Why Blame the Age of the Mother? Lionel Penrose Did Not

The effects of parental age upon the occurrence of abnormalities in offspring never ceased to intrigue Penrose. It was Weinberg who first noted the phenomenon in 1912, and there were others who suggested that it was the father's not the mother's age that played a significant role in the occurrence of infants with, for example, achondroplasia. However, it was Penrose who, again using the partial correlation method employed by Wright, provided the data to prove the hypothesis. His results were a mirror image of those found in families with Down syndrome. In other words, if the maternal age was kept constant, a significantly positive correlation (+0.273) was found between the paternal age and the incidence of achondroplasia, whereas the maternal age effect disappeared completely if the paternal age was regressed out. Furthermore, Penrose noted that the statistical significance of the paternal age effect increased considerably when nonsurviving infants with achondroplasia were excluded from the calculations (PENROSE 1955 , PENROSE 1957 ). It is possible, although no proof exists from the old data, that the infants with "achondroplasia" who died neonatally or shortly thereafter had different diagnoses of more severe, perhaps lethal, short-limbed dwarfing disorders. The survivors represented true instances of new (paternally derived) mutations of the gene.

Together with Haldane, Penrose also studied the paternal age effect upon mutations of genes located on the X chromosome. Haldane had accurately postulated an increased occurrence of hemophilia in the grandsons of older maternal grandfathers, implying another example of a higher mutation rate in males. Four decades later, it was Crow who finally completed the story by summarizing data showing that, at the molecular level, the rate for base substitutions (the cause of the achondroplasia mutation) is indeed higher in males than in females; he also showed that the phenomenon can be attributed partially to the larger number of cell divisions, estimated to be about 430 at age 30 in the male, as contrasted with the female germ line, in whom there are only about 24 divisions from zygote to egg (CROW 1997A , CROW 1997B ). More specifically, the mutation in achondroplasia, in the fibroblast growth factor receptor 3 gene (FGFR3) on 4p16.3, consists of a single substitution of the normal glycine residue by an arginine residue at codon 380. This same Gly380Arg mutation is, surprisingly, present in almost all of the hundreds of patients with achondroplasia who have had mutational analysis to date, and it is of paternal origin in those in which the parental origin could be determined (HORTON 1997 ). Thus, we owe our understanding of the paternal age factor, its causes as well as underlying mechanisms, to the imaginatively creative minds of three generations of genetics heroes

Risk of Non-Familial Autism Is Often Related To the Age of the Father at a Child's Birth

Published on the EBD Blog

In order to access the links and the complete comment section please read this paper where it was originally published: THE EBD BLOG


cFathers’ Age as Contributor to Risk for Autism
Leslie FeldmanThe average age of fatherhood is increasing in the US and in Western Europe. Some research shows that offspring of older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. “The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent” (Malaspina et al., 2006). Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladóttir and colleagues (2007) reported increased diagnosese of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age. Crow said, the evidence suggested that the greatest mutational health hazard in the population is fertile old men.

A study by Reichenberg et al. (2006) found a strong connection between cases of autism and advancing paternal age. Reichenberg and colleagues, who found more autism as paternal age increased, also found that the ratio of girls to boys in this cohort was 1:1, suggesting that this was a special subset of autism, maybe de novo rather than familial autism.

What might be the mechanism that produces higher rates of disorders among children of older fathers? The DNA in a 20 year-old male has been copied approximately100 times but in a 50 year-old father it has been copied over 800 times. Singh and colleagues (2003) studied differences in the sperm of older and younger men. Men over age 35 have sperm with lower motility and more highly damaged DNA in the form of double-strand breaks. The older group also had fewer apoptotic cells, an important discovery. (Apoptosis is form of cell death that protects the parent organism from problems or that permits differentiation, as in resorption of a tadpole’s tail.) A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage, as most other cells do. As a result, the only way to avoid passing DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age. Singh is quoted in Science Blog (Sullivan, 2002) as explaining that, “In older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated.”

Sources

The following list of sources is for works cited in this document or for other studies finding a connection between age of fathers at conception and various disorders. Access to some of the Web-based resources may be limited because of the policies of the publishers.

Atladóttir, H. O., Parner, E. T., Schendel, D., Dalsgaard, S., Thomsen, P. H., & Thorsen, P. (2007). Time trends in reported diagnoses of childhood neuropsychiatric disorders. Arch Pediatr Adolesc Med., 161, 193-198. Link

Brown et al. (2002): Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry, 159, 1528-1533. Link

Bray, I., Gunnell, D., & Smith, G. D. (2006). Advanced paternal age: How old is too old? Journal of Epidemiology and Community Health, 60, 851-853. Link

Burd et al., (1999). Prenatal and perinatal risk factors for autism. J. Perinatal. Med., 27, 441-450. Link

Byrne, M., Agerbo, E., Ewald, H., Easton, W. W., & Mortensen, P. D. (2003). Parental age and risk of schizophrenia, A case control study. Arch Gen Psychiatry, 60, 673-678. Link

Centers for Disease Control, (2006). How common are Autism Spectrum Disorders (ASD)? Link

Centers for Disease Control. (2002). Prevalence of the Autism Spectrum Disorders (ASDs) in multiple areas of the United States, 2000 and 2002. Atlanta, GA: Author. Link

Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. USA, 94, 8380-8386. Link

Dalman, C., & Allebeck, D. (2002). Paternal age and schizophrenia: Further support for an association. Am J Psychiatry, 159, 1591-1592. Link

Gillberg, C. (1980). Maternal age and infantile autism. J. Autism and Developmental Disorders, 10, 293-297. Link

Lauritsen M. B., Pedersen, C. B., & Mortensen, P. B. (2005) Effect of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychology and Psychiatry, 46, 963-971. Link

Miller, M. C. (2006) A new key to Autism. Aetna IntelliHealth, September 25. Link

Malaspina, D., et al. (2001): Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry, 58, 361-367. Link

Malaspina, D. (2006). In session with Dolores Malaspina, MD, MSPH: Impact of childhood trauma on psychiatric illness (interview by N. Sussman). Primary Psychiatry, 13(7), 33-36. Link

Malaspina, D. (2006). Schizophrenia risk and the paternal germ line. Schizophrenia Research Forum. Link

Rasmussen, F. (2006) Paternal age, size at birth, size in young adulthood&mdashrisk factors for schizophrenia. Eur Journal of Endocrinology, 155 Suppl 1:S65-69. Link

Reichenburg, A., Gross, R., Weiser, M. Bresnahan, M., Silverman, J. Harlap, S., et al. (2006). Advancing paternal age and autism. Arch Gen Psychiatry, 63, 1026-1032. Link

Singh, N. P., Muller, C. H., & Burger, R. E. (2003). Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertility and Sterility, 80, 1420-1430. Link

Sipos, A., Rasmussen, R., Harrison, G., Tynelius, P., Lews, G., Leon, D. A., et al. (2004). Paternal age and schizophrenia: A population based cohort study. BMJ, 329, 1070. Link

Sullivan, B. J. (2002). Research reveals a cellular basis for a male biological clock. Science Blog, 2002-11-25 22:31. Link

Tarin, J. J., Brines, J., & Cano, A. (1998). Long-term effects of delayed parenthood. Human Reproduction, 13, 2371-2376. Link

Tsuchiya, K. J., Takagai, S., Kawai, M., Matsumoto, H., Nakamura, K., Minabe, Y., et al. (2005). Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophrenia Research, 76, 337-342. Link

Wohl, M. & Gorwood, P. (2006). Paternal ages below or above 35 are associated with a different risk for schizophrenia in offspring. Eur. Psychiatry, Dec 1 [Epub ahead of print]. Link

Zammit, S., Allebeck, P., Dalman, C., Lundgerg, I., Hemming, T., Owen, M. J., et al. (2003). Paternal age and risk for schizophrenia. Br. J. Psychiatry, 183, 405-408. Link

3 Comments »
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Pingback by EBDblog » Paternal age–more — 21 February 2007 @ 3:08 pm

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5601a1.htm

February 9, 2007 / 56(SS01);1-11

Prevalence of Autism Spectrum Disorders — Autism and Developmental Disabilities Monitoring Network, Six Sites, United States, 2000

Corresponding author: Catherine Rice, PhD, Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDC, 1600 Clifton Road, N.E., MS E-86, Atlanta, GA 30333. Telephone: 404-498-3860; Fax: 404-498-3550; E-mail: crice@cdc.gov.

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5601a1.htm

Comment by Leslie Feldman — 21 February 2007 @ 7:36 pm

Dr. Narendra P.Singh suggested that I elaborate about what happens when the DNA in the primitive sperm making cells divides hundreds and hundreds of times as men age.

I will try.

Mutations arise with each cell division and the mutation rate increases with age. There are base substitutions and deletions and other copying errors. In a man of 45 there have been 770 cell divisions ancestral to a sperm. See James F. Crow’s paper, “The high spontaneous mutation rate: Is it a health risk? in the sources section of the paper.

Comment by Leslie Feldman — 22 February 2007 @ 7:38 pm








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