Paternal age effect

Evidence for a paternal age effect has been proposed for several 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. 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. These conditions are Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, achondroplasia, thanatophoric dysplasia, multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2b. However, the risk for achondroplasia is still considered clinically negligible. 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). The strength of the association differs between studies. It has been suggested that these miscarriages are caused by chromosome abnormalities in the sperm of aging men. 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. 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. 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. 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. A 2010 study found the relationship between parental age and psychotic disorders to be stronger with maternal age than paternal age. 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. but the association is weak and there are confounding effects. but research findings are inconsistent, and a clear association has not been established. Down syndrome It appears that a paternal-age effect might exist concerning Down syndrome, but it is small when compared to the maternal-age effect. Intelligence A review in 2005 found a U-shaped relationship between paternal age and low intelligence quotients (IQs). 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. 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, A 2010 study from Spain also found an association between advanced paternal age and intellectual disability. 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. 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. 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. Another study from 2014 found an initially positive association between paternal age and offspring IQ that disappeared when adjusting for parental IQs. 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). 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. 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. 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 affects health and mortality, this may affect the health and aging rate of the 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. ==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. To adjust for genetic liability, some studies compare full siblings. Additionally, 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. 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. ==Mechanisms==

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects. As men age, most telomeres shorten, but sperm telomeres increase in length. 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. DNA point mutations In contrast to oogenesis, the production of sperm cells is a lifelong process. By age 40, the spermatogonia will have undergone about 660 such divisions, compared to 200 at age 20. 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. Such an advantage would allow the mutated cells to increase in number through clonal expansion. 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). Epigenetic changes The production of sperm cells involves DNA methylation, an epigenetic process that regulates the expression of genes. Paternal age affects offspring's behavior, possibly via an epigenetic mechanism recruiting a transcriptional repressor REST. 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. 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%. 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 related to mutations on the X chromosome which are passed to daughters who are then at risk for having sons with X-linked diseases. ==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. 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. 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. 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. Scientific interest in paternal age effects is relevant because the average paternal age increased in countries such as the United Kingdom, Australia and Germany, and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States. Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage. ==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; 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." 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. == See also ==