Paternal Age, Schizophrenia, and Autism

Paternal Age, Schizophrenia, and Autism


http://clinpsyc.blogspot.com/2007/03/paternal-age-schizophrenia-and-autism.html
A good chunk of studies have accumulated over the past few years (e.g., 1, 2, 3, 4, 5) that show a strong link between increasing paternal (father’s) age and risk of schizophrenia in children.

One researcher has described the link as follows:



We found that paternal age explained over a quarter of the risk for schizophrenia in the population. At the time, people were skeptical. But the findings have been replicated many times now, and not a single study has failed to find this strong relationship between father's age and the risk for schizophrenia. And at this point, other explanations for the relationship have been ruled out, including social factors in the family, prenatal care, and parental psychiatric ailments. There simply seems to be a relationship between paternal age and schizophrenia risk.

Wow – one quarter of the risk for schizophrenia explained by paternal age? I’ll admit that these types of studies are not my area of expertise, but from my review of some of these studies, I’m willing to buy that paternal age is a significant risk. These findings have indeed been replicated on numerous occasions.


One of the main researchers in the area, Dolores Malaspina (quoted above), has said that findings such as this should not discourage parents from having children at whatever age they choose. I am not in agreement – older parents should be made aware of the risk and make an informed decision.


Why the effect? Here’s what seems to be a decent explanation…


"Every cell division makes a copy of DNA," [researcher] Gavrilova says. "And the same thing happens with the next division and this final copy is of less quality. This can introduce a slight risk of error in the genetic material of the new sperm. You can call it a kind of copy error.

The longer a man ages, the greater the chance of sperm mutations that could lead to schizophrenia or other problems in offspring.

There is also research linking autism to older fathers. It appears that such information is not widely known. I was certainly not familiar with it until recently. Consider the trends in Western societies – fathers having children at older ages is likely leading to a decent sized increase in rates of schizophrenia, autism, and perhaps other problems as well. While this is excellent news if one is in the antipsychotic business, is this really good news for everyone else?


Shouldn't this information be more widely discussed?


Hat Tip: Just Noticeable Differences.


Posted by CL Psych at 3/16/2007 05:44:00 AM
Labels: autism, paternal age, schizophrenia
3 comments: Stephany said...
This is a great post; and definitely a topic worth discussing. My children's Father was 38 yrs. old when my youngest was born. I have read various articles regarding schizophrenia/ autism links to the age of the Father.My daughter has a questionable psychiatric diagnosis, along with a "High Functioning" Autistic dx of P.D.D./ it might be interesting to note here, that my daughter was treated for "possible" psychiatric bipolar disorder at age 11-17 yrs; before the P.D.D. dx that she received at age 17.5 years old.

Treating autistic children's behaviors with psychiatric medications is a controversial topic in iteself, and worth looking into further.

I am including a link to an article from 2002 that could be of further interest:

http://info.med.yale.edu/chldstdy/plomdevelop/genetics/02novgen.htm



From the article:

"Future research should include longer-term studies of atypical antipsychotics to gather longitudinal efficacy and safety data."

Sunday, March 18, 2007 10:40:00 AM

fathers' ages were strongly associated with a diagnosis of schizophrenia or a related disorder. The risk of schizophrenia increased steadily with the

INCREASING PATERNAL AGE.


THERE ARE TEN STUDIES FROM ALL OVER THE WORLD WITH THE SAME RESULT.


April 12, 2001


Father's Age Linked to Risk of Schizophrenia

By ERICA GOODE

The risk of having a child with schizophrenia may increase with a father's advancing age, researchers reported yesterday.

The researchers, who examined the relationship between the fathers' ages and schizophrenia among 87,907 Israelis born from 1964 through 1976, found that the older the father, the more likely he was to have a child who suffered from schizophrenia, a devastating mental illness.

Men who were 45 through 49, for example, were twice as likely to have offspring with schizophrenia or a related disorder as were men under 25, the researchers found. The overall risk of having a child with the illness, however, remained small.

"The finding is a very strong association of schizophrenia risk and father's age," said Dr. Delores Malaspina, an associate professor of clinical psychiatry at the Columbia University College of Physicians and Surgeons and the lead author of the report, which appears in this month's issue of the journal Archives of General Psychiatry.

Other scientists were more skeptical. They noted that confirmation through other studies was needed before such a link could be said to be established, and they cautioned that in the history of schizophrenia research, many apparent associations had eventually proved spurious or impossible to replicate.

If the results of the study hold up to scrutiny, Dr. Malaspina said, "The next question is, `What might explain that finding?' " One possibility, the researchers argue in their report, is that some cases of schizophrenia are a result of genetic abnormalities in sperm cells that become more likely as a man ages.

Stem cells in the testicles divide throughout a man's life in a process that leads to the production of sperm. Each cell division carries the chance for copying errors in reproducing the DNA. By the age of 40, research suggests, about 660 such divisions have taken place. Genetic mutations can also occur from exposure to radiation or chemicals over a man's life.

In contrast, the divisions of cells that produce a woman's eggs occur only before birth.

A number of physical illnesses and birth defects have been linked to genetic mutations during sperm production in older fathers, including Apert syndrome, a rare congenital deformity of the skull, fingers and toes, and achondroplasia, the most common form of dwarfism.

Some cases of schizophrenia, the researchers suggested, might be associated with similar mutations.

The illness runs in families, and is known to have a strong genetic component, though efforts to identify the specific gene or genes that predispose a person to schizophrenia have so far been inconclusive. The disease affects 1 of every 100 Americans and is more common in men. Full-blown symptoms often first appear in late adolescence or early adulthood.

In some cases, people who do not have a family history of schizophrenia also develop the illness. Dr. Malaspina said that the findings of her study "suggest that relevant mutations are there" in such sporadic cases "as well as in familial cases."

Dr. James F. Crow, a professor emeritus of genetics at the University of Wisconsin, said, "I think this is very strong evidence for a mutation component to schizophrenia, but it's quite an open question as to how much of a component."

But other scientists cautioned that other explanations beside spontaneous genetic mutation could also account for the study's results.

For example, said Dr. Ann Pulver, director of the epidemiology and genetics program in psychiatry at Johns Hopkins University, "It may be that the fathers of schizophrenics have unusual characteristics that delay reproduction."

"I think this is an interesting contribution to the epidemiological literature, that paternal age may be a risk factor for a subgroup of schizophrenic patients," Dr. Pulver said. "And it may be that advanced paternal age is associated with a mutation. But that is a hypothesis and one would need to test it.
father's increasing age.


In the study, Dr. Malaspina and her colleagues took advantage of the Jerusalem Perinatal Study, a research archive that includes information about all births in one area of Jerusalem. Records from the study were correlated with those of a national registry of psychiatric illness kept by the Israeli government.

The researchers found that in 1,337 people admitted to psychiatric hospitals before 1998, the fathers' ages were strongly associated with a diagnosis of schizophrenia or a related disorder. The risk of schizophrenia increased steadily with the father's increasing age. Advancing age of the fathers, the investigators reported, accounted for 26 percent of the cases of schizophrenia in the study; for fathers over 50, two out of every three cases of the illness could be attributed to the father's age.

Gerald D. Fischbach, M.D., Scientific Director of the Simons Foundation

Gerald D. Fischbach

Gerald D. Fischbach, M.D., is Executive Vice President for Health and Biomedical Sciences; Dean of the Faculties of Health Sciences and Dean of the Faculty of Medicine at the College of Physicians and Surgeons of Columbia University. Dr. Fischbach received his M.D. degree in 1965 from Cornell University Medical School and interned at the University of Washington Hospital. He began his research career at the National Institutes of Health, serving from 1966-1973. He subsequently served on the faculty of Harvard Medical School, first as Associate Professor of Pharmacology from 1973-1978 and then as Professor until 1981. From 1981-1990, Dr. Fischbach was the Edison Professor of Neurobiology and Head of the Department of Anatomy and Neurobiology at Washington University School of Medicine. In 1990, he returned to Harvard Medical School where he was the Nathan Marsh Pusey Professor of Neurobiology and Chairman of the Neurobiology Departments of Harvard Medical School and Massachusetts General Hospital until 1998. He served as Director of the National Institute of Neurological Disorders and Stroke, National Institutes of Health from 1998-2001.





NIH's Gerald D. Fischbach,Named Columbia's Vice President for Health and Biomedical Sciences






Gerald D. Fischbach

Gerald D. Fischbach, M.D., Director of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH), has been named Columbia University's Vice President for Health and Biomedical Sciences, Dean of the Faculty of Health Sciences and Dean of the Faculty of Medicine, Columbia President George Rupp announced Tues., Dec. 5. Fischbach will also be the Harold and Margaret Hatch Professor of the University in the Faculties of Health Sciences and of Medicine.

A pioneering researcher Fischbach was the Nathan Marsh Pusey Professor of Neurobiology and Chairman of the Neurobiology Departments at both the Harvard Medical School and Massachusetts General Hospital before assuming his current position at NIH in 1998.

At Columbia he will head a division that includes four health science professional schools with 27 academic departments, 3,000 students and 2,300 full-time faculty; a biotechnology park; some 40 biomedical research and treatment centers; and physician practice affiliations with two dozen hospitals. The Health Sciences Division has an annual operating budget of $815 million and has $230 million in sponsored research grants.

Fischbach replaces Herbert Pardes, M.D., who left Columbia in December 1999

HOW AUTISM RESEARCH DOLLARS BENEFIT VENTURE CAPITALISTS AND WILL DO NOTHING TO PREVENT AUTISM OR HELP THOSE ALREADY BORN WITH THE DISORDER

The findings could help to determine the risk of having a second child with autism, and the knowledge of which genes are involved may lead to the development of new therapies. NOT UNLESS THEY USE MICRO ARRAY TECHNOLOGY ON THE DNA OF THE SPERM AND SPERMATAGONIA OF THE FATHERS

"This work received the vast bulk of its funding from the Simons Foundation, which generously supported the research when it was little more than an idea and a technique," Wigler said.

Supporters of the research included the Simons Foundation, the National Institute of Mental Health, Autism Speaks, Cure Autism Now, and the Southwestern Autism Research and Resource Center.

"This discovery sets a new framework for understanding, diagnosing and potentially treating autism," said CSHL President Bruce Stillman.

CSHL is pursuing a $200 million capital campaign to fund such ventures as the construction of new research facilities dedicated to the study of autism.


THIS MONEY WILL ONLY BENEFIT INVESTORS/WHO WILL CREATE MORE MONEY FOR THEMSELVES

SOME SPORADIC AUTISM CAN BE PREVENTED IF MEN FATHER ALL THEIR BABIES BY 30 AND CRYOPRESERVE SEMEN IN CLIENT DEPOSITOR SPERM BANK ACCOUNTS. THIS WILL DO MORE GOOD FOR SPORADIC GENETIC DISORDERS SUCH AS ALZHEIMER'S, AUTISM, SCHIZOPHRENIA, PROSTATE CANCER, DIABETES1, MS, ACUTE LYMPHOBLASTIC LEUKEMIA, DUCHENNES MUSCULAR DYSTROPHY, HEMOPHILIA, PRE-MENOPAUSAL BREAST CANCER, FRAGILE-X, RETINOBLASTOMA, ETC. ETC.

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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