Paternal age effect: Difference between revisions

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The paternal age effect is the statistical relationship between paternal age at conception and biological effects on the child. Such effects can relate to miscarriage risk, birthweight, congenital disorders and health-related conditions including mortality and longevity, or risk of psychological outcomes. The age-risk relationship appears to be "saucer-shaped" (U-shaped) or J-shaped, with a higher risk in very young fathers, the lowest risk at 20–40 years of age, and increased risk in older men.

A 2009 review concludes that the absolute risk for genetic anomalies in offspring is low, and states that "There is no clear association between adverse health outcome and paternal age but longitudinal studies are needed."^[1] Some research even indicates a longevity advantage for offspring of older fathers.^[2]

On the other hand, the genetic quality of sperm, as well as its volume and motility, all typically decrease with age,^[3] leading the population geneticist James F. Crow to claim that the "greatest mutational health hazard to the human genome is fertile older males".^[4]

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".^[5]

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 behavioral differences.^[6] Conditions proposed to show correlation with paternal age include the following:^[1]

Studies published between 2002 and 2008 have been consistent in associating advanced paternal age with miscarriage,^{[7][8][9][10]} stillbirth,^[11] and fetal death (which includes both miscarriage and stillbirth).^[12] A 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.^[13]

A systematic review published in 2010 concluded 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.^[14] 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.^[14] There was no association of paternal age with preterm births or with small for gestational age births.^[14]

In a 2008 retrospective study found a paternal age of 40 years or greater was not associated with infant death in the first year of life.^[15] However, the risks of were elevated for infants whose fathers were less than 20 years old.^[15][16]

Schizophrenia is associated with advanced paternal age with 12 out of 14 studies supporting a relationship.^[17] Paternal age older than 55 is a moderate risk factor for schizophrenia.^[18]

Most 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.^[19]

The risk of bipolar disorder ("manic depression") particularly for early-onset disease, is J-shaped, with the lowest risk for children of 20-24-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.^[20]

Paternal age may be associated with an increased risk of breast cancer,^[21] but the association is weak and there are confounding effects.^[1]

A higher paternal age is a possible risk factor for type 1 diabetes.^[22]

It appears that a paternal-age effect exists with respect to Down syndrome, but is very small in comparison to maternal-age effect.^[23]

By 1998, "Intellectual disability or decreased learning capacity of unknown aetiology" was thought to be associated with increased paternal age.^[24] In 2005, Malaspina and colleagues detected an "inverted U-shaped relationship" between paternal age and intelligence quotients (IQs) in 44,175 people from Israel.^[25] 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.^[25] 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."^[25]

A 2009 study by Saha et al. examined 33,437 children at 8 months, 4 years, and 7 years.^[26][27] 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.^[26] An editorial accompanying the paper by Saha et al. emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence.^[28] A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of intellectual disability.^[29]

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).^[30] 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.^[31] 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.^[32]

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.^[2]

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,^{[24][33][34][35]} Crouzon syndrome,^[24][33] and Pfeiffer syndrome.^[24][33][36] Mutations in the FGFR3 gene lead to the formation of achondroplasia,^[24][33] thanatophoric dysplasia,^[24] hypochondroplasia, and Muenke syndrome.^[36] These disorders occur spontaneously as a result of advanced paternal age and at the rate of 1 in 30,000 for achondroplasia births.^[37][38] 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,^[39] and the HRAS mutations which cause Costello syndrome.^{[24][40][41][42]}

Other conditions and diseases which have been suggested as having a possible correlation with paternal age include: chondrodystrophy,^[43] acrodysostosis,^[24] aniridia,^[24]basal cell nevus syndrome,^[24] cataracts,^[24] Cerebral palsy, athetoid/dystonic,^[24] CHARGE syndrome,^[44][45] cleft palate,^[24][46] cleidocranial dysostosis,^[24] craniosynostosis,^[47]diaphragmatic hernia,^[46] Duchenne muscular dystrophy,^[24] exostoses, multiple,^[24] congenital malformations in extremities,^[24][48] fibrodysplasia ossificans progressiva,^[24][33] Heart defects,^[24][43] Hemiplegia,^[24] Hemophilia A,^[24] Klinefelter's syndrome,^[49] Lesch-Nyhan syndrome,^[24] Marfan syndrome,^[33] nasal aplasia,^[24]neural tube defects,^[24] oculodentodigital syndrome,^[24] osteogenesis imperfecta type IIA,^[24]polycystic kidney disease,^[24] Polyposis coli,^[24] Preauricular cyst,^[24] Progeria,^[24] psychotic disorders,^[24][50] von Recklinghausen neurofibromatosis,^[24][33] retinitis pigmentosa,^[24]retinoblastoma, bilateral,^[24] situs inversus,^[43] Soto's basal cell nevus,^[24]Treacher-Collins Syndrome,^[24] tuberous sclerosis,^[24] Urethral stenosis,^[24] Waardenburg syndrome,^[24] and Wilms' tumor.^[24]

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:^[51]

Older men have decreased pregnancy rates, increased time to pregnancy, and increased infertility at a given point in time.^[52] 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.^[53]

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects.

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.^[44] 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.^[44] 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.^[54] . Regarding the increased risk at very young paternal ages, an international study indicates that the DNA mutation rate in very young fathers may also be elevated.^[55]

Epigenetic processes such as parental imprinting could explain the association between paternal age and schizophrenia.^[56]

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.^[2]

A distinct set of monogenetic 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, Crouzon syndrome, and Pfeiffer syndrome. Mutations in the FGFR3 gene lead to the formation of achondroplasia, thanatophoric dysplasia, hypochondroplasia, and Muenke syndrome. 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.^[40][41][57] 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.^[58]

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,^[51] 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.

A 2001 review on variation in semen quality and fertility by male age concluded that older men had lower semen volume, lower sperm motility, and a decreased percent of normal sperm.^[52] 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.^[59]

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.^[60]

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.^[61]

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.^[44] 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.^{[44][62]: 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,^[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]: 329 [67][68]} In 2012, two 96-year-old men, Nanu Ram Jogi and Ramjit Raghav, both from India, claimed to have fathered children that year.,^[69][70]

The American College of Medical Genetics recommends obstetric ultrasonography at 18–20 weeks gestation in cases of advanced paternal age "to evaluate fetal growth and 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."^[71] 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."^[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, greatgrandchildren and later generations.^[4]

• Maternal age effect
• Pregnancy over age 50

• Fisch H, Braun S (2005). The male biological clock: the startling news about aging, sexuality, and fertility in men. New York: Free Press. ISBN 0-7432-5991-2.
• Gavrilov, L.A., Gavrilova, N.S. Human longevity and parental age at conception. In: J.-M.Robine, T.B.L. Kirkwood, M. Allard (eds.) Sex and Longevity: Sexuality, Gender, Reproduction, Parenthood, Berlin, Heidelberg: Springer-Verlag, 2000, 7-31.
• Gavrilov, L.A., Gavrilova, N.S. Parental age at conception and offspring longevity. Reviews in Clinical Gerontology, 1997, 7: 5-12.
• Gavrilov, L.A., Gavrilova, N.S. When Fatherhood Should Stop? Letter. Science, 1997, 277(5322): 17-18.

• Crow JF (1997). "The high spontaneous mutation rate: Is it a health risk?". Proc Natl Acad Sci U S A. 94 (16): 8380–6. doi:10.1073/pnas.94.16.8380. PMC 33757. PMID 9237985.
• Malaspina L (28 March 2006). "Schizophrenia risk and the paternal germ line". Schizophrenia Research Forum. Retrieved 25 February 2010.
• Rabin R (27 February 2007). "It seems the fertility clock ticks for men, too". New York Times. Retrieved 25 February 2010.
• Raeburn P (Feb 2009). "The father factor: how dad's age increases baby's risk of mental illness". Sci Am Mind.
• National Library of Medicine. "Medical Subject Headings. 2010 MeSH. MeSH descriptor data. Paternal age".