Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

J Gynecol Obstet Biol Reprod (Paris). 2010 Apr;39(1 Suppl):36-8.

[Influence of paternal age]
[Article in French]

Velez de la Calle JF, Broussin B, Lelaidier C, Fallet C.

Unité FIV, Clinique Pasteur, 34, Rue du Moulin à Poudre, Brest, France.

Abstract
Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

PMID: 20728806 [PubMed - in process]

Older Fathers: Increased risk of having children with autism, schizophrenia

Parenting
Older Fathers: Increased risk of having children with autism, schizophrenia
Older fathers: link to autism, schizophrenia.
By Paul Raeburn on January 28, 2009 - 1:52pm in About Fathers

Just after my two-year-old son, Henry, was born, I was surprised and disturbed to learn that he was at increased risk of autism, schizophrenia, bipolar disorder and other ills-because of my age.


My wife, Elizabeth, and I knew about the risks associated with the children of older mothers, with Down syndrome being the most widely recognized. She was tested for whatever was testable while she was pregnant with Henry, and he seemed to be healthy in every respect.

There is, however, no pre-natal test for autism or schizophrenia. And yet the risks are substantial: A 40-year-old man has the same chance of fathering a child with schizophrenia as does a 40-year-old woman of giving birth to a child with Down syndrome.

Why do we know so much about the genetic ailments associated with older mothers, but almost nothing about the diseases associated with older fathers?

In an article I've just written for Scientific American Mind, I note that the number of older fathers is on the rise, meaning the number of children at increased risk for autism and schizophrenia is also on the rise.

Nobody understand why this should be true. A woman's eggs are constructed and stored before she is born. It's reasonable to think that as they age, they might acquire genetic errors that could lead to disease. But sperm are freshly manufactured whenever they're needed; they are not stored. So what could be going on there?

The speculation is that something is going wrong with the so-called spermatogonial cells, the factories that make sperm. It's unclear what is happening, but the situation clearly deserves further research.

And why are older fathers not told of the risks?

That seems wrong to me. Some time ago, I called Charles J. Epstein, past president of the college of medical genetics, and Marilyn C. Jones, the current president, and asked them if they could explain why this don't ask-don't tell policy made sense, especially considering the new findings. "To put it out there every time somebody comes to you for counseling probably engenders more fear than light," Epstein said.

Jones agreed. "Paternal age is usually not addressed in counseling couples of advanced age because there is no simple test to address the risk," she said. "If there is nothing to offer a couple but increasing anxiety, many counselors and physicians do not bring the issue up."

Why then all the fuss about Down syndrome in the children of older women, when the risks for the children of older fathers are about the same? "You bring up Down syndrome, because you get sued if you don't," Epstein said. "And there are options. You can go through prenatal diagnosis, you have the option to terminate."

Epstein points out that the general rate of abnormalities of all kinds in newborns is about 2-4%. So even a 3% risk of schizophrenia in the children of men over 50 is not out of line with other risks. And it sounds less frightening when put this way: A 50-year-old man has a 97% chance of having a child without schizophrenia.

Still, I wish I had known what the risks were before we decided to have children. Would we have gone ahead anyway? That's difficult to say. But at least we would have had all the information we needed to make an intelligent decision.

Study Backs Link Between Father’s Age, Schizophrenia

Study Backs Link Between Father’s Age, Schizophrenia
ISLAMABAD: Children born to older fathers have a higher than normal risk of developing schizophrenia later in life, Swedish scientists said on Friday.
They suspect that accumulating mutations in the sperm of older men add to the risk of their children suffering from the psychotic disorder.
"There is an association between paternal age and the risk of schizophrenia in the offspring," Professor Finn Rasmussen, of the Karolinska Institute in Stockholm, told.
Other researchers have suggested such a link before but Rasmussen said his study of 700,000 people in Sweden is the largest and most significant.
"On a population level this is important because of the increasing paternal age of the population," he added.
Career demands and other factors have resulted in couples postponing having children. In England and Wales the average paternal age has increased from 29.2 in 1980 to 32.1 in 2002.
Rasmussen and his team, who reported their research in the British Medical Journal, estimated that the three-year age increase in the last 20 years could result in 12-15 percent more cases of schizophrenia.
The causes of schizophrenia are unknown. Scientists believe it affects chemicals in the brain and that there is a biological link which can predispose a person to the disease.
It affects about 24 million people worldwide, mostly in the 15-35 age group. Although it is a treatable illness, more than 50 percent of sufferers do not receive appropriate care, according to the World Health Organization.
Schizophrenia usually begins in the late teens and early 20s and is characterized by hallucinations, delusions, hearing voices and changes in behavior.
In their study of people born between 1973 and 1980, Rasmussen and his colleagues analyzed hospital admissions for schizophrenia and other disorders between 1989 and 2001.
They calculated that, overall, 15.5 percent of schizophrenia cases in the study group may have been due to the patient having a father who was over 30 years at the birth.
The risk increases with age, so a child born to a man of 50 could have a higher risk than one whose father was 30.
"The occurrence of mutation in sperm increases with age," Rasmussen added.

And, older fathers are more likely to have children with autism, schizophrenia, and Down syndrome and to have daughters who go on to develop breast ca

Buzzworthy


Unfortunate legacies
How a man lives, works and ages could have long-term implications for the health of his offspring, Science News writes, citing a growing body of research into the topic:

Teenage dads face increased risk that their babies will be born prematurely, have low birth weight, or die at birth or shortly afterward, a new study in Human Reproduction shows.

Babies of firefighters, painters, woodworkers, janitors, and men exposed to solvents and other chemicals in the workplace are more likely to be miscarried, stillborn, or to develop cancer later in life, according to a review in the February Basic & Clinical Pharmacology & Toxicology.

Fathers who smoke or are exposed at work to chemicals called polycyclic aromatic hydrocarbons put their children at risk of developing brain tumors.

And, older fathers are more likely to have children with autism, schizophrenia, and Down syndrome and to have daughters who go on to develop breast cancer.

It's all a matter of math, writer Tina Hesman Saey explains:

Women are born with all the eggs they will produce in their lifetime. The cells that give rise to eggs divide 24 times, all before birth. But the cells that produce sperm continue to divide throughout a man's lifetime. Each year after puberty, a man's sperm-producing cells replicate about 23 times. Every time the cells divide is another chance for error.

As a result, the sperm produced by a 40-year-old man have gone through about 610 rounds of replication. That's 610 chances of introducing a mutation in the DNA, or improperly divvying up genetic material.

Posted by Brian Chin at April 3, 2008 8:24 a.m.
Category: Science explains why
Comments

Reproducibility of the association between advanced paternal age and schizophrenia is suggestive of a Causal Link

Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population
Auteur(s) / Author(s)
TSUCHIYA Kenji J. (1) ; TAKAGAI Shu (1) ; KAWAI Masayoshi (1) ; MATSUMOTO Hideo (2) ; NAKAMURA Kazuhiko (1) ; MINABE Yoshio (1) ; MORI Norio (1) ; TAKEI Nori (1 3) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, JAPON
(2) Department of Psychiatry, Tokai University School of Medicine, Isehara, JAPON
(3) Division of Psychological Medicine, Institute of Psychiatry, London, ROYAUME-UNI

Résumé / Abstract
Objective: Advanced paternal age at birth as a risk for schizophrenia in the adult offspring has been reported in previous studies exclusively conducted in Western countries and Israel. The question has arisen whether this finding could be replicated in countries with socially and culturally different attitudes toward marriage, including factors such as age at marriage. To address this question, we conducted a case-control study of a Japanese population. Methods: The subjects were representative inpatients with a DSM-IV diagnosis of schizophrenia. Unrelated healthy volunteers were recruited as control subjects. This study was conducted as one of a series of the projects by use of The Mother and Child Health Handbooks (MCHHs), from which information on parental characteristics around the time of birth, including parental ages at birth, had been extracted and recorded on computer. Results: Ninety-nine subjects with schizophrenia and 381 healthy control subjects enrolled for the study. Advanced paternal, but not maternal, age was associated with an elevated risk for schizophrenia. Reproducibility of the association across different cultures is suggestive of a causal link.
Revue / Journal Title
Schizophrenia research (Schizophr. res.) ISSN 0920-9964
Source / Source
2005, vol. 76, no2-3, pp. 337-342 [6 page(s) (article)] (18 ref.)
Langue / Language
Anglais

Editeur / Publisher
Elsevier Science, Amsterdam, PAYS-BAS (1988) (Revue)


Copyright 2006 INIST-CNRS. All rights reserved

Toute reproduction ou diffusion même partielle, par quelque procédé ou sur tout support que ce soit, ne pourra être faite

MANY EXAMPLES OF DISEASES RESULTING FROM CHANGES IN COPY NUMBERS PROBABLY SOMETHING TO DUE WITH EGGS & SPERM

Charles Lee, Ph.D.

This analysis of so-called copy number variation (CNV) has now revealed some startling results.

It would seem the assumption that the DNA of any two humans is 99.9% similar in content and identity no longer holds.

The researchers were astonished to locate 1,447 CNVs in nearly 2,900 genes, the starting "templates" written in the DNA that are used by cells to make the proteins which drive our bodies.

This is a huge, hitherto unrecognised, level of variation between one individual and the next.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA," said Matthew Hurles, of the UK's Wellcome Trust Sanger Institute.

"One of the real surprises of these results was just how much of our DNA varies in copy number. We estimate this to be at least 12% of the genome.

"The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."

Evolving story

The new understanding will change the way in which scientists search for genes involved in disease.


"Many examples of diseases resulting from changes in copy number are emerging," commented Charles Lee, one of the project's leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, US.

"A recent review lists 17 conditions of the nervous system alone - including Parkinson's disease and Alzheimer's disease - that can result from such copy number changes."

Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

As well as aiding the investigation of disease and the development of new drugs, the research will also inform the study of human evolution, which probes genetic variation in modern populations for what it can say about their relationship to ancestral peoples.

----------------

285 of the approximately 3,000 CNVs are already known to be
associated with disease, and copy number variations of some of
these genes have been or are now being speculated as risk
factors for ailments such as AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease and
schizophrenia.
One interesting observation that the researchers made during this study was that many of the CNVs have
population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in
certain populations. For example, previous research found that the deletion of the UGT2B17 gene may lead to an
increased risk of prostate cancer in African American men. As a result of this and other research, the consortium is
expanding their studies to thousands of healthy individuals from populations outside of the HapMap collection.

Father's Age is a Major Risk Factor for Schizophrenia

Primary Psychiatry

Dr. Dolores Malaspina interviewed by Dr. Norman Sussman

What is the most irrefutable finding that you and your colleagues have made?
"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.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 Penrose 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."

Paternal age and intelligence: implications for age-related genomic changes in male germ cells.

Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY.
New York State Psychiatric Institute and Columbia University, New York, NY 10032, USA. dm9@columbia.edu

BACKGROUND: A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence.............................







with later paternal age lowering non-verbal IQ scores more than verbal IQ scores. CONCLUSION: We found independent effects of maternal and paternal age on offspring IQ scores. The paternal age effect may be explained by de novo mutations or abnormal methylation of paternally imprinted genes, whereas maternal age may affect fetal neurodevelopment through age-related alterations in the in-utero environment. The influence of late paternal age to modify non-verbal IQ may be related to the pathways that increase the risk for schizophrenia in the offspring of older fathers.

PMID: 15900226 [PubMed - indexed for MEDLINE

Evolution of male fertility as a function of age and risks in progeny

1: Contracept Fertil Sex (Paris). 1991 Nov;19(11):945-9. Links
[Evolution of male fertility as a function of age and risks in progeny][Article in French]
Auroux MR.
PIP: Testicular aging starts form age 30 with progressive deterioration of vascularization, the density of capillaries, the diminution of the efficacy of the blood-testis barrier, the aging of Sertoli cells, which results in fall of production of androgen-binding protein. These changes lead to a slow reduction of the number of spermatozoa, although it is their quality that is responsible for male fertility. Analysis of the number, morphology, and mobility of spermatozoa of men aged 25-59 showed that the quality varies depending on age: the maximum values are reached between age 25 and 35, decreasing afterwards. The aging finally results in a degradation of the number and especially in the quality of spermatozoa, which is not satisfactory in individuals of very young age either. Whether male of female, parental aging poses a problem, because fertility diminishes and the risk of anomalies of the conceptus increase with the age of parents. It has been demonstrated that the new, autosomal dominant mutations responsible for fetal deaths or the numerous malformation syndromes, such as achondroplasia, Apert's disease, ossifying fibrodysplasia, and Marfan's syndrome, may be linked to paternal aging. The frequency of each of these syndromes is very low: 15-28 cases per million births for achondroplasia. Also, the frequency of anomalies attributable to paternal aging after the 40s reaches .3-.5% of births. Neurofibromatosis or von Recklinghausen's disease, hemophilia A, the myopathy of Duchenne, schizophrenia, and the performance of 18-year-old males on psychometric tests have been associated with paternal aging. The aging of gonads cannot be prevented, but one could avoid the consequences of the aging of gametes by avoiding having children after 35 or 40 years of age. This has been recommended to women for about 15 years, and perhaps should also be recommended to men.

PMID: 12284763 [PubMed - indexed for MEDLINE]

Paternal Age Above 35

Paternal Ages Above and below 35 are associated with a different risk of schizophrenia
concerned heart View Delete
1: Eur Psychiatry. 2006 Dec 1; [Epub ahead of print] Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.
INSERM U675, 16 rue Henri Huchard 75018 Paris, France; AP-HP (Paris VII), C.H.U Louis Mourier, Service de psychiatrie du Professeur Ades, 178 rue des Renouillers, 92701 Colombes Cedex, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win((R))) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.

"I noticed that many children with schizophrenia had old fathers" Christina Dallman physician

Father's age raises schizophrenia risk

September 06 2002 at 06:55PM

Stockholm - Swedish scientists have found that older men face a much greater risk of fathering schizophrenic children than younger men.

Schizophrenia is a widespread and debilitating form of mental disease with symptoms ranging from delusions and an altered sense of self to apathy and social withdrawal.

Scientists at Sweden's Karolinska Institute found that children fathered by men aged 45 or older were three times as likely to develop schizophrenia as offspring of men aged 20-24.

"We already knew there was an increased risk when older women have children," Christina Dahlman, the physician who led the study, said.

"When I looked closer at the men, I noticed that many children with schizophrenia had old fathers."

The findings, released this week, support earlier studies by Israeli and American scientists.

As in many Western countries, couples in Sweden are delaying having their first child. In the past three decades, the average age of a first-time mother has risen by five years to 28,5 years.

Dahlman and colleague Peter Allebeck studied 524 schizophrenics for more than seven years and found that being fathered by an older man doubled the risk of developing the disease.

As most older men tended to have older wives, the cumulative risk was three times greater.

The reasons for the link were unclear, but Dahlman said sperm cell mutations, which increase with a man's age, have been known to cause various other diseases.

Children of older men may also lose their fathers at an early age, possibly increasing the risk of schizophrenia.

Around 24 million people worldwide suffer from schizophrenia, according to the World Health Organisation. Symptoms can be treated but there is no cure.

Like 35 and Down Syndrome for Women

Old fathers raise risk of brain disorder
By Jacqueline Maley
October 23, 2004
There is a "strong association" between men who become fathers after the age of 50 and of schizophrenia in their children, a study has found.

Swedish research that tracked over 700,000 young people found 15 per cent of schizophrenia cases could be attributed to older fathers. Researchers believe the link may be due to sperm mutations, which accumulate as men get older.

Compared with men who become fathers between 21 and 24, those who father children at the age of 50 or older have four to five times the chance of their offspring developing schizophrenia. The link was stronger if there was no family history of the disorder.

The link between schizophrenia and older paternity had been made before, but this was the first large study to look at a range of factors that could confound the results, said Professor John McGrath, a psychiatric epidemiologist at the Queensland Centre for Mental Health Research.

"If all babies had fathers less than 30, the paper suggests, the incidence of schizophrenia would reduce by 15 per cent," he said.

In the 1970s it was commonly believed that mothers caused their children's schizophrenia, Professor McGrath said. "There is now an interesting new lead looking at father's age, and this study adds weight to that.

"Schizophrenia is a group of brain disorders, and we're struggling to find out what causes them. This study ... will help to tease apart the causal pathway."

In Australia about 1 per cent of people develop schizophrenia. A study published in 2002 in People and Place, a Monash University journal, found consecutive generations of Australian men were becoming parents later.

In 2002 the average age of fathers was 32, compared with an average age of 29 in 1982, according to data from the Australian Bureau of Statistics.

The executive director of the mental health lobby group SANE Australia, Barbara Hocking, said the Swedish research, published in the British medical journal BMJ, was "major, major stuff".

She likened the research to the link between mothers over 35 and an increased risk of Down syndrome in their children. "It helps people understand what risk factors may be, so you can take action to reduce them."

Excepts from the Harvard Mental Health Letter September 2006

Minding Your Mind



New Key to Autism


September 25, 2006


By Michael Craig Miller, M.D.
Harvard Medical School

Convincing Evidence
What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older


This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Until recently, health care professionals have focused almost exclusively on the mother's age as a risk factor for health problems in the child. But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family.

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program.

Paternal Age as A Risk Factor CANADIAN JOURNAL OF PSYCHIATRY NOVEMBER 2002

Letters to the Editor

Paternal Age as a Risk Factor
Dear Editor:

Recent research reports have focused attention on the association between advanced paternal age and increased risk of schizophrenia in offspring (1,2). In addition to schizophrenia, numerous genetic illnesses are reported to have the same association with increased paternal age (3). An increased mutation rate related to increased paternal age has been documented in the male gametogenesis (4). Most of these illnesses are autosomal-dominant disorders (5). Two x-linked recessive illnesses—hemophilia A and Lesch-Nyhan disease—have been frequently found with increased maternal grandpaternal age (6–8). It is proposed that the origin of schizophrenia can in some cases be related to a mutation in the gametogenesis of the father that is related to aging. It is further proposed that, as with hemophilia A and Lesch-Nyhan disease, the mutated gene or genes in some cases of schizophrenia and other genetic illnesses can be transmitted to future generations. In such cases, the illness could be expressed in a distant relative far removed in time from the original mutational event. Further genetic research on germline mutations related to paternal age is needed to establish the significance of paternal age as a risk factor.

References
1. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, and others. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58:361–7.

2. Raschka LB. Parental age and schizophrenia. Magyar Andrologia [Hungarian Andrology] 1998;111:47–50.

3. Tarin JJ, Brines J, Cano A. Long-term effects of delayed parenthood. Hum Reprod 1998;13:2371–6.

4. Crow JF. How much do we know about spontaneious human mutation rates? Environ Mol Mutagen 1993;21:122–9.

5. Carothers AD, McAllion SJ, Paterson CR. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986;23:227–30.

6. Rimoin DL. Mutation in man. In: Emery AEH, Rimoin DA, editors. Principles and practice of medical genetics. Edinburgh (UK): Churchill Livingstone; 1983. p 32–3.

7. Crow JF. The high spontaneious mutation rate: is it a risk? Proc Natl Acad Sic USA 1997;94:8380–6.

8. Prevention of avoidable mutational disease: memorandum from a WHO meeting. Bull World Health Organ 1986;64:205–16.

Leslie B Raschka, MD, FRCPC
Toronto, Ontario

The Age of the Father and the Health of Future Generations by Leslie B. Raschka M.D.

THE AGE OF THE FATHER AND THE
HEALTH OF FUTURE GENERATIONS
Word Count: 903
　
Leslie B. Raschka M.D., Associate Professor (retired),
Department of Psychiatry, University of Toronto
Address: 27 Edgecombe ave, Toronto, Ontario, Canada
M5N 2Xl, Tel. (416) 783-6938
2
Abstract
Purpose: To assess the role of paternal age in the origin of genetic illness in future generations.
Data Sources: All reference data originated in English language international scientific literature and findings of original research conducted by myself.
Study Selection: Original articles published between 1938 and 1998 were selected according to the stated purpose. One article was written by myself.
Data Extraction: The present paper deals with 4 subtopics: andrology, genetics, pathology, and psychiatry.
Results: Nine articles reporting on 1399 patients described the deterioration of the quality of semen related to ageing. Five articles reported an increased mutation rate in the male germ cells as compared to the female germ cell. Twenty-four articles reported on 1230 patients and related studies described paternal age effect on increased mutation rate causing genetic illness. Eight articles reporting on 10,347 patients described increased prevalence of mental illness as related to older paternal age.
Conclusions: The age of the father is an important determinant of the health of future generations. Children conceived by fathers older than 36 years of age are at increased risk for genetic illness due to recent mutation in the male germ cell.
3The genetic illness of a child could originate in a mutation related to the age of the father or to a mutation in the spermatogenesis caused by ageing in previous generations. The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations.
　Key Words: Age of the father, mutation, genetic illness
4 Demographic changes taking place in the 20th Century have directed attention to all possible determinants of the health of future generations. The relationship between maternal age and Down Syndrome is a currently recognized scientific fact. The study of the reproductive efficiency of the male is also relevant to the health of future generations. Most children are born healthy regardless of paternal age; however, the age of the father is a determinant of ill health for a significant minority in future generations.
　
5 Andrology
Ageing in the male is expressed in a progressive decline both in the quality and quantity of the sperm (1). Changes include a decrease in motility (2), decreased vitality and an increased percentage of malformed sperm (3, 4, 5, 6, 7). The deterioration associated with ageing can be noticed first in men between the ages of 35 to 40 years (8, 9).
　
6 Genetics
The mutation rate is higher in the male than in the female germ cell (10, 11, 12, 13, 14). While the ageing male germ cell is especially sensitive to mutation (15) there is a significant difference in mutation, rates among different genes. There is evidence that mutation frequencies for a number of different genes causing illness increase with advancing paternal age. The rate of increase differs among different genes (16); not all genes are subject to the paternal age effect. Almost all new mutations were reported to occur in the male germ cell; however, paternal age effect is not equally pronounced in all mutations (12). It is operant in recent germline mutations. Inherited illnesses such as hemophilia A have their origins in mutations in earlier generations where, for example, increased maternal grandparental age was found and new germline mutation related to increased paternal age transmitted to future generations can result in hereditary illness. In the development of illness, more than one gene can be involved. The phenotypic expression can be influenced by modifying genes. The importance of mutations for the health of future generations was born out by the Bulletin of the World Health Organization 1986 (17), which states that about 1% of children will be born with a serious genetic disease and another 1% will develop a serious genetic illness later in life.
7 Pathology
The relationship between increased paternal age and pathological conditions of known genetic origin was reported for achondroplasia in nineteen publications (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34); for Apert Syndrome in sixteen publications (15, 19, 20, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35); on Marfan Syndrome in thirteen publications (15, 20, 21, 22, 23, 25, 26, 27, 30, 31, 32, 33, 34); on osteogenesis imperfecta in five publications (16, 19, 24, 25, 29); on basal cell naevus syndrome in three publications (22, 26, 32); in Waardenburg Syndrome in five publications (22, 26, 31, 32, 33); on Crouzon Syndrome in seven publications (22, 26, 28, 31, 32, 33, 35); on oculo-denta; digital syndrome in four publications (22, 26, 31, 32); on thanatophoric dysplasia in three publications (28, 29, 35); on Pfeiffer Syndrome in three publications (28, 32, 35); on tuberous sclerosis in three publications (31, 33, 36); on multiple endocrine neoplasm in three publications (32, 34, 37); on myositis ossificans in nine publications (15, 19, 21, 22, 24, 30, 31, 32, 33); and on Treacher Collins disease, four publications (22, 26, 31, 33). All of these illnesses are transmitted in an autosomal dominant fashion. Increased risk for X-linked conditions associated with increased maternal grand-parental age is known to exist regarding classical hemophilia and was reported in nine publications (15, 17, 23, 25, 26 31, 32, 34, 38). This is also true for Lesch-Nyhan syndrome, reported in five publications (10, 17, 27, 31, 38). The mutation is transmitted to the child through carrier mothers.
8Psychiatry
Mutations occurring in the course of gametogenesis in the male and the association of psychosis was described in one article (39). Older maternal and paternal age in schizophrenia was reported in four articles (39, 40, 41, 42). My own study involving 574 patients has shown that the increased age of the father is a causative factor in a sub-group of the schizophrenic population (43). Two other articles, reporting on 662 and 8000 patients respectively, confirmed my conclusions, as well as indicating that increased maternal age was secondary to increased paternal age (41, 42). Three articles reporting on 1081 patients described increased paternal age in Alzheimer’s disease (44, 45, 46).
　
9 Discussion
All genetic illnesses have their origin in a distant or recent mutation. Paternal age is an important determinant of mutation frequency in new germ cell mutation, causing both autosomal dominant and X-linked recessive illnesses. The role of other mutagenic factors is not the subject of this study. The results of my own research are supported by other information which indicates that the leading cause of genetic illness present in human populations is the ageing process in the male. Conceiving children by men younger than 35 years of age would prevent many genetic illnesses in future generations.
　
10 Bibliography
1. Johnson L, Nguyen H B, Petty C S, et al. Quantification of Human Spermatogenesis: Germ Cell Degeneration during Spermatocytogenesis and Meiosis in Testes from Younger and Older Adult Men. Biol Reprod 1987; 37: 739.
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If all babies had fathers less than 30, the paper suggests the incidence of schizophrenia would reduce by at least 15%

Like the discovery of the connection between mothers over 35 and Down Syndrome Swedish Research that tracked over 700,000 young people published in 2004.



There is a "strong association" between men who become fathers after the age of 50 and of schizophrenia in their children, a study has found.

Swedish research that tracked over 700,000 young people found 15 per cent of schizophrenia cases could be attributed to older fathers. Researchers believe the link may be due to sperm mutations, which accumulate as men get older.

Compared with men who become fathers between 21 and 24, those who father children at the age of 50 or older have four to five times the chance of their offspring developing schizophrenia. The link was stronger if there was no family history of the disorder.

The link between schizophrenia and older paternity had been made before, but this was the first large study to look at a range of factors that could confound the results, said Professor John McGrath, a psychiatric epidemiologist at the Queensland Centre for Mental Health Research.

"If all babies had fathers less than 30, the paper suggests, the incidence of schizophrenia would reduce by 15 per cent," he said.