Sperm Cryopreservation? Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation

I used to think that men could solve the problem of the male biological clock by cryopreserving sperm in their mid 20s but Dr. Maurice Auroux says there are some problems associated cryopreserving sperm and embryos.


Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation.Auroux M.
CHU de Bicêtre (Université Paris-Sud), Andrologie et Biologie de la Procreation, Le Kremlin-Bicêtre, France.

In addition to gross malformations, many problems relating to the formation of gametes and embryos can generate, within a continuum of abnormalities, a number of problems that are less evident. On the basis of genetic and/or biochemical or cytological changes, these effects generally appear long after birth as functional difficulties that range from growth changes and altered endocrine functions and cancer to very late behavioural disorders. Such problems may have effects on males and females before conception, on the embryo during gestation, and may also impact on the success of assisted reproduction techniques. For this reason, we have examined the experimental and clinical data that indicate the long-term consequences, for progeny, of iatrogenic and toxic environmental factors on the male reproductive system, and in particular the effect that one specific condition-cryopreservation-may have on gametes and the conceptus. We then focus on the interpretation given to these data which, in general, emphasize the need not only for further experiments to help understand the mechanism of anomalies and increase the level of vigilance in humans, but also to extend follow-up investigations in children.

PMID: 11129688 [PubMed - indexed for MEDLINE]

Why Is The Next Generation of Adults Fatter, More Asthmatic, and Suffering From Far More Neurological Disorders Than Any Previous Generation

"According to a new report out today, the health care system faces an unprecedented public health time bomb: the next generation of young people is going to need far more in the way of health care services than previous 20- and 30-something generations.

You’d think that with 77 million baby boomers moving toward retirement where taxpayer-financed Medicare picks up the health care tab, employers would get some breathing room. Younger workers generally require much less health care, which translates into lower insurance costs for those who employ them.

But the study in this week’s Journal of the American Medical Association documents a grim prognosis for the next generation of workers: they are going to be fatter, more asthmatic, and suffering from far more neurological disorders than any previous generation of American young people. And its young people who are most likely to go without health care coverage.

“We’re going to see increased health expenditures for people in their 20s,” said James Perrin, a professor of pediatrics at the Harvard Medical School and lead author of the report. “They’ll be coming to institutions for health care without any means of paying for it.”

How bad is it? About 18 percent of American children and adolescents are now considered obese, up from just five percent in the early 1970s when the baby boomers were entering the workforce. That translates into earlier onset of type 2 diabetes, hypertension and heart disease, chronic conditions that usually require ongoing, often lifelong medical interventions. With obesity already accounting for 10 percent of medical expenses, a doubling of adult rates will add $100 billion a year to health care costs, according to the study.

Childhood asthma persists into adulthood for about a quarter of all persons afflicted with the wheezing disorder. And today, about one in every 11 young persons has asthma, double the rate of the 1980s. Again, that translates into millions of young workers who will need immediate health care assistance as they enter the workforce, even as they lose work days and productivity because of their condition.

Ditto for neurological disorders like attention deficit and autism, which were virtually unheard of in the 1960s and 70s. Perrin and his fellow authors admit that some of the reported rise in these conditions may be associated with diagnostic creep. But whatever the cause, children who need treatments are much more likely to turn into adults who need treatment, and that translates into higher health care costs. “Employees with mental health conditions generate about three times the health care costs of other employees,” the authors noted.

Finally, blacks, Hispanics, Native Americans and low-income whites suffer far higher rates of obesity, asthma and attention deficit disorder compared to their better-off counterparts. These are precisely the groups in society most likely to be without health insurance.

The social factors behind these escalating childhood and adolescent epidemics are well-known: rising income inequality, poor diet, unrestricted television junk food advertising aimed at children and young adults, sedentary lifestyles, rising rates of pre-term and multiple births, environmental exposures – especially for poor, urban children. Universal health care does nothing to solve any of these problems.

We’ve already been told that if the social factors leading to these epidemics go unaddressed, the next generation of Americans may be the first in our history to lead shorter lives. What this latest study points out is that they’re also going to consume a lot more health care all along the way......."

Learn About the Paternal Age Effect and Have Healthier Children

Angus Clarke, "I am aware of the paternal age effect in many disorders and in clearly this is the case in autism..."

Professor Angus Clarke
Principal Investigator and Professor in Clinical Genetics




Angus Clarke was born in 1954. He studied Medical and Natural Sciences in Cambridge, taking his Part II in Genetics, and then qualified in Medicine from Oxford University in 1979. After registration, he worked in general medicine and then paediatrics. As a research registrar in the Department of Medical Genetics in Cardiff, he studied the clinical and molecular genetic aspects of ectodermal dysplasia. Subsequently, he worked in clinical genetics and paediatric neurology in Newcastle upon Tyne, developing an interest in Rett syndrome and neuromuscular disorders.

He returned to Cardiff in 1989 as Senior Lecturer in Clinical Genetics. He is now Professor in Clinical Genetics. As well as teaching he also works as a clinician. With his colleague, Peter Harper, he wrote the book, Genetics, Society and Clinical Practice. He directs the Cardiff MSc course in Genetic Counselling.

Research interests:
social and ethical issues raised by advances in human genetics
the genetic counselling process




"I am aware of the paternal age effect in many disorders - and clearly in the case of autism, as with this one family. I am not aware of it in relation to autism in general - but there are cerainly a number of grounds for discouraging the deferral of child bearing to older ages (for men and women) including gene mutations, chromosome anomalies and reduced fertility. Education about the disbenefits of deferring child bearing is important but it is unclear how to achieve this as education is probably a weak force when it is asked to effect major change in a powerful social force.

Don't think that the problems of later child bearing are unrecognised - but if you have useful ways of addressing this then of course do share these"

Best wishes,

Angus Clarke

Older men have an increased risk of having a child with abnormalities, new research suggests. Old research suggests this too

Irish Health Headlines

Birth Defects Higher Among Children with Older Fathers

Older men have an increased risk of having a child with abnormalities, new research suggests.

The common belief is that there is no age limit for men when it comes to fathering a child. Unlike women who undergo menopause, men do not have a fixed “andropause”. However, this view is being challenged as new evidence shows that the rates of birth defects such as achondroplasia (short stature) and autism is higher among children with older fathers.

A recent study carried out at a large Israeli army database found that children of men over 40 were 5.75 times more likely to have an autism disorder than those who had fathers under 30. Another Israeli study suggested that the risk of schizophrenia in children is almost double if the father is in his late 40s.

Prof Sheena Lewis, a consultant in reproductive medicine at Queen's University Belfast, said that as men get older their sperm DNA becomes more fragmented. By the time a man is 50, the cells that create a man’s sperm have replicated up to 800 times, creating many possibilities for error.

According to Prof Lewis:

Anonymous on-line survey for parents of children with autism spectrum disorders up and running

Advanced Grandparental Age as a Risk Factor for Autism

This study is currently recruiting patients.
Verified by University of Mississippi Medical Center June 2007

Sponsored by: University of Mississippi Medical Center
Information provided by: University of Mississippi Medical Center
ClinicalTrials.gov Identifier: NCT00464477


Purpose

The Division of Medical Genetics at the University of Mississippi Medical Center is recruiting parents of children with a pervasive developmental disorder (including autism, autistic spectrum disorder, PDD-NOS, Asperger syndrome, childhood disintegrative disorder, and Rett syndrome) to participate in a study to help determine potential causes of the increasing prevalence of these disorders. The study is being conducted using an anonymous on-line survey available to parents through a secure link.

The study consists of approximately 90 questions about the affected child, siblings, parents, and grandparents, which will take roughly 10-15 minutes to complete. Several families will also be invited to participate in a phone interview. Both the survey and the phone interview are conducted using a self-designated code to protect anonymity and patient privacy. No identifying information such as name, date of birth, address, or phone number will be asked. Only questions regarding the year of birth of family members will be asked.

Condition
Autistic Disorder
Pervasive Developmental Disorder
Asperger Syndrome
Childhood Disintegrative Disorder
Rett Syndrome


MedlinePlus related topics: Asperger's Syndrome; Autism; Mental Health; Rett Syndrome
Genetics Home Reference related topics: Rett syndrome

Study Type: Observational
Study Design: Natural History, Cross-Sectional, Random Sample, Retrospective Study

Official Title: Advanced Grandparental Age as a Risk Factor for Autism and Other Pervasive Developmental Disorders

Further study details as provided by University of Mississippi Medical Center:

Total Enrollment: 100
Study start: June 2007; Expected completion: December 2007


Autism is a genetically heterogeneous entity. Although numerous studies have demonstrated a strong genetic basis, no clear etiology has been identified to date. Recently, two studies have demonstrated an increased risk of autism in children born to fathers over the age of 40. However, given the large male-to-female predominance of autism, it is likely that new mutations on the X chromosome account for a significant number of affected cases. Due to the maternal origin of the X chromosome in males, we hypothesize that advanced maternal-grandpaternal age may also be a risk factor for autism. Precedence for this theory exists with other X-linked disorders such as Duchenne muscular dystrophy and Rett syndrome. Additionally, it has been demonstrated that maternal psychiatric illness, but not paternal psychiatric illness, is more prevalent among parents of children with autism. Using anonymous surveys of families with autistic children, we seek to identify the ages of grandparents at the time the parents were born in order to determine if advanced maternal-grandpaternal age is associated with an increased risk for autism when adjusted for advanced maternal and paternal age. Additionally, we will seek out sister-pairs in order to identify any statistical significance between the ages of the maternal grandfather at delivery of each sister. If advanced maternal-grandpaternal age is, in fact, a risk factor, it would help direct molecular researchers towards genes on the X chromosome as potential etiologies for autism. Also, further study of potential mutagenic exposures in the environment of grandparents may help elucidate the reason for the increasing incidence of autism in recent decades.
Eligibility

Genders Eligible for Study: Both
Criteria
Inclusion Criteria:

Individuals of any age with autism, autistic disorder, autistic spectrum disorder, Asperger syndrome, pervasive developmental disorder, PDD-NOS, Rett syndrome, or Childhood disintegrative disorder
Location and Contact Information

Please refer to this study by ClinicalTrials.gov identifier NCT00464477

Omar Abdul-Rahman, MD 601-984-1900 OAbdulrahman@prevmed.umsmed.edu


United States, Mississippi
University of Mississippi Medical Center, Jackson, Mississippi, 39216, United States; Recruiting
Omar Abdul-Rahman, MD 601-984-1900 OAbdulrahman@prevmed.umsmed.edu



Study chairs or principal investigators

Omar Abdul-Rahman, MD, Principal Investigator, University of Mississippi Medical Center
More Information

If you would like to participate in this anonymous on-line survey, please go here

Study ID Numbers: 2007-0023
Last Updated: June 18, 2007
Record first received: April 20, 2007
ClinicalTrials.gov Identifier: NCT00464477
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on June 20, 2007

So Why Not Inform The Public About the Risk Factors For Autism CDC????

The CDC/goverment could have announced in 1958 the warning that older fathers and schizophrenia were connected. They certainly could have done so in 2001. If the pharmaceutical industry/academic research industry is going to profit from an announement the public will hear about it immediately. If the public could prevent schizophrenia, autism, diabetes, Alzheimer's, cancers, mental retardation, in their children through knowing to father babies before 33 the public will not be told and the disorders will be called of "mysterious origin".

Autism and Mystery fits the Interest of Those Who Profit from Autism, Most Psychiatrists in Schizophrenia and Autism research know full well the risk factors.

Remember that childhood schizophrenia is no longer diagnosed since 1994, it is called autism and sporadic schizophrenia is proven to be caused by older men fathering babies. By 33 the sperm stem cells are rapidly accumuating changes in DNA.Women whose father's were older when they were conceived are at a very high risk of having children with genetic disorders. So are people with diabetes, autoimmune thyroid disorders and other autoimmun disease.
Why The Problem with Vaccinations in Autism?

OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates among patients with schizophrenia than among comparison subjects (crude incidence rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher prevalence rates among parents of schizophrenia patients than among parents of comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8). Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren’s syndrome had higher prevalence rates among patients with schizophrenia than among comparison subjects and also among family members of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.




THE GENETICS OF AUTISM
OVERVIEW
Autism is a severe neurodevelopmental disorder of unknown etiology, with profound consequences for affected individuals and their families. Autism is the classical pervasive developmental disorder (PDD); a group of disorders which also includes Asperger’s syndrome, atypical autism, childhood disintegrative disorder, PDD not otherwise specified (PDDNOS) and Rett syndrome. These disorders are classically defined by a combination of qualitative impairments in three principal areas: verbal and non-verbal communication, reciprocal social interaction, and repetitive and stereotyped patterns of interests and activities.

There is now convincing evidence from twin and family studies for the involvement of genetic factors in the development of autism. The absence of any strong consistent evidence for an environmental, biochemical or neuroanatomical cause has led to an increasing number of genetic studies worldwide to determine the basis of this complex disorder.

]

The Autism /Vaccines Connection is not the Mercury/Thimerisal it is the Inability to Handle The Antigens Themselves

The Causes of autism are not at all a mystery. The people calling it mysterious know very well the many routes to autism which used to be called early childhood schizophrenia in many of the cases. The diagnostic manual has also lumped what used to be called mental retardation into the autism category. Older father's mutations in sperm stem cell DNA are the cause of a great deal of mental retardation. We need to be educated about the male biological clock.

People need to understand the connections between autoimmune disorders, late paternal age (33+), older maternal grandfathers, family history of ASDs, schizophrenia, OCD, and having an autistic child. If they choose to risk this afflication in their children they should be careful about the vaccine schedule.

In genes controlling the development of the brain and nervous system. Many other lesser genetic disorders are also caused by genetic changes in sperm DNA that increase with a man's age. The Center for Disease Control will never inform the public, nor will the NIH, or NIMH, or NARSAD or NAMI.

If you want to do something to prevent autism get informed by reading about it. No one is going to tell the public that older paternal age is past 31 32 and is that increasing genetic disorders in offspring is the male biological clock caused by mutations in sperm DNA. Sperm come from somehere, they are not made fresh out of nothing. Everyone in the field of autism/schizophrenia research knows that the incidence increases with paternal age and maternal grandparental age at the mother's birth. Most researchers are happy to keep this secret from the public and get funded to do research that does nothing postitive but make more money for themselves, pharmceutical companies and genomic studies institutes. They will take your genes to make money for themselves and not help your child.

With the number of men fathering over 35, when over 33 is old and dangerous, there has to be more autism./schizophrenia, diabetes, MS, Lupus, fibromyalgia, endometriosis, Alzheimer's disease, heart disease, Crohn's disease, IBD, Duchenne's, hemophilia, prostate cancer, breast cancer, colon cancer, ovarian cancer, etc. etc. etc.

Some industries are very happy about the rise in autism/schizophrenia think pharmaceuticals, academia,psychiatric researchers on the whole, special ed etc. The March of Dimes is set up to distract from Paternal Age as the major cause of birth defects. Many researchers with big research departments know that their whole professional life revolves around the fact that no one informed the public in the 1950s that older paternal age causes birth defects and damaged children. Any researcher who try to inform of the connection was called crazy and not allowed to publish in any reputable journal. It is a bit like the connection between smoking and cancer, we have been taught that older fathers are wonderful and to be admired. This is pure PR.

For a good discussion on the paternal age roots of non-familial schizophrenia including childhood schizophrenia/autism, its name since 1994, read through the following paper by Dr. Dolores Malaspina, Chair of the Department of Psychiatry at NYU School of Medicine.

Schizophrenia Risk and the Paternal Germ LineBy Dolores Malaspina
Dolores Malaspina

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.
Seminal findingsWe initially examined the relationship between paternal age and the risk for schizophrenia because it is well established that paternal age is the major source of de novo mutations in the human population, and most schizophrenia cases have no family history of psychosis. In 2001, we demonstrated a monotonic increase in the risk of schizophrenia as paternal age advanced in the rich database of the Jerusalem Perinatal Cohort. Compared with the offspring of fathers aged 20-24 years, in well-controlled analyses, each decade of paternal age multiplied the risk for schizophrenia by 1.4 (95 percent confidence interval: 1.2-1.7), so that the relative risk (RR) for offspring of fathers aged 45+ was 3.0 (1.6-5.5), with 1/46 of these offspring developing schizophrenia. There were no comparable maternal age effects (Malaspina et al., 2001).
Epidemiological evidenceThis finding has now been replicated in numerous cohorts from diverse populations (Sipos et al., 2004; El-Saadi et al., 2004; Zammit et al., 2003; Byrne et al., 2003; Dalman and Allenbeck, 2002; Brown et al., 2002; Tsuchiya et al., 2005). By and large, each study shows a tripling of the risk for schizophrenia for the offspring of the oldest group of fathers, in comparison to the risk in a reference group of younger fathers. There is also a "dosage effect" of increasing paternal age; risk is roughly doubled for the offspring of men in their forties and is tripled for paternal age >50 years. These studies are methodologically sound, and most of them have employed prospective exposure data and validated psychiatric diagnoses. Together they demonstrate that the paternal age effect is not explained by other factors, including family history, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, and birth complications. Furthermore, the paternal age effect is specific for schizophrenia versus other adult onset psychiatric disorders. This is not the case for any other known schizophrenia risk factor, including many of the putative susceptibility genes (Craddock et al., 2006).
There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study. The data support the hypothesis that paternal age increases schizophrenia risk through a de novo genetic mechanism. The remarkable uniformity of the results across different cultures lends further coherence to the conclusion that this robust relationship is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, which is independent of regional environmental, infectious, or other routes.
Indeed, the consistency of these data is unparalleled in schizophrenia research, with the exception of the increase in risk to the relatives of schizophrenia probands (i.e., 10 percent for a sibling). Yet, while having an affected first-degree relative confers a relatively higher risk for illness than having a father >50 years (~10 percent versus ~2 percent), paternal age explains a far greater portion of the population attributable risk for schizophrenia. This is because a family history is infrequent among schizophrenia cases, whereas paternal age explained 26.6 percent of the schizophrenia cases in our Jerusalem cohort. If we had only considered the risk in the cases with paternal age >30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. 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.
Biological plausibilityWe used several approaches to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, we established a translational animal model using inbred mice. Previously it had been reported that the offspring of aged male rodents had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies (Auroux et al., 1983). Our model carefully compared behavioral performance between the progeny of 18-24-month-old sires with that of 4-month-old sires. We replicated Auroux's findings, demonstrating significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires (Bradley-Moore et al., 2002).
Next, we examined if parental age was related to intelligence in healthy adolescents. We reasoned that if de novo genetic changes can cause schizophrenia, there might be effects of later paternal age on cognitive function, since cognitive problems are intertwined with core aspects of schizophrenia. For this study, we cross-linked data from the Jerusalem birth cohort with the neuropsychological data from the Israeli draft board (Malaspina et al., 2005a). We found that maternal and paternal age had independent effects on IQ scores, each accounting for ~2 percent of the total variance. Older paternal age was exclusively associated with a decrement in nonverbal (performance) intelligence IQ, without effects on verbal ability, suggestive of a specific effect on cognitive processing. In controlled analyses, maternal age showed an inverted U-shaped association with both verbal and performance IQ, suggestive of a generalized effect.
Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.
A variant of schizophreniaA persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).
It is possible that the genetic events that occur in the paternal germ line are affecting the same genes that influence the risk in familial cases. However, there is evidence that this is not the case. First, a number of the loci linked to familial schizophrenia are also associated with bipolar disorder (Craddock et al., 2006), ), whereas advancing paternal age is specific for schizophrenia (Malaspina et al., 2001). Next, a few genetic studies that separately examined familial and sporadic cases found that the "at-risk haplotypes" linked to familial schizophrenia were unassociated with sporadic cases, including dystrobrevin-binding protein (Van Den Bogaert et al., 2003) and neuregulin (Williams et al., 2003). Segregating sporadic cases from the analyses actually strengthened the magnitude of the genetic association in the familial cases, consistent with etiological heterogeneity between familial and sporadic groups.

Read Dr. Malaspina's whole paper and its sources.

See the following post for autism as an extreme autoimmune disorder related to a family history of autoimmune disorders caused by older paternal age in one generation or another.


Pediatrics. 2003 Nov;112(5):e420. Links
Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders.Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ.
Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children Indianapolis 46202-4800, USA.
OBJECTIVES: Increased prevalence of familial autoimmune disease is a common finding among probands with various autoimmune disorders. Autistic disorder (autism) is a highly genetic disorder with known immune and immunogenetic abnormalities. Previous research has found an increased frequency of autoimmune disorders in families with autistic probands. We further investigated this association by determining the frequency of autoimmune disorders in families that have probands with pervasive developmental disorders (PDDs), including autism, compared with 2 control groups. METHODS: Three well-defined study groups, including 1) families that have a child with a PDD, 2) families that have a child with an autoimmune disorder, and 3) families with a healthy control child, constituted the sample. A questionnaire inquiring about which first- and second-degree family members had received a diagnosis of having specific autoimmune disorders was completed by 101 families in each group. RESULTS: The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto's thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. CONCLUSIONS: Autoimmunity was increased significantly in families with PDD compared with those of healthy and autoimmune control subjects. These preliminary findings warrant additional investigation into immune and autoimmune mechanisms in autism.

PMID: 14595086 [PubMed - indexed for MEDLINE]

The Observed Human Sperm Mutation Frequency Cannot Explain the Achondroplasia Paternal Age Effect

Published online before print October 23, 2002, 10.1073/pnas.232568699
PNAS | November 12, 2002 | vol. 99 | no. 23 | 14952-14957


The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect
Irene Tiemann-Boege *, William Navidi , Raji Grewal , Dan Cohn ¶, Brenda Eskenazi ||, Andrew J. Wyrobek **, and Norman Arnheim *

*Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340; Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401; New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08820;¶ Burns and Allen Cedars-Sinai Research Institute/Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; ||School of Public Health, University of California, Berkeley, CA 94720; and **Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94550

Communicated by Michael S. Waterman, University of Southern California, Los Angeles, CA and approved September 19, 2002 (received for review August 10, 2002)





The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (FGFR3) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay.


Abbreviations: FGFR, fibroblast growth factor receptor; USC, University of Southern California; LLNL, Lawrence Livermore National Laboratory; kt-PCR, kinetic PCR; C.I., confidence interval



--------------------------------------------------------------------------------
Geneticists and evolutionary biologists debate the extent to which the lifelong spermatogonial stem cell divisions unique to male gametogenesis contribute to a higher mutation frequency in males (1–8). One source of support for the hypothesis that mutations increase with spermatogonial stem cell divisions comes from the observation of certain human genetic conditions where the incidence of new mutations increases with the age of the father. Epidemiological studies on a number of dominantly inherited conditions indicate that the average age of the fathers is older among unaffected couples having a child with the condition (a sporadic case caused by a new mutation), than the average paternal age in the population (1, 2, 4, 7). Achondroplasia, the most common form of dwarfism, is one of these conditions (9–11). Studies on sporadic achondroplasia cases have reported an exponential increase with paternal age (1, 2, 4, 7, 10).
In mice, a significant increase in the overall male germ cell mutation frequency as measured by the lacI assay was observed between 15 and 28 months of age (12). In humans, no direct molecular measurement of how germ-line nucleotide substitution frequencies change with age exists. Achondroplasia provides a unique opportunity to directly test the relationship between paternal age and sperm mutation frequency at the molecular level. First, 97–99% of the de novo mutations leading to this condition result from a G-to-A transition mutation at base pair 1138 (G1138A) in exon 10 of fibroblast growth factor receptor 3 (FGFR3) (13–15). The cytosine at base pair 1138 is part of a CpG dinucleotide and, if methylated, is highly susceptible to mutation caused by spontaneous deamination (16). Second, all sporadic achondroplasia cases have been found to inherit the G1138A mutation from their father (17). Third, recent data on the population incidence of sporadic achondroplasia (10, 18–20) predict the average frequency of sperm carrying the mutation in normal individuals will be in a range detectable by modern molecular methods (1/15,000 to 1/70,000). Our studies on sperm DNA from men of different ages suggest that the observed increase in G1138A mutation frequency cannot satisfactorily explain the exponential increase in sporadic achondroplasia cases with paternal age.......................








The lifelong spermatogonial stem cell replications have been suggested as an explanation for an increase in the frequency of mutant sperm that results in the increased incidence of sporadic achondroplasia with paternal age (1, 2, 4). A mathematical discrepancy between the cell replication model based on a linear equation to calculate the number of spermatogonial stem cell divisions (4, 26) and the exponential rise in sporadic achondroplasia with paternal age (1, 2, 4, 7, 10) has been pointed out (1, 2, 4, 7). Of course, other age-related mutation mechanisms that do not depend solely on premeiotic cell replications may be responsible for the birth data. However, no matter what the mutation mechanism, our direct measurement of the G1138A mutation frequency in sperm appears to rule out the idea that an age-dependent increase in sperm containing the GC-to-AT transition mutation at position 1138 explains the rapid rise in incidence of sporadic achondroplasia with paternal age (Fig. 3). Below, we discuss six possibilities that might account for this inconsistency.
Fathers of children with sporadic achondroplasia could form a subgroup with distinct mutation properties (because of genetic or environmental factors) compared with our sperm donors. To address this possibility, we studied sperm DNA from four men who fathered a child with achondroplasia. When matched for age to the appropriate sperm donor age group, two (ages 31 and 32) fell within the observed 95% C.I., a third (age 35) had counts that exceeded, by 2-fold, the upper bound of the 95% C.I., whereas the oldest father (age 51) had counts below the lower bound of the 95% C.I. Although the data suggest that fathers of sporadic cases are representative of our sperm donors, the sample size is small. Additional studies will be needed before we can exclude the possibility that population heterogeneity is the explanation for the discrepancy between our mutation data and the achondroplasia paternal age effect.

As yet unappreciated ascertainment biases in the population studies may have overestimated the magnitude of the age effect for the fathers of sporadic achondroplasia cases.

An age-related sperm donor sampling bias could underestimate an age trend in the G1138A frequency data although we can already exclude racial background as a source of bias between young and old donors in both study groups.

Our PCR assay is clearly biased toward overestimating the number of mutants in individuals with <15 counts (Fig. 1). Among the 118 sperm donors, 24 had <15 counts. To assess the impact of this bias, the age distribution of sperm donors expected to father children with sporadic achondroplasia was again compared with the actual age distribution after making a correction to the counts of all individuals with <15 G1138A mutants (Table 1). This correction favored the null hypothesis because it lowered the counts in the youngest age groups and increased the counts in the older age groups. Thus, for ages <40 we set counts <15 equal to 0, while for ages >40 we set counts <15 equal to 15. Despite this severe correction the null hypothesis was still rejected (log likelihood ratio = 20.7268 = 0.0033). The data from the USC and LLNL cohorts were also examined individually by using the same correction (see Table 3). Despite the lower sample size, the USC cohort gave a log likelihood ratio = 25.1466 (= 3.21 x 10–4). The LLNL cohort gave a log likelihood ratio = 10.6348 (= 0.100). Our rather extreme correction is exacerbated in the LLNL cohort because the 18- to 24-year-old category contains only six individuals and all but one of them have <15 counts.

Our results would be formally consistent with the null hypothesis if there was an age-dependent exponential increase in the formation of germ-line premutagenic lesions (16) at the G1138A site that are neither converted to a full mutation or repaired before fertilization (27). One obvious candidate for such a premutagenic lesion is an unrepaired G/T mismatch resulting from deamination of 5-methyl cytosine (16). The cytosine at base pair 1138 is highly methylated in sperm (data not shown and ref. 28). A single sperm with a G/T mismatch would produce PCR product in our assay. However, the observed counts from a population of such sperm would be half of that produced by the same number of sperm carrying A/T transition mutations. A second possible premutagenic lesion contains an apyrimidinic (AP) site on one strand caused by removal of a thymine at a GT mismatch by a glycosylase (16). Taq polymerase is known to pause significantly opposite an abasic site (29) and primers with an internal abasic site can be extended but the extension products are poorly copied during PCR (30). Also, exposure to high temperatures during PCR may lead to strand breaks at abasic sites. It is likely therefore that after the first two steps of our assay, the products from sperm containing a G/AP lesion would be far less than that from an equal number of mutant sperm carrying the AT bp leading to a significant underestimate of the frequency of this premutagenic lesion. Is there any evidence that premutagenic lesions in sperm can lead to achondroplasia? If unrepaired immediately after zygote formation, sperm carrying a G/T lesion would produce a mosaic embryo (+/+ and +/G1138A) after the first cell division. If a G/AP lesion is converted to a G/T or G/G mismatch after zygote formation the embryo can become mosaic for an G1138A or G1138C mutation, respectively, after the first cell division. The G1138C mutation is found in 2% of all sporadic achondroplasia cases (14). Because individuals with the achondroplasia phenotype that have been reported to be mosaic for the G1138A mutation are exceedingly rare (reviewed in ref. 31), cases of sporadic achondroplasia caused by the above repair patterns of premutagenic lesions are likely to be infrequent. On the other hand, sperm carrying a G/T premutagenic lesion could lead to achondroplasia if the G was replaced by an A immediately after zygote formation. The other immediate repair alternative would lead to a WT embryo. Virtually nothing is known about the relative likelihood of the repair alternatives before the first zygotic cell division in early mammalian embryos.

Finally, the discrepancy between the observed G1138A mutation frequency and the achondroplasia paternal age effect might be explained by selection. The G1138A mutation leads to an increased tyrosine kinase activity of FGFR3 protein and influences downstream signal transduction mediated by the Ras-mitogen-activated protein kinase-dependent and/or STAT1 signaling pathways, resulting in a variety of possible biological consequences (32). FGFR3 protein is found in all adult human male germ cells except elongating spermatids (33). The germ cells of the fetal, immature, and adult rat testis exhibit cell- and stage-specific localization of FGFs and FGFRs (including FGFR3 IIIc), which has been taken to imply that signaling via FGF ligands and receptors is spatially and temporally regulated in this organ (34). Although highly speculative, mature sperm derived from cells carrying the FGFR3 achondroplasia mutation may have a selective advantage for sperm motility or capacitation in utero. The molecular mechanisms involved in capacitation are not well known, but protein phosphorylation on tyrosine residues appears to be important (35) and relevant given FGFR3 function. To explain the paternal age effect, any selective advantage would have to increase with age perhaps in association with known changes that occur in the male reproductive system during normal aging (36).

more than 50% of families with 2 diffuse gastric cancer cases diagnosed prior to age 50 years will carry germline mutations in the CDH1 gene,"

Cancerpage.com
Both Independent and Germline Cadherin Mutations Underlie Diffuse ...
Cancerpage.com - Marietta,GA,USA
... more than 50% of families with 2 diffuse gastric cancer cases diagnosed prior to age 50 years will carry germline mutations in the CDH1 gene," they add. ...
See all stories on this topic Also a risk of breast cancer with these mutations.


1: JAMA. 2007 Jun 6;297(21):2360-72. Epub 2007 Jun 3.Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer.Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, Fontaine D, Coit D, Yoon S, Chung D, Lauwers G, Pizzuti A, Vaccaro C, Redal MA, Oliveira C, Tischkowitz M, Olschwang S, Gallinger S, Lynch H, Green J, Ford J, Pharoah P, Fernandez B, Huntsman D.
Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

CONTEXT: Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer. OBJECTIVE: To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry. DESIGN, SETTING, AND PATIENTS: Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations. RESULTS: Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%). CONCLUSIONS: Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.

PMID: 17545690 [PubMed - in process]

Will the Wellcome Trust and the Consortium Find that MS and Type 1 Look the Same Genetically Too? Paternal Age is High and These Disorders Increase

Do these variants come into the population with advancing paternal age? Is that why type 1 is almost 90% de novo/non-familial and rising 3% every year with high paternal age? Why is MS going to look like type 1 too?





High Average Paternal Age is Why Type 1 Diabetes, MS, Probably Crohn's, AutoImmune Thyroid Disorders INCREASE There Is A Male Biological Clock and Advancing Paternal Age Equals Genetic Disorders!



Source: Wellcome Trust
Date: June 7, 2007
More on: Diseases and Conditions, Diabetes, Chronic Illness, Stroke Prevention, Genes, Heart Disease

Largest Ever Study Of Genetics Of Common Diseases Published


"The link between type 1 diabetes and Crohn's disease is one of the most exciting findings to come out of the Consortium," says Professor John Todd from the University of Cambridge, who led the study into type 1 diabetes. "It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood and we hope that progress in treating Crohn's disease may give us clues on how to treat type 1 diabetes in the future."

Research from the Consortium has already played a major part in identifying the clearest genetic link yet to obesity and three new genes linked to type 2 diabetes, published in April in advance of the main study. It has found independently a major gene region on chromosome 9 identified by independent studies on coronary heart disease.

Researchers analysed DNA samples taken from people in the UK -- 2,000 patients for each disease and 3,000 control samples -- to identify common genetic variations for seven major diseases. These are bipolar disorder, Crohn's disease, coronary heart disease, hypertension, rheumatoid arthritis and type 1 and type 2 diabetes. For each disease, the researchers will study larger population samples to confirm their results.

Although the human genome is made up of more than three billion sub-units of DNA, called nucleotides (or bases), most of these show little in the way of differences between individuals. A substantial part of the variation in DNA sequence between individuals is due to single-nucleotide polymorphisms (differences), also known as SNPs. There are approximately 8 million common SNPs in European populations. Fortunately, because SNPs that lie close together on chromosomes often tell quite similar stories, researchers in the Consortium were able to explore this variation through analysing a subset of these SNPs (in fact approximately 500,000).

"Human genetics has a chequered history of irreproducible results, but this landmark collaboration of scientists in Britain has shown conclusively that the new approach of analysing a large subset of genetic variants in large samples of patients and healthy individuals works," says Professor Donnelly. "We are now able to effectively scan most of the common variation in the human genome to look for variants associated with diseases. This approach will undoubtedly herald major advances in how we understand and tackle disease in the future."

Further analysis as part of the Consortium will be looking at tuberculosis (TB), breast cancer, autoimmune thyroid disease, multiple sclerosis and ankylosing spondylitis. The results are expected later this year.

"One of the Major Problems Facing Us in Healthcare is That IVF Has Become a Massive Commercial Industry", Lord Robert Winston

IVF EXPERT PUTS BOOT INTO IVF INDUSTRY

The contrarian Lord Robert Winston, one of the pioneers of IVF, has once again attacked his colleagues in the IVF industry, this time for having been corrupted by money and for exploiting women who are desperate to get pregnant. "One of the major problems facing us in healthcare is that IVF has become a massive commercial industry," he said at the Guardian Hay Festival. "It's very easy to exploit people by the fact that they're desperate and you've got the technology which they want, which may not work."
Lord Winston was particularly scathing about his London colleagues: "Amazing sums of money are being made through IVF. It is really rather depressing to consider that some IVF treatments in London are charged at 10 times the fee that is charged in Melbourne, where there is excellent medicine, where IVF is just as successful, where they have comparable salaries. So one has to ask oneself what has happened. What has happened, of course, is that money is corrupting this whole technology."

Nor did he spare the UK's fertility watchdog, the Human Fertility and Embryology Authority: "The regulatory authority has done a consistently bad job. It's not prevented the exploitation of women, it's not put out very good information to couples, it's not limited the number of unscientific treatments people have access to, it doesn't prevent sex selection and all sorts of other things people don't like because there are all sorts of ways around the law." ~ Guardian, May 31

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

Genetic Variants for Type 1 Type 2 Diabetes, Crohn's, Rheumatoid Arthritis,Bipolar, Coronary Heart Disease, Hyperstension Located

From arthritis to diabetes: scientists unlock genetic secrets of diseases afflicting millions


· Huge study covers seven common illnesses
·

Alok Jha, science correspondent
Thursday June 7, 2007
The Guardian

Read the whole article at the Guardian

It's been much more challenging to identify the rather common variants in diseases such as diabetes and Crohn's disease, where there are multiple genes involved but the effects of individual genes has been much smaller," said Mark Walport, director of the Wellcome Trust.

By studying the DNA from 17,000 people, the 50 research groups identified 24 new genetic links for bipolar disorder, Crohn's disease, heart disease, type 1 and type 2 diabetes, rheumatoid arthritis and high blood pressure, tripling the number of genes already associated with them.

"This study is a landmark in the field of diabetes research," said Karen Addington of the Juvenile Diabetes Research Foundation. Dr Walport said that the study, one of the largest genetic research projects to date, had carried out genetic analysis at a "scale that's never been done before."

Research into the links between genes and disease has focused on small numbers of samples, often from relatives who share a higher than usual risk of suffering a particular illness. But the new approach pioneered by the research team, known as a genome-wide association study, heralds the future for this kind of research.

In the study, scientists analysed DNA samples from 2,000 patients per disease, comparing them with 3,000 "control" samples from healthy volunteers and looking at around 500,000 genetic differences in each sample. The full results of the Wellcome trust Case Control Project are published today in Nature and Nature Genetics. "Just a few years ago it would have been thought wildly optimistic that it would be possible in the near future to study a thousand genetic variants in each of a thousand people," said Dr Walport.

Main findings

Crohn's disease: Eight new genetic links were found to increase a person's susceptibility to this illness, which affects between 30,000 and 60,000 people in the UK. Having a single copy of any of the disease variants of these genes increases the risk by up to 40%.

Diabetes: Type 1 diabetes affects around 350,000 people in the UK; 1.9 million people have type 2. The study highlighted four new regions of the genome that increase the risk of type 1 diabetes. The research also confirmed that Type 2 diabetes has a genetic component.

Bipolar disorder: Also known as manic depression. It is marked by extreme mood swings and affects abut 100 million people worldwide. Many of the genes identified in the study seem to play a key role in the way nerve cells in the brain talk to each other.

Coronary heart disease: The study found several genetic regions that increased the risk of heart disease. The risk increased by 50% in people carrying one version of the disease variant. For those carrying both the risk was almost doubled. Coronary disease is Britain's biggest killer, claiming 105,000 lives each year.

Hypertension (high blood pressure): The research suggests that high blood pressure arises because of a wide range of interacting factors, including three genes identified in the study . The disorder affects more than 16 million Britons and a billion people worldwide.

Rheumatoid arthritis: This disease affects almost 400,000 people in the UK. The project identified three locations in the genome that had a possible role in predisposing people to the condition.

Women over 40 lead surge of IVF Here Come Lots More Autistic Kids Because of the Father's Age

Why don't people make the connection between older parents and autism? diabetes? Crohn's? Lupus? Cancer?

Hopefully the women who are Gay or single will find sperm donors 30 or under.


http://news.independent.co.uk/health/article2617454.ece?

Women over 40 lead surge in demand for IVF
By Jeremy Laurance, Health Editor
Published: 06 June 2007
Women over the age of 40 are flocking to fertility clinics in a final attempt to start a family before their biological clock stops ticking, latest figures show.

The fortysomethings are the fastest-growing group of patients seeking IVF, up from less than 1,000 in 1991 to more than 6,000 in 2006.

Demand for IVF has soared for all age groups in the past decade, with almost 40,000 cycles of treatment provided in 2006. Forty-plus women have led the surge, rising from 10 per cent of all cycles in 2000 to more than 15 per cent in 2006.

Experts said the trend was a consequence of the social pressures on women to delay starting a family while establishing their careers and growing awareness of the potential of fertility treatment. But they warned that many older women faced having their hopes dashed as success rates for IVF declined sharply with advancing years.

The figures also reveal rising demand from single and lesbian women. Cycles of treatment provided to single women increased from 600 in 1999 to more than 1,200 in 2006. The number of treatment cycles for lesbian couples rose from 300 to almost 1,000 in the same period.

Medical advances and improvements in technique have seen success rates for treatment increase dramatically. The overall live birth rate has risenfrom 14 per cent per cycle of treatment in 1991, to 21 per cent in 2006. The success rates are even higher for women under the age of 35 with more than one in four becoming pregnant at the first attempt. But the rates fall sharply after women pass the age of 35, declining to 12 per cent at age 40.

Moreover, the over-40s have not seen the improvement in live birth rates experienced by younger women. Success rates have improved only slightly over the past 15 years as doctors have run up against the barrier of female biological clock. After the age of 43, more than 95 per cent of patients treated return home childless.

Angela McNab, chief executive of the Human Fertilisation and Embryology Authority (HFEA), which published the figures on the occasion of the authority's annual conference in London yesterday, said the growth in demand from women over 40 was worrying. "Scandinavian countries are seeing the trend to delay motherhood even more markedly," she said. "It is a matter of concern. We may need to remind women about the biological clock and the difficulty of achieving pregnancy over 40."

She denied that clinics were pushing the treatment to older women, citing the practice of some doctors to refuse treatment to women in their forties. "I don't think the clinics are over-selling IVF [to older women]," she said. "I think there is greater awareness among the public about infertility and the range of treatments available."

NHS trusts refuse to fund treatment for women over the age of 40 on advice from the National Institute for Clinical Excellence (Nice) because of the low success rate, leaving women to pay for the treatment.

The average cost of a cycle of treatment ranges from £4,000 to £8,000. A woman having three or four cycles faces a bill of at least £12,000 and up to £32,000.

Sam Abdalla, director of the Lister fertility clinic, said society was imposing a "massive strain" on women by forcing them to choose between family and career. "It puts more of a burden on the women because it reduces their chances of conceiving and puts more strain on the treatment, especially in women over 45." He added that treatment in women over 40 was "less successful, with fewer pregnancies, a higher miscarriage rate and a lower live birth rate". But he stressed that the vast majority of women seeking treatment - 85 per cent - were under 40 with around half under 35..........................................................................
............................................................................

The figures show a rise in the proportion of couples in whom male infertility is reported. Experts said this was likely to be due to better diagnosis of male problems rather than an increase in men with infertility.

The Trailer of Michael Moore's "Sicko"

Would the knowledge of the Paternal Age Effect Reduce Cancer, Alzheimer's, Autism, Diabetes, MS, etc.? yes it would






From Business Week

Small Excerpt of a long and interesing article in by Ron Grover


Top News June 4, 2007, 12:01AM EST text size: TT
Michael Moore Wants to Reform Health Care
Big Pharma is already girding for battle against the filmmaker's latest effort, due in theaters this month. Will the new flick spur change in the U.S.?
by Ron Grover


"But many others, including those in the medical community, are hoping Moore will help make a difference. "Anything—including a film—that can bring this issue into the public eye is good for the debate," says heart surgeon Dr. William Plested, president of the American Medical Assn. "So, I'm cheering on Michael Moore, even though I haven't seen the film."

What role will Moore play in the debate? The filmmaker says he intends to hold a series of premieres for his film, with top Washington politicians and Schwarzenegger and others in California as well. "It takes something that grabs folks' attention in this state to get folks to write their assemblymen—and maybe a movie can do that," says Steve Maviglio, a top aide to California Assembly Speaker Fabian Nunez, who has his own universal health-care plan. Moore is also a close friend of fellow Michigan resident Representative John Conyers, chairman of the House Judiciary Committee, who has introduced his own national heath insurance overhaul. Moore says he'll likely testify before Conyers' committee on the bill.

Paternal Age and risk of Schizophrenia

Glyn Lewis
The British Journal of Psychiatry (2003) 183: 405-408
© 2003 The Royal College of Psychiatrists

Paternal age and risk for schizophrenia
STANLEY ZAMMIT, MRCPsych
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

PETER ALLEBECK, MD

Department of Social Medicine, Gothenburg University, Sweden

CHRISTINA DALMAN, MD

Psychiatric Epidemiology, Stockholm Centre of Public Health, Sweden

INGVAR LUNDBERG, MD and TOMAS HEMMINGSON, PhD

Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden

MICHAEL J. OWEN, FRCPsych

Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

GLYN LEWIS, PhD

Division of Psychiatry, University of Bristol, Bristol, UK

Correspondence: Dr S.G. Zammit, Department of Psychological Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK. Tel: +44 (0)2920 743058; fax: +44 (0)2920 746595; e-mail:zammits@cardiff.cardiff.ac.ac.uk

Declaration of interest None. Funding detailed in Acknowledgements.




Background Previously reported associations between advancing paternal age and schizophrenia could be due to an increase in paternal germ cell mutations or be confounded by heritable personality traits associated with schizophrenia that result in delayed parenthood.

Aims To investigate this association while adjusting for personality traits related to poor social integration in the subjects.

Method A cohort of 50 087 adolescent males was followed up by record linkage to determine hospital admissions for schizophrenia between 1970 and 1996.

Results Advancing paternal age was associated with an increased risk of developing schizophrenia in a‘dose-dependent’manner. The adjusted odds ratio for each 10-year increase in paternal age was 1.3 (95% CI1.0–1.5; P=0.015).

Conclusions Advancing paternal age is an independent risk factor for schizophrenia. Adjusting for social integration in subjects made little difference to this association, consistent with the hypothesis that advancing paternal age may increase liability to schizophrenia owing to accumulating germ cell mutations.




The first reported association between paternal age and schizophrenia was in 1958 (Johanson, 1958), a finding replicated by a number of other studies since then (Gregory, 1959; Hare & Moran, 1979; Kinnell, 1983; Raschka, 1998). All of these studies have been case–control designs, using general population statistics for control comparisons. Although the findings have been reasonably consistent, the use of control groups that are probably not wholly representative of the cases means that selection bias is a possible explanation for the association (Bertranpetit & Fananas, 1993). For example, cases may have been more likely to be recruited from urban areas than general population controls, which could be important given that paternal age is different in urban compared with rural areas. Bertranpetit & Fananas used controls drawn from the same population as the cases, matched for age, gender, place of birth, employment and neighbourhood, and failed to find any association between paternal age and schizophrenia (Bertranpetit & Fananas, 1993). Although a few other studies also have failed to find an association (Granville-Grossman, 1966; Costello et al, 1968; Gillberg, 1982), inefficient statistical tests (see Moran, 1968) and small sample sizes are likely to have contributed to these negative findings.

More recently, an association between paternal age and schizophrenia has been reported in an Israeli population-based birth cohort (Malaspina et al, 2001). This was the first cohort study to investigate this association and it overcame many of the problems related to study design that affected previous studies. However, it was unable to adjust for personality traits, which may be an important confounder in the relationship between schizophrenia and paternal age.

Two studies since then have reported a marginally significant association but, again, they were unable to adjust for the effects of personality (Brown et al, 2002; Dalman & Allebeck, 2002). In this study we examine the relationship between paternal age and schizophrenia, using data from a Swedish cohort of 50 087 men with a 27-year record linkage follow-up, while controlling for a number of confounders, including personality traits relating to social integration of the subjects.




Subjects
The cohort consisted of 50 087 men conscripted into the Swedish army during 1969–1970. Over 98% were 18–20 years of age. Only 2–3% of the male population were excused conscription on account of severe mental or physical disability, therefore selection as well as information bias are unlikely. Assessment at conscription included tests of IQ and self-administered questionnaires on family, social background, behaviour during adolescence and substance use. Only 3% of the sample had missing data for one or more of the self-reported questions, and less than 6% had missing data on paternal age.

All subjects underwent a structured interview conducted by a psychologist and those reporting any psychiatric symptoms were interviewed by a psychiatrist and given a diagnosis according to ICD–8 (World Health Organization, 1974) where applicable. All subjects have been made anonymous, and permission to use the database was granted by the Karolinska Institute Research Ethics Committee and the Swedish Data Inspection Board. Thirty-four cases of psychosis diagnosed at conscription were excluded from the study. Parental age at birth of subjects was obtained from the Statistics of Sweden Registers, blind to diagnosis.

Follow-up
The Swedish National Hospital Discharge Register recorded about 70% of all psychiatric admissions in 1970, rising to 83% in 1973. Coverage was 97% from 1974 until 1983, 80–95% between 1984 and 1986 and has been virtually complete since 1987. The linkage reported here was from 1970 until 1996 and covers the period of greatest risk of schizophrenia for men (ages 18–45 years). The incomplete registration during some periods is unlikely to have affected the results in any way. Patients were given clinical diagnoses according to the Nordic version of ICD–8 (ICD–9 from 1987). Swedish psychiatrists tend to use a narrow definition of schizophrenia (Jablensky, 1986) and show good agreement with DSM–III criteria (Kristjansson et al, 1987). In addition, over 90% of people with schizophrenia are admitted to hospital at some point over a 10-year period (Geddes & Kendell, 1995), and outcome misclassification is therefore likely to be low. Outcomes investigated were schizophrenia (codes 295.00–295.99) and other psychoses (including alcoholic, affective, drug-induced and paranoid psychoses).

Analysis
Logistic regression was used to calculate odds ratios and 95% confidence intervals for schizophrenia when given the paternal age, both before and after adjustment for potential confounders. Likelihood ratio tests were used to compare different models.

Personality variables concerned with interpersonal relationships, IQ score, place of upbringing, cannabis use and maternal age have been found to be associated with schizophrenia (Andreasson et al, 1987; Lewis et al, 1992; David et al, 1997; Malmberg et al, 1998; Zammit et al, 2002) and were associated with paternal age in this cohort. These were included in the regression models, although some of these variables could lie along the causal pathway between paternal age and schizophrenia rather than confound the relationship. Nevertheless, investigation of these within the models could give important insights into the pathways involved in any association.

For the investigation that paternal age may have a stronger effect in sporadic rather than familial cases of schizophrenia, the familial cases were defined as subjects who had a family history of any mental health problems requiring treatment with psychotropic medication. For the purposes of analysis, paternal age was subdivided a priori into five categories (ages 15–24, 25–34, 35–44, 45–54 and 55 years) because a linear effect of paternal age was unlikely, given the prior knowledge regarding accumulation of paternal germ cell mutations (Crow, 1997).



Of the 50 053 subjects included in the analysis (34 subjects were excluded as they had a psychotic illness at the time of conscription), 362 (0.7%, 95% CI 0.65–0.80%) were diagnosed as having schizophrenia by 1996. Data on paternal age were missing on 25 (6.9%) of those developing schizophrenia and on 2768 (5.6%) of controls (2=1.3, d.f.=1, P=0.27). For subjects with schizophrenia, paternal age ranged from 19 to 65 years (mean=33.5, s.d.=7.7), whereas for controls the paternal age ranged from 15 to 75 years (mean=32.2, s.d.=7.0).

A summary of the potential confounders in relation to paternal age is presented in Table 1. For the purposes of this table only, poor social integration and IQ score were treated as dichotomous variables using the 10th percentile as a cut-off point for coding.




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Table 1 Summary of confounders according to paternal age categories including number (and percentage) of subjects




The crude and adjusted odds ratios (ORs) with 95% confidence intervals for developing schizophrenia when given the paternal age are presented in Table 2. The crude odds ratio for schizophrenia when given a linear trend of paternal age was highly significant (crude OR for linear trend across age categories=1.3, 95% CI 1.1–1.5, P0.001), and this association persisted after adjustment for confounders (adjusted OR for linear trend=1.3, 95% CI 1.0–1.5, P0.02). As a sensitivity analysis we excluded the oldest age category (55 years), which resulted in an adjusted odds ratio for a linear trend of 1.2 (95% CI 1.0–1.5, P=0.04).




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Table 2 Crude and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) for developing schizophrenia and other psychoses according to paternal age




A non-linear (within a logistic model) relationship between paternal age and risk of schizophrenia was investigated by inclusion of a quadratic term, but there was no evidence that this fitted the model better than a linear relationship (likelihood ratio test: 2=0.1, d.f.=1, P=0.64). The hypothesis that paternal age may have a stronger effect in sporadic cases rather than familial cases of schizophrenia (Malaspina et al, 2001) was investigated, but a likelihood ratio test failed to show evidence of any statistical interaction (likelihood ratio test: 2=9.8, d.f.=1, P=0.20).

Although there was an association between maternal age and schizophrenia in the crude analysis (crude OR for linear trend across maternal age categories=1.1, 95% CI 1.0–1.2, P=0.006), this disappeared after adjusting for paternal age (adjusted OR for linear trend=1.0, 95% CI 0.9–1.1, P=0.90).

We also investigated whether paternal age was associated with other (non-schizophrenia) psychoses (n=446). There was no association between paternal age and other psychoses in the crude analysis (OR for linear trend=1.1, 95% CI 1.0–1.3, P=0.09) and this did not change after adjustment for confounders (adjusted OR=1.1, 95% CI 0.9–1.3, P=0.46).




Mutation hypothesis
Two main theories have been proposed to explain the association between advancing paternal age and schizophrenia. First, an increase in mutations arising in paternal germ cells with advancing age could increase the risk of schizophrenia. Such a mechanism has been implicated as underlying the increased paternal age in several autosomal dominant diseases, as well as diseases with more complex genetic aetiologies (Malaspina et al, 2001). The occurrence of new mutations in this way could help to explain the apparent maintenance of schizophrenia in the population in the face of reduced reproductive fitness (Book, 1953; Fananas & Bertranpetit, 1995).

The persistence of an association with paternal age after adjustment for poor social integration, drug use and low IQ score, all of which are established risk factors for schizophrenia, suggests that these factors are not along the causal pathway. Therefore, if the germ cell mutation hypothesis is correct, advancing paternal age must affect the susceptibility to schizophrenia by other means, perhaps by a more direct influence on cerebral function.

Observations suggest that the accumulation of germ cell mutations is likely to be non-linear and probably exponential in nature (Crow, 1997). The increase in odds ratios for schizophrenia with advancing paternal age was non-linear in this study (an exponential increase in risk with advancing paternal age is equivalent to a linear relationship within a logistic model). Although it has been suggested that paternal age may have a stronger effect in sporadic cases rather than familial cases of schizophrenia if point mutations accumulate with advancing age (Malaspina et al, 2001), we found no evidence of any interaction between family history of psychiatric disease and paternal age on risk of schizophrenia, although tests for interactions tend to lack power.

The population-attributable fraction of schizophrenia for this sample that is due to having a father aged >45 years at birth is approximately 13%. However, mean paternal age has increased over the past 20 years (Office for National Statistics, 2001), suggesting that this may be an underestimate of the true population-attributable fraction resulting from advanced paternal age. This may have important consequences for genetic studies, because recent mutations are much less amenable to detection by approaches that rely upon linkage disequilibrium with marker loci. The involvement of such mutations in conferring susceptibility can be detected only by direct association methods (Owen et al, 2000). Moreover, the inclusion of subjects who have older fathers in linkage disequilibrium studies will enrich for more recent mutations and, consequently, the power of linkage disequilibrium methods to identify susceptibility genes for schizophrenia may be reduced.

Confounding by personality
A second explanation for the association observed is that it is due to confounding. If older fathers have personality traits that are known to be associated with schizophrenia (such as schizoid or schizotypal traits), then these traits are likely to be shared by their offspring as a result of both heredity and upbringing (Coolidge et al, 2001). Such traits could result in an increased risk of developing schizophrenia in the offspring, and also in a later age of parenthood in the father as a result of a reduced ability for social integration (Granville-Grossman, 1966; Hare & Moran, 1979).

A further study by Malaspina et al found that paternal age was more likely to be advanced in sporadic cases of schizophrenia compared with those with a family history of psychosis (Malaspina et al, 2002). This suggests that family history and paternal age may be acting as independent risk factors for this disorder. Although it is possible to interpret this as evidence against confounding by personality, family history of psychosis is unlikely to be a strong marker for personality traits that predispose towards delayed parenthood.

In our analyses, adjusting for poor social integration in the conscripts reduced the odds ratio for schizophrenia only minimally, suggesting that personality traits relating to social integration do not play a substantial role in explaining the association between paternal age and schizophrenia. The absence of direct information on paternal personality means that some residual confounding is very likely and cannot be excluded as an explanation for the association. However, we would expect that if a strong effect of personality existed then this would be evident in the measures of personality in the subjects themselves.

In conclusion, our result of an association between advancing paternal age and schizophrenia was not affected by adjusting for social integration of the subjects. This supports the hypothesis that accumulating germ cell mutations may lead to an increase in genetic liability to schizophrenia in the offspring.





CLINICAL IMPLICATIONS


Paternity at advanced age increases the risk of schizophrenia in the offspring.

Inclusion of subjects who have older fathers in studies that rely upon linkage disequilibrium may reduce the statistical power of such approaches.

LIMITATIONS


These findings may not be applicable to women because only men were included in this study.

Because the record linkage was for hospital admissions, it may be that some subjects with schizophrenia were not included as cases.

Because direct measurements of personality traits in the fathers were not available, some residual confounding is likely.



This research is funded from a Clinical Training Fellowship grant awarded to S.Z. by the Medical Research Council UK (grant no. G84/5689). We also thank Jonas Sadigh for assistance with data management.



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Received for publication September 26, 2002. Revision received June 4, 2003. Accepted for publication June 19, 2003.