later in the child's life. Health risks include impaired cognitive development, low birth weight, mental disorders, and gender specific deficits in the offspring.

Developmental origins of health and disease (DOHaD) is an approach to medical research factors that can lead to the development of human diseases during early life development. These factors include the role of prenatal and perinatal exposure to environmental factors, such as undernutrition, stress, environmental chemical, etc. This approach includes an emphasis on epigenetic causes of adult chronic non-communicable diseases. As well as physical human disease, the psychopathology of the foetus can also be predicted by epigenetic factors.

The epigenetics of schizophrenia is the study of how inherited epigenetic changes are regulated and modified by the environment and external factors and how these changes influence the onset and development of, and vulnerability to, schizophrenia. Epigenetics concerns the heritability of those changes, too. Schizophrenia is a debilitating and often misunderstood disorder that affects up to 1% of the world's population. Although schizophrenia is a heavily studied disorder, it has remained largely impervious to scientific understanding; epigenetics offers a new avenue for research, understanding, and treatment.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

Obesity is defined as an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. This is often described as a body mass index (BMI) over 30. However, BMI does not account for whether the excess weight is fat or muscle, and is not a measure of body composition. For most people, however, BMI is an indication used worldwide to estimate nutritional status. Obesity is usually the result of consuming more calories than the body needs and not expending that energy by doing exercise. There are genetic causes and hormonal disorders that cause people to gain significant amounts of weight but this is rare. People in the obese category are much more likely to suffer from fertility problems than people of normal healthy weight.

Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.

Gene-environment interplay describes how genes and environments work together to produce a phenotype, or observable trait. Many human traits are influenced by gene-environment interplay. It is a key component in understanding how genes and the environment come together to impact human development. Examples of gene-environment interplay include gene-environment interaction and gene-environment correlation. Another type of gene-environment interplay is epigenetics, which is the study of how environmental factors can affect gene expression without altering DNA sequences.

Anne Goriely is a Belgian geneticist who is a professor of human genetics at the University of Oxford. Her research investigates the molecular mechanisms that underpin genetic variation, particularly mutations in the male germline.

References

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