Paternal age effect
|Advanced Paternal Age|
How old is too old?
The paternal age effect (PAE) is the study of the statistical relationship between an advanced paternal age to sperm and semen abnormalities, fertility, pregnancy outcomes, birth outcome (such as birthweight), probability that the offspring will have a health-related condition, or risk of mortality, or social and other psychological outcomes. The paternal age effect is of two different types. One effect is directly related to advanced paternal age and autosomalmutations in the offspring. The other (PAE) is an indirect effect in relation to mutations on the X chromosome which are passed to daughters at risk for having sons with X-linked diseases.1 A 2009 review focusing on the effect to children said that the absolute risk for genetic anomalies in offspring is low, and concludes "There is no clear association between adverse health outcome and paternal age but longitudinal studies are needed."2
The genetic quality of sperm, as well as its volume and motility, all typically decrease with age,3 though telomere length of the sperm actually tends to increase, with possible positive consequences on offspring longevity.4 The population geneticist James F. Crow said that the fact that DNA in sperm degrades as men age and can then be passed along to children in permanently degraded and irreparable form, which they likely pass on as well, means that the "greatest mutational health hazard to the human genome is fertile older males". He 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 mutations allow the child to reproduce, but cause more serious problems for grandchildren, greatgrandchildren and later generations.5
Because paternity did not become provable until 1970, and the cost of definitively establishing it only recently became low enough to do it on widespread basis, this has meant that only limited scientific research into paternal age effect problems of degraded DNA has been done. Harry Fisch, a physician who has done research in this area, says that research into paternal age effect degradation of DNA is "in its infancy".6
- 1 History
- 2 Semen and sperm abnormalities
- 3 Fertility
- 4 Adverse pregnancy outcomes and pre-eclampsia
- 5 Adverse birth outcomes
- 6 Associated diseases
- 7 Disorders, mechanism, and other conditions
- 8 Mortality of offspring
- 9 Paternal mortality before adulthood of child
- 10 Social associations
- 11 Pathophysiology
- 12 Clinical implications
- 13 See also
- 14 References
- 15 Further reading
- 16 External links
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.7 Although Weinberg "made no distinction between paternal age, maternal age and birth order" in his hypothesis, by 1953 the term "paternal age effect" had occurred in the medical literature on achondroplasia.78:375
Scientific interest in paternal age effects increased in the late 20th and early 21st centuries because the average paternal age increased in countries such as the United Kingdom,9 Australia,10 and Germany,11 and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States.12 Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage.11 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 96.11:3291314 In 2012, two 96-year-old men, Nanu Ram Jogi and Ramjit Raghav, both from India, claimed to have fathered children that year.,1516
A 2001 review by Kidd et al. examined 1980-1999 scientific literature on variation in semen quality and fertility by male age.17 It concluded that older men had lower semen volume, lower sperm motility, and a decreased percent of normal sperm.17 One common factor is the abnormal regulation of sperm once a mutation arises. It has been seen that once taking place, the mutation will almost always be positively selected for and over time will lead to the mutant sperm replacing all non-mutant sperm. In younger males, this process is corrected and regulated by the growth factor receptor-RAS signal transduction pathway.18
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.19
A review of the literature by Kidd et al. (2001) determined that older men had decreased pregnancy rates, increased time to pregnancy, and increased subfecundity (i.e., infertility of a couple at a given point in time).17 Increasing paternal age may also increase the risk of reproductive failure, which has led some researchers to compare age 40 to the "Amber Light" in a man's reproductive life.20
Studies published between 2002 and 2008 have been consistent in associating advanced paternal age with miscarriage (spontaneous abortion),21222324 stillbirth,25 and fetal death (which includes both miscarriage and stillbirth).26 In addition, one 2002 study linked paternal age with pre-eclampsia, a complication of pregnancy that can be associated with adverse health outcomes for both the pregnant woman and the fetus.27
A systematic review published in 2010 of 10 studies published in 1972-2008 concluded that the relationship of the risk of low birthweight in infants with paternal age is "saucer-shaped"; that is, the highest risks occur at low and at high paternal ages.28 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 50.28 There was no association of paternal age with preterm births or with small for gestational age births.28
In a 2008 retrospective cohort study of 2,614,966 births, a paternal age of 40 years or greater was not associated with neonatal death ("death of a live birth within 28 days") or post-neonatal death ("death of a live birth between 28–364 days of age") compared with a paternal age of 20–29 years.29 However, the risks of neonatal mortality and post-neonatal mortality were elevated for infants whose fathers were less than 20 years old.2930
Evidence for a paternal age effect has been proposed for a number of conditions and diseases. In many of these, the statistical evidence of association is weak, and the association may be related by confounding factors, or behavioral differences.31 Conditions proposed to show correlation with paternal age include the following:2
Most studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated an association between the two, but some have not.
Risk of bipolar disorder appears to increase with increasing age of the father. (Arch. Gen. Psychiatry 65, 1034–1040; 2008)medical citation needed
Before 1998, four studies had been published concerning a possible association between diabetes mellitus type 1 and paternal age. Of these, Blom et al. (1989), Patterson et al. (1994), and Bock et al. (1994) were described as not finding an association, and Wadsworth et al. (1997) was described as finding a decreased risk with older paternal age.3435 The literature from 1998 onwards continues to show inconsistent results:
- In a case-control study conducted in Taipei and published in 1998, a multiple logistic regression found an odds ratio of 0.33 for paternal ages 30–39 versus paternal ages under 30, while the risk for paternal ages 40 and above was not significantly different from the risk for paternal ages less than 30.36
- In 1999, Rami et al. published the results of a population-based case-control study from Austria with 114 cases of type 1 diabetes and 495 matched controls.35 The mean paternal age of cases was 31.7 years, which was significantly higher than the mean paternal age of controls of 30.1 years.35
- A 1999 Danish case-control study detected no association between paternal age and risk of type 1 diabetes.37
- In a prospective study from the United Kingdom, Bingley et al. noted increasing relative risks for type 1 diabetes in childhood in each paternal age group 20 years and older versus paternal age less than 20; for example, in the multivariate analysis the relative risk for 40-45 year old fathers was 1.57.38
- A Norwegian study of 2001 found no association with paternal age after adjustment for maternal age.39
- In a 2005 study set in Northern Ireland, paternal age of 35 years or more was associated with a relative risk of 1.52 compared with a paternal age of less than 25 years.40
It appears that a paternal-age effect exists with respect to Down syndrome, but is very small in comparison to maternal-age effect.41
By 1998, "Intellectual disability or decreased learning capacity of unknown aetiology" was thought to be associated with increased paternal age.43 In 2005, Malaspina and colleagues detected an "inverted U-shaped relationship" between paternal age and intelligence quotients (IQs) in 44,175 people from Israel.44 There was a peak at paternal ages of 25-44; fathers younger than 25 and older than 44 tended to have children with lower IQs.44 Malaspina et al. also reviewed the literature and found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence."44
A 2009 study by Saha et al. examined 33,437 children at 8 months, 4 years, and 7 years.4546 The researchers found that paternal age was associated with poorer scores in almost all neurocognitive tests used, but that maternal age was associated with better scores on the same tests.45 An editorial accompanying the paper by Saha et al. emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence.47 A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of intellectual disability.48
Studies reveal that the following list of congenital disorders, collectively known as paternal age effect (PAE) disorders, are all caused by a small number of dominantly-acting point mutations and almost exclusively originate from unaffected fathers, suggesting that the mutations are taking place during spermatogenesis. Mutations in the fibroblast growth factor receptor genes FGFR2, cause Apert syndrome,43495051 Crouzon syndrome,434952 and Pfeiffer syndrome.434953 Mutations in the FGFR3 gene lead to the formation of achondroplasia,4349 thanatophoric dysplasia,43 hypochondroplasia, and Muenke syndrome.53 These disorders occur spontaneously as a result of advanced paternal age and at the rate of 1 in 30,000 for achondroplasia births.5455 Other conditions involving the mutations in the RET gene lead to multiple endocrine neoplasia type 2A and 2B, the PTPN11 gene which leads to Noonan syndrome,56 and the HRAS mutations which cause Costello syndrome.57584359 In recent studies of multiple endocrine neoplasia Type 2A and 2B and Apert syndrome, a total of 92 new mutations were discovered and all were found to be paternal in origin.575860 These studies which show an extreme paternal bias for PAE mutations is argued to be caused by the distinct phenomenon of clonal expansion of spermatogonial cells with gain-of-function protein properties. This mechanism known as “selfish selection”, results in an enrichment of mutant sperm over time and may preferentially carry alterations in genes that could have far-reaching consequences for the health of future generations.61
Other conditions and diseases which have been suggested as having a possible correlation with paternal age include: Chondrodystrophy,62 Acrodysostosis,4352 Aniridia,43Basal cell nevus syndrome,4352 Cataracts,43 Cerebral palsy, athetoid/dystonic,43 CHARGE syndrome,763 Cleft palate,436465 Cleidocranial dysostosis,4352Craniosynostosis,66Diaphragmatic hernia,65 Duchenne muscular dystrophy,43 Exostoses, multiple,4352 congenital malformations in extremities,4367 Fibrodysplasia ossificans progressiva,4349 Heart defects,436264 Hemangioma,64 Hemiplegia,43 Hemophilia A,43 Hydrocephalus,64 Klinefelter's syndrome,68 Lesch-Nyhan syndrome,43 Marfan syndrome,49 Nasal aplasia,4364 Neural tube defects,43 Oculodentodigital syndrome,4352 Osteogenesis imperfecta type IIA,43Polycystic kidney disease,43 Polyposis coli,43 Preauricular cyst,4364 Progeria,4352 Psychotic disorders,4369 von Recklinghausen neurofibromatosis,4349 Retinitis pigmentosa,4370 Retinoblastoma, bilateral,43 Situs inversus,62 Soto's basal cell nevus,4352Treacher-Collins Syndrome,4352 Tuberous sclerosis,43 Urethral stenosis,4364 Waardenburg syndrome,4352 and Wilms' tumor43
As early as 1946, Pearl's analysis of human pedigree data led him to conclude that in order to be longevous, one should “pick long-lived parents."71 This would imply a positive effect of paternal age on lifespan, similar to the "Methuselah fly" effect seen in drosophila.72
A 2008 paper from Denmark found a U-shaped association between paternal age and the overall mortality rate in children (i.e., mortality rate up to age 18).73 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.74 Surprisingly, the researchers found a correlation between paternal age and offspring death by injury or poisoning, indicating the need to control for social and behavioral confounding factors.75
In 2012, Eisenberg et al. published a study which 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 "pace of senescence" 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.4
The risk of the father dying before the child becomes an adult increases by increased paternal age, such as can be demonstrated by the following data from France in 2007:76
|Paternal age at childbirth||25||30||35||40||45|
|Risk of father not surviving until child's 18th birthday (in %)76||2.2||3.3||5.4||8.3||12.1|
Later age at parenthood is associated with a more stable family environment, higher socio-economic position, higher income and better living conditions, as well as better parenting practices,76 but it is more or less uncertain whether these entities are effects of advanced parental age, are contributors to advanced parental age, or common effects of a certain state such as personality type.
At least two hypothesized chains of causality exist whereby increased paternal age may lead to health effects:
- Genetic mutations: In contrast to oogenesis, which involves 22 mitotic divisions before birth and 2 meiotic divisions after birth, spermatogenesis involves 30 mitotic divisions before puberty, and 4 mitotic and 2 meiotic divisions after puberty.7 Advanced paternal age may therefore lead to "copy error" in replication or the accumulation of mutagens, thereby leading to de novo mutations in sperm DNA.7 A study of 78 Icelandic families found that each additional year in the age of the father causes about two new mutations in the child.77
- Epigenetic processes such as parental imprinting could explain the association between paternal age and schizophrenia.78
The American College of Medical Genetics notes that there is no standard definition of "advanced paternal age."79 Although the College recommends obstetric ultrasonography at 18–20 weeks gestation in cases of advanced paternal age "to evaluate fetal growth and development," it notes that this procedure "is unlikely to detect many of the conditions of interest."79 Bray et al.. (2006) expressed an opinion that 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."9
- "Definition of Advanced paternal age".
- H. Tournaye, "Male Reproductive Ageing," in Bewley, Ledger, and Nikolaou, eds., Reproductive Ageing, Cambridge University Press (2009), ISBN 9781906985134 (accessed 15 November 2013)
- Gurevich, Rachel (June 10, 2008). "Does Age Affect Male Fertility?". About.com:Fertility. About.com. Retrieved 14 February 2010.
- Eisenberg, Dan T.A.; Hayes, M. Geoffrey; Kuzawa, Christopher W. (June 11, 2012). "Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants". Proc Natl Acad Sci U S A. 109 (26): 10251–10256. doi:10.1073/pnas.1202092109. Retrieved 28 June 2014.
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- Goriely, Anne; Wilkie, Andrew (2012). "Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease". The American Journal of Human Genetics 90 (2): 175–200. Retrieved 12 September 2014.
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- see Correlation does not imply causation
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