Evidence for a<unk>  has been proposed for a number of conditions, diseases and other<unk> s. In many of these, the statistical evidence of association is weak, and the association may be related by confounding factors or behavioural differences. Conditions proposed to show correlation with<unk> <unk>  include the following: Single-gene disorders Advanced<unk> <unk>  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. The most significant<unk>  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. However, the risk for achondroplasia is still considered clinically negligible. The FGFR genes may be particularly prone to a<unk>  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). Pregnancy<unk> s Several studies have reported that advanced<unk> <unk>  is associated with an increased risk of miscarriage. 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. An increased risk for stillbirth has also been suggested for pregnancies fathered by men over 45. Birth outcomes A systematic review published in 2010 concluded that the graph of the risk of low birthweight in infants with<unk> <unk>  is "saucer-shaped" (U-shaped); that is, the highest risks occur at low and at high<unk> <unk> s. Compared with a<unk> <unk>  of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a<unk> <unk>  of 20 and approximately 1.2 at a<unk> <unk>  of 50. There was no association of<unk> <unk>  with preterm births or with small for gestational<unk>  births. Mental illness Schizophrenia is associated with advanced<unk> <unk> . Some studies examining autism spectrum disorder (ASD) and advanced<unk> <unk>  have demonstrated an association between the two, although there also appears to be an increase with<unk> <unk> . 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<unk> <unk> . A second study also found a risk of schizophrenia in both fathers above<unk>  50 and fathers below<unk>  25. The risk in younger fathers was noted to<unk>  only male children. A 2010 study found the relationship between parental<unk>  and psychotic disorders to be stronger with<unk> <unk>  than<unk> <unk> . 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. A 2017 review concluded that the vast majority of studies supported a relationship between older<unk> <unk>  and autism and schizophrenia but that there is less convincing and also inconsistent evidence for associations with other psychiatric illnesses. Cancers<unk> <unk>  may be associated with an increased risk of breast cancer, but the association is weak and there are confounding<unk> s. According to a 2017 review, there is consistent evidence of an increase in incidence of childhood acute lymphoblastic leukemia with<unk> <unk> . Results for associations with other childhood cancers are more mixed (e.g. retinoblastoma) or generally negative. Diabetes mellitus High<unk> <unk>  has been suggested as a risk factor for type 1 diabetes, but research findings are inconsistent, and a clear association has not been established. Down syndrome It appears that a<unk>  might exist with respect to Down syndrome, but it is very small in comparison to the<unk> -age<unk> . Intelligence A review in 2005 found a U-shaped relationship between<unk> <unk>  and low intelligence quotients (IQs). The highest IQ was found at<unk> <unk> s of 25–29; fathers younger than 25 and older than 29 tended to have children with lower IQs. It also found that "at least a half dozen other studies ... have demonstrated significant associations between<unk> <unk>  and human intelligence." A 2009 study examined children at 8 months, 4 years and 7 years and found that higher<unk> <unk>  was associated with poorer scores in almost all neurocognitive tests used but that higher<unk> <unk>  was associated with better scores on the same tests; this was a reverse<unk>  to that observed in the 2005 review, which found that<unk> <unk>  began to correlate with lower intelligence at a younger<unk>  than<unk> <unk> , however two other past studies were in agreement with the 2009 study's results. An editorial accompanying the 2009 paper emphasized the importance of controlling for socioeconomic status in studies of<unk> <unk>  and intelligence. A 2010 study from Spain also found an association between advanced<unk> <unk>  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<unk>  could be explained by adjusting for<unk>  education and number of siblings. A 2012 Scottish study found no significant association between<unk> <unk>  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<unk> <unk>  and offspring IQ. Another study from 2014 found an initially positive association between<unk> <unk>  and offspring IQ that disappeared when adjusting for parental IQs. Life expectancy A 2008 paper found a U-shaped association between<unk> <unk>  and the overall mortality rate in children (i.e., mortality rate up to<unk>  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<unk>  health, which could have a large<unk>  on child mortality. The researchers also found a correlation between<unk> <unk>  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<unk>  at paternity tends to increase telomere length in offspring for up to two generations. Since telomere length has<unk> s on health and mortality, this may have<unk> s on health and the rate of aging in these offspring. The authors speculated that this<unk>  may provide a mechanism by which populations have some plasticity in adapting longevity to different social and ecological contexts. Fertility of the father A 2001 review suggested older men have decreased pregnancy rates, increased time to pregnancy and increased infertility at a given point in time. When controlling for the<unk>  of the female partner, comparisons between men under 30 and men over 50 found relative decreases in pregnancy rates between 23% and 38%.
Paternal age effect
Fetal programming
Maternal effect
Replication error phenotype
Germline mosaicism
Human genetic enhancement
Germline mutation
Structural inheritance