Fathers’ age as contributor to risk for autism
What did Leslie Feldman and I discuss about causes of autism in 2007?
Editor’s Note: Given all the discussion—should I say “speculation?”—about the causes of autism in the spring of 2025, I wanted to return to an idea that Leslie Feldman suggested ~20 years ago and that we examined in a post on EBDBlog.com in 2013. Here’s a reprint of a post about that idea. Please understand that I do not want to argue that de novo mutations accounts for all cases of autism, but rather that we advocates should not ignore potential genetic causes. Please see the addendum at the end of the reprinted content.—JohnL
Fathers’ Age as Contributor to Risk for Autism
Leslie Feldman
John Wills Lloyd, editor
The 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, Atladottir and colleagues (2007) reported increased diagnoses 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.”
Originally published February, 2007.
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.1
Atladottir, 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.
Brown et al. (2002): Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry, 159, 1528-1533.
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.
Burd et al., (1999). Prenatal and perinatal risk factors for autism. J. Perinatal. Med., 27, 441-450.
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.
Centers for Disease Control, (2006). How common are Autism Spectrum Disorders (ASD)?
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.
Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. USA, 94, 8380-8386.
Dalman, C., & Allebeck, D. (2002). Paternal age and schizophrenia: Further support for an association. Am J Psychiatry, 159, 1591-1592.
Gillberg, C. (1980). Maternal age and infantile autism. J. Autism and Developmental Disorders, 10, 293-297.
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.
Miller, M. C. (2006) A new key to Autism. Aetna IntelliHealth, September 25.
Malaspina, D., et al. (2001): Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry, 58, 361-367.
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.
Malaspina, D. (2006). Schizophrenia risk and the paternal germ line. Schizophrenia Research Forum.
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.
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.
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.
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.
Sullivan, B. J. (2002). Research reveals a cellular basis for a male biological clock. Science Blog, 2002-11-25 22:31.
Tarin, J. J., Brines, J., & Cano, A. (1998). Long-term effects of delayed parenthood. Human Reproduction, 13, 2371-2376.
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.
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].
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.
Update
De novo changes in genetic material in sperm may not fully explain the cause of autism, but the topic is still worth considering. Publications in the last few years have continued to examine the topic, and found connections (see Zweifel & Woodward, 2022) between advanced paternal age and autism.
Please remember that this observation is essentially a correlation, an association. The connection between advanced paternal age and autism might be explained by factors other than de novo mutations. Perhaps old fathers provide different experiences for their offspring than younger fathers (see Dehesh et al., 2024; Pugsley et al. 2022).
Indeed, to understand the causes of autism, we need to be alert to the possibility of interactions between bio-genetic and environmental factors. Conceptually, it may be that biologic factors make individuals more vulnerable to untoward environmental factors. A diathesis-stress model, illustrated by Singletary (2015), could have a lot to offer in guiding understanding.2
In general, I encourage us (both you, Dear Readers, and myself) to avoid outright dismissal of genetic causes. Not only may there be complex genetic contributions from genes, but there is the very real possibility of gene-x-environment interactions.
Additional sources
Alonso-Gonzalez, A., Rodriguez-Fontenla, C., & Carracedo, A. (2018). De novo mutations (DNMs) in autism spectrum disorder (ASD): Pathway and network analysis. Frontiers in Genetics, 9, 406. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00406/full
Dehesh, T., Mosleh-Shirazi, M. A., Jafari, S., Abolhadi, E., & Dehesh, P. (2024) assessment of the effects of parental age on the development of autism in children: A systematic review and a meta-analysis. BMC Psychology, 12(1), 685. https://doi.org/10.1186/s40359-024-02184-9
Pugsley, K., Scherer, S.W., Bellgrove, M.A. et al. (2022). Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands. Mol Psychiatry 27, 710–730. https://doi.org/10.1038/s41380-021-01142-w
Singletary, W. M. (2015). An integrative model of autism spectrum disorder: ASD as a neurobiological disorder of experienced environmental deprivation, early life stress and allostatic overload. Neuropsychoanalysis, 17(2), 81-119.
Zweifel, J. E., & Woodward, J. T. (2022). The risky business of advanced paternal age: Neurodevelopmental and psychosocial implications for children of older fathers. Fertility and Sterility, 118(6), 1013-1021. https://www.sciencedirect.com/science/article/pii/S0015028222019793
Footnote
The references in the original came from Leslie Feldman. I did not check them for accuracy or format. Caveat reader!
By citing Singletary (2015), I don’t mean to endorse his particular model, but to encourage those of us interested in causes to keep the possibility of bio-env interactions.