Paternal age effect

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Advanced Paternal Age
Nuevas aficiones (7984692236).jpg
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]

History[edit]

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.[7][8]: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]:329[13][14] In 2012, two 96-year-old men, Nanu Ram Jogi and Ramjit Raghav, both from India, claimed to have fathered children that year.,[15][16]

Semen and sperm abnormalities[edit]

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]

Fertility[edit]

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]

Adverse pregnancy outcomes and pre-eclampsia[edit]

Studies published between 2002 and 2008 have been consistent in associating advanced paternal age with miscarriage (spontaneous abortion),[21][22][23][24] 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]

Adverse birth outcomes[edit]

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.[29][30]

Notable conditions and diseases[edit]

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]

Alzheimer's disease[edit]

Bertram and colleagues reviewed the 1982–1995 literature on paternal age and Alzheimer's disease, noting that five studies found a positive relationship, two found no relationship, and one found a negative relationship.[32] Because some cases of Alzheimer's are related to genetics, the researchers performed a case-control study that examined 154 people: 52 had Alzheimer's with a low probability of having a major gene for Alzheimer's ("low MGAD"), 52 had Alzheimer's disease with a high probability of having a major gene for Alzheimer's disease ("high MGAD"), and 50 were age- and sex-matched controls.[32] The mean age at onset in the two Alzheimer's groups was 66.6 years.[32] The mean age of fathers of the "low MGAD" group was significantly higher than the mean age of fathers of people in the other two groups, which the researchers interpreted as evidence that increased paternal age is a risk factor for Alzheimer's not associated with a major gene.[32] However, two studies published in 1997 and 2000 failed to find a relationship between paternal age and Alzheimer's.[33][34]

Autism spectrum disorder[edit]

Most studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated a statistically significant association between the two, but some have not.

Bipolar disorder[edit]

Risk of bipolar disorder appears to increase with increasing age of the father. (Arch. Gen. Psychiatry 65, 1034–1040; 2008)[medical citation needed]

Cancers[edit]

Paternal age may be associated with an increased risk of breast cancer, [35] but the association is weak and there are confounding effects.[2]

Diabetes mellitus[edit]

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.[36][37] 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.[38]
  • 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.[37] 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.[37]
  • A 1999 Danish case-control study detected no association between paternal age and risk of type 1 diabetes.[39]
  • 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.[40]
  • A Norwegian study of 2001 found no association with paternal age after adjustment for maternal age.[41]
  • 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.[42]

Down syndrome[edit]

It appears that a paternal-age effect exists with respect to Down syndrome, but is very small in comparison to maternal-age effect.[43]

Intellectual disability and decreased intelligence[edit]

By 1998, "Intellectual disability or decreased learning capacity of unknown aetiology" was thought to be associated with increased paternal age.[44] In 2005, Malaspina and colleagues detected an "inverted U-shaped relationship" between paternal age and intelligence quotients (IQs) in 44,175 people from Israel.[45] 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.[45] 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."[45]

A 2009 study by Saha et al. examined 33,437 children at 8 months, 4 years, and 7 years.[46][47] 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.[46] An editorial accompanying the paper by Saha et al. emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence.[48] A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of intellectual disability.[49]

Schizophrenia[edit]

Paternal age older than 55 is a risk moderate risk factor for schizophrenia.[50]

Disorders, mechanism, and other conditions[edit]

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,[44][51][52][53] Crouzon syndrome,[44][51][54] and Pfeiffer syndrome.[44][51][55] Mutations in the FGFR3 gene lead to the formation of achondroplasia,[44][51] thanatophoric dysplasia,[44] hypochondroplasia, and Muenke syndrome.[55] These disorders occur spontaneously as a result of advanced paternal age and at the rate of 1 in 30,000 for achondroplasia births.[56][57] 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,[58] and the HRAS mutations which cause Costello syndrome.[59][60][44][61] 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.[59][60][62] 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.[63]

Other conditions and diseases which have been suggested as having a possible correlation with paternal age include: Chondrodystrophy,[64] Acrodysostosis,[44][54] Aniridia,[44]Basal cell nevus syndrome,[44][54] Cataracts,[44] Cerebral palsy, athetoid/dystonic,[44] CHARGE syndrome,[7][65] Cleft palate,[44][66][67] Cleidocranial dysostosis,[44][54]Craniosynostosis,[68]Diaphragmatic hernia,[67] Duchenne muscular dystrophy,[44] Exostoses, multiple,[44][54] congenital malformations in extremities,[44][69] Fibrodysplasia ossificans progressiva,[44][51] Heart defects,[44][64][66] Hemangioma,[66] Hemiplegia,[44] Hemophilia A,[44] Hydrocephalus,[66] Klinefelter's syndrome,[70] Lesch-Nyhan syndrome,[44] Marfan syndrome,[51] Nasal aplasia,[44][66] Neural tube defects,[44] Oculodentodigital syndrome,[44][54] Osteogenesis imperfecta type IIA,[44]Polycystic kidney disease,[44] Polyposis coli,[44] Preauricular cyst,[44][66] Progeria,[44][54] Psychotic disorders,[44][71] von Recklinghausen neurofibromatosis,[44][51] Retinitis pigmentosa,[44][72] Retinoblastoma, bilateral,[44] Situs inversus,[64] Soto's basal cell nevus,[44][54]Treacher-Collins Syndrome,[44][54] Tuberous sclerosis,[44] Urethral stenosis,[44][66] Waardenburg syndrome,[44][54] and Wilms' tumor[44]

Mortality of offspring[edit]

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."[73] This would imply a positive effect of paternal age on lifespan, similar to the "Methuselah fly" effect seen in drosophila.[74]

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).[75] 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.[76] 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.[77]

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]

Paternal mortality before adulthood of child[edit]

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:[78]

Paternal age at childbirth 25 30 35 40 45
Risk of father not surviving until child's 18th birthday (in %)[78] 2.2 3.3 5.4 8.3 12.1

Social associations[edit]

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,[78] 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.

Pathophysiology[edit]

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.[79]
  • Epigenetic processes such as parental imprinting could explain the association between paternal age and schizophrenia.[80]

Clinical implications[edit]

The American College of Medical Genetics notes that there is no standard definition of "advanced paternal age."[81] 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."[81] 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]

See also[edit]

References[edit]

  1. ^ "Definition of Advanced paternal age". 
  2. ^ a b c H. Tournaye, "Male Reproductive Ageing," in Bewley, Ledger, and Nikolaou, eds., Reproductive Ageing, Cambridge University Press (2009), ISBN 9781906985134 (accessed 15 November 2013)
  3. ^ Gurevich, Rachel (06-10-2008). "Does Age Affect Male Fertility?". About.com:Fertility. About.com. Retrieved 14 February 2010.  Check date values in: |date= (help)
  4. ^ a b 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. 
  5. ^ Crow, James F. (August 5, 1997). "Proc Natl Acad Sci U S A." 94 (16). pp. 8380–8386. doi:10.1073/pnas.94.16.8380. PMC 33757. PMID 9237985. Retrieved 29 March 2013. 
  6. ^ Vanderbes, Jennifer (June 25, 2011). "What's That Ticking Sound? The Male Biological Clock". Wall Street Journal. Retrieved 3 December 2013. 
  7. ^ a b c d e Crow JF (2000). "The origins, patterns and implications of human spontaneous mutation". Nature Reviews Genetics 1 (1): 40–7. doi:10.1038/35049558. PMID 11262873. 
  8. ^ Krooth RS (1953). "Comments on the estimation of the mutation rate for achondroplasia". American Journal of Human Genetics 5 (4): 373–6. PMC 1716528. PMID 13104383. 
  9. ^ a b Bray I, Gunnell D, Smith GD (2006). "Advanced paternal age: How old is too old?". J Epidemiol Community Health 60 (10): 851–3. doi:10.1136/jech.2005.045179. PMC 2566050. PMID 16973530. 
  10. ^ Australian Bureau of Statistics (11 November 2009). "3301.0 - Births, Australia, 2008. Summary of findings. Births". Retrieved 25 February 2010. 
  11. ^ a b c Kühnert B, Nieschlag E (2004). "Reproductive functions of the ageing male". Hum Reprod Update 10 (4): 327–39. doi:10.1093/humupd/dmh030. PMID 15192059. 
  12. ^ Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Mathews TJ (2009). "Births: final data for 2006". National Vital Statistics Reports (Hyattsville, MD: National Center for Health Statistics) 57 (7): 1–104. Retrieved 25 February 2010. 
  13. ^ Seymour FI, Duffy C, Koerner A (1935). "A case of authenticated fertility in a man, aged 94". J Am Med Assoc 105 (18): 1423–4. doi:10.1001/jama.1935.92760440002009a. 
  14. ^ "A father again at 96; North Carolinan's baby a sister to boy born two years ago". New York Times. 4 June 1936. p. 10. 
  15. ^ Nanu Ram Jogi fathers another child aged 96, article in the Times of India, 16 October 2012
  16. ^ "World's oldest dad, 97, devastated after wife leaves him following disappearance of their son". The Daily Mail (London). 3 October 2013. 
  17. ^ a b c Kidd SA, Eskenazi B, Wyrobek AJ (2001). "Effects of male age on semen quality and fertility: a review of the literature". Fertil Steril 75 (2): 237–48. doi:10.1016/S0015-0282(00)01679-4. PMID 11172821. 
  18. ^ 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 Extra |pages= or |at= (help). Retrieved 12 September 2014. 
  19. ^ Johnson, Sheri L.; Dunleavy, Jessica; Gemmell, Neil J.; Nakagawa, Shinichi (January 2015). "Consistent age-dependent declines in human semen quality: A systematic review and meta-analysis". Ageing Research Reviews 19: 22–33. doi:10.1016/j.arr.2014.10.007. 
  20. ^ De La Rochebrochard, E; McElreavey, K; Thonneau, P (2003). "Paternal age over 40 years: the "amber light" in the reproductive life of men?". Journal of andrology 24 (4): 459–65. PMID 12826682. 
  21. ^ de la Rochebrochard E, Thonneau P (2002). "Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study". Hum Reprod 17 (6): 1649–56. doi:10.1093/humrep/17.6.1649. PMID 12042293. 
  22. ^ Slama R, Bouyer J, Windham G, Fenster L, Werwatz A, Swan SH (2005). "Influence of paternal age on the risk of spontaneous abortion". Am J Epidemiol 161 (9): 816–23. doi:10.1093/aje/kwi097. PMID 15840613. 
  23. ^ Kleinhaus K, Perrin M, Friedlander Y, Paltiel O, Malaspina D, Harlap S (2006). "Paternal age and spontaneous abortion". Obstet Gynecol 108 (2): 369–77. doi:10.1097/01.AOG.0000224606.26514.3a. PMID 16880308. 
  24. ^ Belloc S, Cohen-Bacrie P, Benkhalifa M, Cohen-Bacrie M, De Mouzon J, Hazout A, Ménézo Y (2008). "Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination". Reprod Biomed Online 17 (3): 392–7. doi:10.1016/S1472-6483(10)60223-4. PMID 18765010. [dead link]
  25. ^ Astolfi P, De Pasquale A, Zonta LA (2004). "Late paternity and stillbirth risk". Hum Reprod 19 (11): 2497–501. doi:10.1093/humrep/deh449. PMID 15319387. 
  26. ^ Nybo Andersen AM, Hansen KD, Andersen PK, Davey Smith G (2004). "Advanced paternal age and risk of fetal death: a cohort study". Am J Epidemiol 160 (12): 1214–22. doi:10.1093/aje/kwh332. PMID 15583374. 
  27. ^ Harlap S, Paltiel O, Deutsch L, Knaanie A, Masalha S, Tiram E, Caplan LS, Malaspina D, Friedlander Y (2002). "Paternal age and preeclampsia". Epidemiology 13 (6): 660–7. doi:10.1097/01.EDE.0000031708.99480.70. PMID 12410007. 
  28. ^ a b c Shah PS; Knowledge Synthesis Group on determinants of preterm/low birthweight births (2010). "Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review". Am J Obstet Gynecol 202 (2): 103–23. doi:10.1016/j.ajog.2009.08.026. PMID 20113689. 
  29. ^ a b Chen XK, Wen SW, Krewski D, Fleming N, Yang Q, Walker MC (2008). "Paternal age and adverse birth outcomes: teenager or 40+, who is at risk?". Hum Reprod 23 (6): 1290–6. doi:10.1093/humrep/dem403. PMID 18256111. 
  30. ^ Laurance J (7 February 2008). "Older fathers have healthier offspring". The Independent (London). Retrieved 25 February 2010. 
  31. ^ see Correlation does not imply causation
  32. ^ a b c d Bertram L, Busch R, Spiegl M, Lautenschlager NT, Müller U, Kurz A (1998). "Paternal age is a risk factor for Alzheimer disease in the absence of a major gene". Neurogenetics 1 (4): 277–80. doi:10.1007/s100480050041. PMID 10732803. 
  33. ^ Tsolaki M, Fountoulakis K, Chantzi E, Kazis A (1997). "Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of a Greek population". Int Psychogeriatr 9 (3): 327–41. doi:10.1017/S104161029700447X. PMID 9513031. 
  34. ^ Ptok U, Papassotiropoulos A, Maier W, Heun R (2000). "Advanced parental age: a risk factor for Alzheimer's disease or depression in the elderly?". Int Psychogeriatr 12 (4): 445–51. doi:10.1017/S1041610200006566. PMID 11263711. 
  35. ^ Xue F, Michels KB (2007). "Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence". Lancet Oncol 8 (12): 1088–100. doi:10.1016/S1470-2045(07)70377-7. PMID 18054879. 
  36. ^ Patterson CC, Carson DJ, Hadden DR, Waugh NR, Cole SK (1994). "A case-control investigation of perinatal risk factors for childhood IDDM in Northern Ireland and Scotland". Diabetes Care 17 (5): 376–81. doi:10.2337/diacare.17.5.376. PMID 8062603. 
  37. ^ a b c Rami B, Schneider U, Imhof A, Waldhör T, Schober E (1999). "Risk factors for type I diabetes mellitus in children in Austria". Eur J Pediatr 158 (5): 362–6. doi:10.1007/s004310051092. PMID 10333115. 
  38. ^ Tai TY, Wang CY, Lin LL, Lee LT, Tsai ST, Chen CJ (1998). "A case-control study on risk factors for Type 1 diabetes in Taipei City". Diabetes Res Clin Pract 42 (3): 197–203. doi:10.1016/S0168-8227(98)00105-3. PMID 9925351. 
  39. ^ Bache I, Bock T, Vølund A, Buschard K (1999). "Previous maternal abortion, longer gestation, and younger maternal age decrease the risk of type 1 diabetes among male offspring". Diabetes Care 22 (7): 1063–5. doi:10.2337/diacare.22.7.1063. PMID 10388968. 
  40. ^ Bingley PJ, Douek IF, Rogers CA, Gale EA (2000). "Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study". BMJ 321 (7258): 420–4. doi:10.1136/bmj.321.7258.420. PMC 27456. PMID 10938050. 
  41. ^ Stene LC, Magnus P, Lie RT, Søvik O, Joner G (2001). "Maternal and paternal age at delivery, birth order, and risk of childhood onset type 1 diabetes: population based cohort study". BMJ 323 (7309): 369. doi:10.1136/bmj.323.7309.369. PMC 37395. PMID 11509426. 
  42. ^ Cardwell CR, Carson DJ, Patterson CC (2005). "Parental age at delivery, birth order, birth weight and gestational age are associated with the risk of childhood Type 1 diabetes: a UK regional retrospective cohort study". Diabet Med 22 (2): 200–6. doi:10.1111/j.1464-5491.2005.01369.x. PMID 15660739. 
  43. ^ Girirajan S (2009). "Parental-age effects in Down syndrome". J Genet 88 (1): 1–7. doi:10.1007/s12041-009-0001-6. PMID 19417538. 
  44. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an Tarín JJ, Brines J, Cano A (1998). "Long-term effects of delayed parenthood". Hum Reprod 13 (9): 2371–6. doi:10.1093/humrep/13.9.2371. PMID 9806250. 
  45. ^ a b c Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY (2005). "Paternal age and intelligence: implications for age-related genomic changes in male germ cells". Psychiatr Genet 15 (2): 117–25. doi:10.1097/00041444-200506000-00008. PMID 15900226. 
  46. ^ a b Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, Buka SL, McGrath JJ (2009). Brayne, Carol, ed. "Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood". PLoS Med 6 (3): e40. doi:10.1371/journal.pmed.1000040. PMC 2653549. PMID 19278291. 
  47. ^ Dayton L (10 March 2009). "Not the sharpest? Blame old dad". The Australian. Retrieved 25 February 2010. 
  48. ^ Cannon M (2009). "Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence: The clock ticks for men too". PLoS Med 6 (3): e42. doi:10.1371/journal.pmed.1000042. PMC 2653550. PMID 19278293. 
  49. ^ Lopez-Castroman J, Gómez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, Navarrete FF, Ginestar CM, Currier D, Torres MR, Navio-Acosta M, Saiz-Ruiz J, Jimenez-Arriero MA, Baca-Garcia E (2010). "Differences in maternal and paternal age between schizophrenia and other psychiatric disorders". Schizophr Res 116 (2–3): 184–90. doi:10.1016/j.schres.2009.11.006. PMID 19945257. 
  50. ^ Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, Liu T, Hadley T, Rosso IM, Bearden C, Yolken RH (2009). "Paternal age as a risk factor for schizophrenia: how important is it?". Schizophr Res 114 (1–3): 1–5. doi:10.1016/j.schres.2009.06.017. PMID 19683417. 
  51. ^ a b c d e f g Risch N, Reich EW, Wishnick MM, McCarthy JG (1987). "Spontaneous mutation and parental age in humans". American Journal of Human Genetics 41 (2): 218–48. PMC 1684215. PMID 3618593. 
  52. ^ Tolarova MM, Harris JA, Ordway DE, Vargervik K (1997). "Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome". American Journal of Medical Genetics 72 (4): 394–8. doi:10.1002/(SICI)1096-8628(19971112)72:4<394::AID-AJMG4>3.0.CO;2-R. PMID 9375719. 
  53. ^ Yoon SR, Qin J, Glaser RL, Jabs EW, Wexler NS, Sokol R, Arnheim N, Calabrese P (2009). Walsh, Bruce, ed. "The Ups and Downs of Mutation Frequencies during Aging Can Account for the Apert Syndrome Paternal Age Effect". PLoS Genet 5 (7): e1000558. doi:10.1371/journal.pgen.1000558. PMC 2700275. PMID 19593369. 
  54. ^ a b c d e f g h i j Jones KL, Smith DW, Harvey MA, Hall BD, Quan L (1975). "Older paternal age and fresh gene mutation: data on additional disorders". J Pediatr 86 (1): 84–8. doi:10.1016/S0022-3476(75)80709-8. PMID 1110452. 
  55. ^ a b Goriely A, Wilkie AOM (2012). "Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences For Human Disease". Am. J. Human Genet. 90 (2): 175–200. doi:10.1016/j.ajhg.2011.12.017. 
  56. ^ Orioli I.M. et al (1986). "The birth prevalence rates for the skeletal dysplasias". J. Med. Genet. 23: 328–332. doi:10.1136/jmg.23.4.328. 
  57. ^ Waller D.K. (2008). "The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the U.S.". Am. J. Med. Genet. 146A: 2385–9. doi:10.1002/ajmg.a.32485. 
  58. ^ Tartaglia M. et al (2004). "Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome". Am. J. Hum. Genet. 75: 492–7. doi:10.1086/423493. 
  59. ^ a b Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA Jr, Goodfellow PJ (1994). "Parent-of-origin effects in multiple endocrine neoplasia type 2B". American Journal of Human Genetics 55 (6): 1076–82. PMC 1918453. PMID 7977365. 
  60. ^ a b Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, Houdent C, Pallo D, Schlumberger M, Thivolet C, Lenoir GM; Le Groupe d'Etude des Tumeurs a Calcitonine (1997). "Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine". American Journal of Human Genetics 60 (1): 233–7. PMC 1712555. PMID 8981969. 
  61. ^ Sol-Church K. et al (2006). "Paternal bias in parental origin of HRAS mutations in Costello syndrome". Hum. Mutat. 27: 736–741. doi:10.1002/humu.20381. 
  62. ^ Moloney D. et al (1996). "Exclusive paternal origin of new mutations in Apert syndrome". Nat. Genet. 13: 48–53. doi:10.1038/ng0596-48. 
  63. ^ Goriely A, Wilkie AOM (2013). ""Selfish Spermatogonial Selection": A Novel mechanism for the association between advanced paternal age and neurodevelopmental disorders". Am. J. Psychiatry 170: 599–608. doi:10.1176/appi.ajp.2013.12101352. 
  64. ^ a b c Lian ZH, Zack MM, Erickson JD (1986). "Paternal age and the occurrence of birth defects". American Journal of Human Genetics 39 (5): 648–60. PMC 1684057. PMID 3788977. 
  65. ^ Blake KD, Prasad C (2006). "CHARGE syndrome". Orphanet J Rare Dis 1: 34. doi:10.1186/1750-1172-1-34. PMC 1586184. PMID 16959034. 
  66. ^ a b c d e f g Savitz DA, Schwingl PJ, Keels MA (1991). "Influence of paternal age, smoking, and alcohol consumption on congenital anomalies". Teratology 44 (4): 429–40. doi:10.1002/tera.1420440409. PMID 1962288. 
  67. ^ a b Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, Shapira SK (2010). "Association of Paternal Age and Risk for Major Congenital Anomalies from the National Birth Defects Prevention Study, 1997–2004". Annals of Epidemiology 20 (3): 241–9. doi:10.1016/j.annepidem.2009.10.009. PMC 2824069. PMID 20056435. 
  68. ^ Rasmussen SA, Yazdy MM, Frías JL, Honein MA (2008). "Priorities for public health research on craniosynostosis: summary and recommendations from a Centers for Disease Control and Prevention-sponsored meeting". American Journal of Medical Genetics 146A (2): 149–58. doi:10.1002/ajmg.a.32106. PMID 18080327. 
  69. ^ Zhu JL, Madsen KM, Vestergaard M, Olesen AV, Basso O, Olsen J (2005). "Paternal age and congenital malformations". Hum Reprod 20 (11): 3173–7. doi:10.1093/humrep/dei186. PMID 16006461. 
  70. ^ BRS Genetics - Dudek 2009
  71. ^ Miller B, Pihlajamaa J, Haukka J, Cannon M, Henriksson M, Heilä H, Huttunen M, Tanskanen A, Lönnqvist J, Suvisaari J, Kirkpatrick B (16 Feb 2010). "Paternal age and mortality in nonaffective psychosis". Schizophr Res 121 (1–3): 218–26. doi:10.1016/j.schres.2010.01.020. PMID 20163936. 
  72. ^ Kaplan J, Bonneau D, Frézal J, Munnich A, Dufier JL (1990). "Clinical and genetic heterogeneity in retinitis pigmentosa". Hum Genet 85 (6): 635–42. doi:10.1007/BF00193589. PMID 2227956. 
  73. ^ Pearl, Raymond, Man the Animal, Principia Press, Bloomington, IN (1946). (Lectures originally delivered at Indiana University in October, 1938, as the Patten Foundation lectures) archive
  74. ^ Claudia Dreifus, Live Longer With Evolution? Evidence May Lie in Fruit FliesThe New York Times, December 6, 2005. (accessed Nov. 15 2013)
  75. ^ Zhu JL, Vestergaard M, Madsen KM, Olsen J (2008). "Paternal age and mortality in children". Eur J Epidemiol 23 (7): 443–7. doi:10.1007/s10654-008-9253-3. PMID 18437509. 
  76. ^ "In this particular study, no adjustment was made for the health of the mother, and this could have had a large effect on child mortality." National Health Service (UK), "Older Dads and the Death of Children," (accessed 15 November 2013)
  77. ^ Tournaye 2009, p. 102
  78. ^ a b c Schmidt, L.; Sobotka, T.; Bentzen, J. G.; Nyboe Andersen, A.; on behalf of the ESHRE Reproduction Society Task Force (2011). "Demographic and medical consequences of the postponement of parenthood". Human Reproduction Update 18 (1): 29–43. doi:10.1093/humupd/dmr040. PMID 21989171.  edit
  79. ^ Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K (2012). "Rate of de novo mutations and the importance of father's age to disease risk". Nature 488 (7412): 471–5. doi:10.1038/nature11396. PMC 3548427. PMID 22914163. 
  80. ^ Perrin MC, Brown AS, Malaspina D (2007). "Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia". Schizophr Bull 33 (6): 1270–3. doi:10.1093/schbul/sbm093. PMC 2779878. PMID 17712030. 
  81. ^ a b Toriello HV, Meck JM; Professional Practice and Guidelines Committee, American College of Medical Genetics (2008). "Statement on guidance for genetic counseling in advanced paternal age". Genet Med 10 (6): 457–60. doi:10.1097/GIM.0b013e318176fabb. PMC 3111019. PMID 18496227. 

Further reading[edit]

  • 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.

External links[edit]