Paternal Age Explains between 1/4 and 1/3 of all Schizophrenia

Dr. Dolores Malaspina interviewed by Dr. Norman Sussman


"The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children. In the 1960s, an excess of schizophrenia in last-born children was also reported."

http://www.schizophreniaforum.org/for/curr/Malaspina/default.asp




Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the

fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.
genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the

fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.

Infertility Link to Autism Risk/October 26, 2006 Is Father's Age A major factor??

At the American Society for Reproductive Medicine, Professor Mary Croughan of the University of California, who led the research on 4,000 women said that "what has caused then to be unable to conceive goes on to cause problems". Couples with infertility problems are 3X more likely to have a child with serious problems such as autism, cerebral palsy, mental retardation, seizures and cancer. For autism alone, the risk was four times higher.



According to Professor Mary Croughan, lead researcher of the University of California study on 4,000 women and their children aged up to six years, couples with fertility problems were also more likely to have other health problems, like diabetes and heart disease, as well as having a higher risk of pregnancy and labor complications. She said: "What has caused them to be unable to conceive goes on to cause problems.

"It is as if a brick wall has stopped you becoming pregnant. Treatment allows you to climb over the wall, but it is still there and it goes on to cause problems."

The study revealed that the risk of five serious disorders - autism, cerebral palsy, mental retardation, seizures and cancer - was 2.7 times higher among the children born to 2,000 women who experienced fertility problems than among those born to the 2,000 women who did not have difficult conceiving.

Advanced paternal age: how old is too old?

Isabelle Bray, David Gunnel and George Davey Smith
Department of Social Medicine, University of Bristol, UK

Journal of Epidemiology amd Community Health 2006;60:851-853

"Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. .....Accumulated chromosomal aberrations and mutations occurring during the maturation of the male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers and schizophrenia." ......

Best age for childbearing remains 20-35- Delaying risks heartbreak, says experts

British Medical Journal September 16, 2005


"Delaying having children defies nature and risks heartbreak, say experts in this week's BMJ. If women want families and room for manoeuvre they are unwise to wait till their 30s.

They believe the best age for childbearing remains 20-35 and call on doctors and healthcare planners to support women to achieve "biologically optimal childbearing."

Pregnancies in women older than 35 are increasing markedly in Western countries, write Susan Bewley and colleagues. Age related fertility problems increase after 35 and dramatically after 40, and once a woman is pregnant, outcomes for both the mother and child are poorer.

Delaying also affects partners, as semen counts deteriorate gradually every year, and children of older men have an increased risk of schizophrenia and several genetic disorders."


The reasons for these difficulties lie not with women but with a distorted and uninformed view from society, employers, and health planners. Doctors and healthcare planners need to grasp this threat to public health and support women to achieve biologically optimal childbirth, they conclude.

Editorial: Which career first? BMJ Volume 331, pp 588-9

In 1981 Geneticist JM Friedman said it was Good Public Health Policy That Both Men and Women Complete Their Family before age 40

"Thus, it is good public health policy to recommend that both men and women complete their family before age 40, if possible.

JM Friedman in an article called Genetic disease in the offspring of older fathers. Obstetrics & Gynecology 1981:57 745-749


Genetic disease in the offspring of older fathers
JM Friedman


Autosomal dominant genetic diseases may result from the transmission of a trait by a carrier parent or from gene mutation in one of the gametes from which the child develops. The mean age of fathers of affected persons has been found to be greater than expected for several autosomal dominant diseases due to new mutations. To assess the clinical importance of this observation, the relative and absolute frequencies of offspring with autosomal dominant diseases due to mutation in the sperm from fathers of various ages have been calculated. The relative frequency of new autosomal dominant mutations in children increases logarithmically with paternal age during the usual years of fatherhood. The absolute frequency of autosomal dominant disease due to new mutations among the offspring of fathers who are 40 years of age or older is estimated to be at least 0.3 to 0.5%. This risk is many times greater than that for children of young fathers and is similar in magnitude to the risk of Down syndrome among the offspring of 35- to 40-year-old mothers. Thus, it is good public health policy to recommend that both men and women complete their family a before age 40, if possible

A Cryobank that Understands and Respects Genetics and Emotional Psychological Issues

If you are seeking to use donor sperm, the N.W. Andrology and Cryobank in Spokane Washington and Missoula Montana has the best age range for donors. "All donors are between 18 and 35 years of age to minimize age related genetic abnormalities."




Donor Standards

Our donors are recruited from the Northwest US. Most of our donors are either currently involved with, or have finished their higher education at the time of their participation in our donor program. All donors are between 18 and 35 years of age in order to minimize age related genetic abnormalities. All donors are frozen in very limited quantities in order to guarantee that the number of pregnancies created from any one donor are limited. Although all donor histories are reviewed to provide you with donors that should give you a great chance of concieving a healthy and normal baby, there is of course no way to guarantee such an outcome. As all donor family histories will present with their own unique positive and negative attributes, we encourage all clients to review donor information thoroughly prior to purchase and use of specimens.

All of our donors are commercial anonymous donors. We do not provide the identity of any of our donors to clients. All of our donors are asked if they are willing to meet with, or be contacted by, legal aged children that could be produced through their donations. If the donor expresses that he is willing to entertain future contact by legal aged children, then the child must approach the Cryobank to initiate the potential donor contact.
Our donor screening meets or exceeds the standards set forth by the FDA, AATB, ASRM. (Food and Drug Administration, American Association of Tissue Banks, American Society for Reproductive Medicine)

something is fishy in Canada Results Were Due In A Couple of weeks

Older Dads and Autism Survey
Update: Sept 13 2006
The research study by Reichenberg et al (2006) attracted a lot of attention from both the scientific community and the autism community, with many comments supporting and others criticising the results. Such a reaction is important because it helps us to explore new areas of research and to design better studies.
Our Older Dads and Autism Survey is not a rigorous scientific study. BUT we are trying to see whether there is merit in conducting a more in-depth study. This survey taught us many things - the most important of which is that so many families want to participate in research to find answers. Within one hour and 20 minutes of posting, we had 100 responses! By the end of the first day (only 7 hours), we had 300! The word has spread and you helped make that happen - Thank you. We had more than 1000 responses in only 5 days! We are sharing some of those findings with you now, and the analysis of our results will be posted early next week. Please continue to invite others to participate and we hope that you will come back to participate in other surveys.

Flea: Old Fathers

Flea: Old Fathers

There are many studies with data on conditions that are associated with increasing paternal age. To not take seriously, the Reichenberg study of more than 318,000 offspring, born in the 1980s, showing that men over 40 were almost six times more likely to father an autistic child as those under 30, is a mistake. The risk goes up to nine times with fathers over 50.


There's a 5-year old I know from our neighborhood playground. I know only two things about her: Her father was 84 when she was born, and she is profoundly autistic.

I know that anectdotes are meaningless and data are everything, but I couldn't help think of this precious little girl when I read of this study in the Archives in General Psychiatry



Data are everything, but I can't help wondering what this study will do to the conversation about autism.

My guess is it will do nothing. Could delayed parenthood be partly responsible for the "autism epidemic"? Americans don't want to hear that their lifestyle choices may have deleterious effects on their children. My guess is that some folks will shun this data as vigorously they shun the data that demonstrate, convincingly, that vaccines do not cause autism

Paternal Age Schizophrenia Risk Higher in Daughters of Old Fathers Some X linkage suggested

Daughters of older fathers are at increased schizophrenia risk according to Danish and US researchers suggesting that a new mutation on the X chromosome might be the cause of some cases of schizophrenia. Dr. Majella Byrne, of Aarhus University in Denmark, and colleagues found that men born when their father was aged 55 or more were at double risk of developing schizophrenia. In women, however the relationship was even stronger. The team found that women born to father aged 50 were more than twice as likely to develop schizophrenia. This increased to a nearly fourfold rsk in those born to fathers aged 55 or more.


Results Advanced paternal and maternal age was associated with increased risk of schizophrenia in univariate analyses. Controlling for socioeconomic factors and family psychiatric history, increased risk of schizophrenia was identified in those with a paternal age of 50 years or older. Sex-specific analyses revealed that the risk of schizophrenia was increased for males with fathers 55 years or older (incidence rate ratio [IRR], 2.10; 95% confidence interval [CI], 1.35-3.28); for females, the risk associated with paternal age was substantial for fathers aged 50 to 54 years (IRR, 2.22; 95% CI, 1.44-3.44) and 55 years or older (IRR, 3.53; 95% CI, 1.82-6.83).

Conclusion Increased risk of schizophrenia was associated with advanced paternal age, particularly in females, lending support to the theory that de novo mutations, possibly X-linked, associated with increased parental age might be responsible for some cases of schizophrenia.


From the National Centre for Register-based Research, Aarhus University, Aarhus, Denmark (Drs Byrne and Mortensen and Mr Agerbo); Institute for Basic Psychiatric Research, Psychiatric Hospital, Aarhus, Risskov, Denmark (Dr Ewald); and Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md (Dr Eaton).

Dr. Barry Starr, Dept. of Genetics Stanford University A cheerful article on how mom and dad affect your risk of schizophrenia

Such a cheerful face and such a very tragic and devastating reality for many offspring of older fathers,

One possible reason why schizophrenia is so common


And how mom and dad affect your chances of getting it

by Dr. Barry Starr

Schizophrenia affects over 2 million people in the U.S. That is close to 1% of the U.S. population.

This is surprisingly common for such a devastating illness. And its frequency is even more puzzling because genes play such a large role in schizophrenia (click here to learn more).

Usually genes that would affect someone as severely as schizophrenia would become less common over time. But this isn’t the case for schizophrenia.







"As a man ages, there is a build up of these damaged sperm so that the odds of a damaged one fertilizing an egg gets higher. Men in their 50s are three times as likely to have a child with schizophrenia as compared to 25 year old dads. These spontaneous mutations increase the number of schizophrenia gene versions in the population."

Male Biological Clock/Diseases That Seem To Come From Nowhere

The High Spontaneous Mutation Rate: Is it a health risk?

Undoubtably It is a tremendous health risk!


Growing evidence suggests that men may be the source of most new genetic mutations in the population, and thus may be responsible for the genetic diseases that seem to come from nowhere. In addition, the older a man gets, the more likely his sperm is to carry genetic mutations.

Statistical evidence supports the premise that an older father is likelier to sire a child with a birth defect than a younger man.

"The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age." "I conclude that for a number of diseases the mutation rate increases with age at much faster rate than linear. This suggests that the greatest mutational hazard in the human population at present is fertile old males."


James F. Crow, University of Wisconsin 1994, Proceedings of the National Academy of Sciences United States of America

Growing Evidence Shows That The Offspring Of Older Fathers Have An Increased Risk of birth defects, some cancers and schizophrenia and autism

My modest intentions at the end of October 2006 were to gather in one place all the articles that link genetic disorders of all kinds with older fathers at the time of conception. I certainly do not have all the studies that have linked aging fathers 33 and over with an increasing risk of genetic disorder in their offspring, but I do present quite a few so far.


In 1912 , a German obstetriction named Wilhelm Weinberg realized that achondroplasia, an inherited form of dwarfism, was more common in the youngest children of large families than their older siblings. In 1955 British geneticist Lionel Penrose pinned the condition to aging fathers and, specifically to gene mutations within their sperm. At least 35 rare genetic disorders have been linked to older fathers.
In an article called, Genetic disease in the offspring of older fathers, by geneticist JM Friedman, published in 1981 it is noted that risk of disease due to new mutations among the offspring of fathers who are40 or older is similiar in magnitude to the risk of Down syndrome among the offspring of 35-40 year-old mothers. "Thus it is good public health policy to recommend that both men and women complete their family before age 40, if possible.