What Happens to Sperm DNA With Advancing Age

Published online on June 9, 2006, 10.1073/pnas.0506468103

Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm

Genetics
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A. J. Wyrobek *, B. Eskenazi , S. Young , N. Arnheim ¶, I. Tiemann-Boege ¶, E. W. Jabs , R. L. Glaser **, F. S. Pearson *, and D. Evenson
*Biosciences Directorate, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94550; School of Public Health, University of California, Berkeley, CA 94720-7380; ¶Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089; Institute of Genetic Medicine, Center for Craniofacial Development and Disorders, Departments of Pediatrics, Medicine, and Surgery, Johns Hopkins University, Baltimore, MD 21205; **Department of Biology, Massachusetts College of Liberal Arts, North Adams, MA 01247; and Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007



Edited by James E. Cleaver, University of California, San Francisco, CA, and approved April 21, 2006 (received for review August 12, 2005)

This study compares the relative effects of advancing male age on multiple genomic defects in human sperm [DNA fragmentation index (DFI), chromatin integrity, gene mutations, and numerical chromosomal abnormalities], characterizes the relationships among these defects and with semen quality, and estimates the incidence of susceptible individuals for a well characterized nonclinical nonsmoking group of 97 men (22-80 years). Adjusting for confounders, we found major associations between age and the frequencies of sperm with DFI and fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia (P < r =" -0.65,">


Ageing and quality of sperm



Last Updated: Sunday, 6 April 2008, 9:34 GMT Previous Page

Ageing and Quality of Sperm

Source: Prof. E. Y. Kwawukume - Obstetrician and Gynaecologist and Chief Executive of Women's Health Foundation-Ghana/The Mirror


Lifestyle and exposure to certain environmental agents could affect the sperm and fertility or the ability to produce healthy sperm to optimise fertility. There are many couples in our society who, after several months of trying to achieve conception, have failed.

Many times, the man is not ready to seek infertility evaluation and they try as much as possible to do what they can on their own to produce healthy sperm. Unfortunately, in a majority of men, self-medication does not work!

Sperm, quantity and quality vary among male and there are several factors which can affect the production of healthy and optimum sperm. Some of these factors are directly under our control but others are not and there is not much that you can do alone but to seek help and have clear understanding about your health.

Women and egg production

The production of eggs by the female and the production of sperm by the male run different pathways. There is no strong evidence that sperms suffer the same age-related degradation or weakness as women's eggs, the older sperms do cause their fair share of genetic problems but in a much different way.

In contrast to females who are born with all their eggs, men have no sperm when they are born. They don't make any sperm until they reach puberty, when a prolific and persistent production begins.

The average man makes about 250 million sperms a day: that's about 6,000 sperm every time his heart beats. As a man ages, sperm production continues unabated, and there’s no strong clinical or scientific evidence that production decreases significantly even in 70 and 80 year-old men.

Sperm production is very high and the body has to cope with this production through DNA. It is therefore not surprising that this repeated copying can lead to small mistakes called mutations and mistakes invariably occur. This could lead to many diseases in the children of older fathers and grandfathers.

Could Schizophrenia Be Entirely Genetic?

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Could Schizophrenia Be Entirely Genetic?
By MedHeadlines • Mar 29th, 2008 • Category: Bipolar Disorder, Family, Genetic Diseases, Headlines, Medical Research, Neurology, Psychology, Schizophrenia
The latest gene-scanning technology may have shed some much-desired light on a potential cause for schizophrenia, a mental disorder characterized by delusions and scrambled thought processes. The disease is believed to affect 1% of the population.

Until now, medical scientists were searching for the cause of the disease in a cluster of factors, none of which produced particularly promising results. Previous studies have searched for shared genetic sequences among patients and how the drugs prescribed for the disease work with brain cells. The cause has remained elusive but recently developed high-resolution technology capable of scanning the complete DNA map has revealed some very rare genetic variations common in schizophrenics that have been heretofore undetectable.

The discovery, considered a paradigm shift by colleagues, is the result of a combined study involving researchers at the National Institute of Health, Cold Spring Harbor Laboratory, and the University of Washington in Seattle. Researchers scanned blood samples from 150 schizophrenics and a control group of 268 samples from people who do not have the disease.

53 mutations in the DNA sequence were detected. These mutations were found to occur in 15% of people with schizophrenia and 5% in those not affected by the disease. The disease usually becomes apparent in adulthood but a very rare form sometimes develops during childhood. When the blood samples of people with this rare childhood form of the disease were analyzed, a rare mutation known to alter genetic function was four times more likely to occur. Heredity plays a role in some of the mutations identified but others spontaneously occur at or shortly after conception.

One of the ways the genetic mutations affect brain function is by distorting the ability to guide neurons to the correct locations in the brain during development. Another alters the shape of a glutamate-transporting molecule. Glutamate is required to excite neurons so signals can be effectively transmitted from cell to cell.

Researchers haven’t yet determined if these genetic mutations work alone to cause schizophrenia or if they work in conjunction with other processes. The research team is optimistic, however, that the ever-improving state of gene-scanning technologies will help solve the mystery of this very disturbing disease. They also express the hope of using similar technologies to learn more about other diseases of the mind, including autism, bipolar disorder, and depression.

Today’s issue of the journal Science carries complete details of the study.

The Very Dangerous Trend (for the offspring) of Delaying Parenthood

CMAJ • January 15, 2008; 178 (2). doi:10.1503/cmaj.071577.
© 2008 Canadian Medical Association or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.



--------------------------------------------------------------------------------
Commentary
Research

Advanced maternal age: Are decisions about the timing of child-bearing a failure to understand the risks?
Karen M. Benzies, RN PhD
Karen Benzies is with the Faculty of Nursing, University of Calgary, Calgary, Alta.

Correspondence to: Dr. Karen M. Benzies, Faculty of Nursing, University of Calgary; 2500 University Dr. NW, Calgary AB T2N 1N4; fax 403 210-8101; benzies@ucalgary.ca

In the developed world, an increasing proportion of births are attributable to women of advanced maternal age ( 35 years).1,2 Between 1995 and 2003, the mean age of first-time mothers in Canada increased from 28.8 to 29.6 years.3 On average, first-time mothers in Canada are older than first-time mothers in other developed countries, including Sweden (mean age 28.3 years), the Netherlands (28.7 years) and the United States (24.9 years).4 Traditionally, women have been the subject of reproductive interventions and policies. However, the trend toward delayed parenthood and risks associated with advanced age also apply to men.5,6 These changing patterns of advanced age of first-time parents are having a significant public health impact owing to increased risks of stillbirth, preterm birth and cesarean delivery.7 Reducing adverse perinatal outcomes requires comprehensive and systematic examination of the complex relations among factors that contribute to decisions about the timing of child-bearing.

In this issue of CMAJ, Huang and colleagues8 report the results of a systematic review of retrospective cohort and case–control studies of the association between advanced maternal age and the risk of stillbirth. Although first-time mothers in Canada are older than those in other developed countries,4 the rate of stillbirth — 3 per 1000 total births — is similar to that in Sweden (3 per 1000), the Netherlands (5 per 1000) and the United States (4 per 1000).9 Huang and colleagues8 are to be commended for the breadth of their review, which included 37 studies from 4 continents reported in 5 languages. Although clinical, methodological and statistical heterogeneity prevented meta-analysis, Huang and colleagues8 found that 77% of the 31 retrospective cohort studies and all 6 of the case–control studies indicated a statistically significant association between advanced maternal age and stillbirth risk. They found a similar association in all 15 population-based cohort studies. They concluded that advanced maternal age likely has an independent effect on stillbirth.

One of the most serious challenges in conducting reviews in this area is the variability in definitions of advanced maternal age and the threshold for reporting stillbirth.10 At a minimum, consensus about definitions and standardized reporting across jurisdictions would lead to more definitive results from systematic reviews. Additional study variability arises from differences in health care and cultural contexts, which are not sufficiently captured in epidemiologic or hospital-based administrative data sets. This limits the ability to generalize findings to other populations. However, as Huang and colleagues8 correctly point out, there remains a great deal to learn about the impact of lifestyle and socioeconomic factors on stillbirth risk. Although large, prospective studies that include information about prepregnancy health of the mother and father, maternal stress and socioeconomic factors are expensive, a clear understanding of the risk of stillbirth will require this level of investment in research.

The results of the review by Huang and colleagues8 are somewhat consistent with those of the study by Fretts10 who identified that, in addition to advanced maternal age, prepregnancy obesity and socioeconomic factors were the most prevalent risk factors related to the 709 Canadian stillbirths recorded in the McGill Obstetrical Neonatal database. Similarly, in a population-based Italian sample, the risk of adverse pregnancy outcomes associated with advanced maternal age was modified by parity and education.1 After adjusting for a large number of known predisposing conditions in a population-based US cohort, Bateman and Simpson11 identified an independent risk of maternal age, with higher rates of stillbirth at both extremes of reproductive age ( 19 and 35 years). Although maternal age contributes to the risk of stillbirth in developed countries, infection, malnutrition, lack of antenatal care and poverty constitute the major risk factors in developing countries.12

The major causes of stillbirth vary by gestational age. Infection is the most common contributor between 24 and 27 weeks' gestation, and unexplained stillbirth is the most common contributor after 28 weeks.10 In the study by Fretts,10 rates of unexplained late fetal loss were more pronounced among women aged 35 years or older. This rate is similar to that reported among women aged 45 years and older in a population-based Swedish study.13 Together, these studies clearly suggest a multifactorial cause of stillbirth and a clear need for prospective studies that include lifestyle and socioeconomic risk factors.

Much remains to be learned about why women and men delay child-bearing and about their knowledge of the associated risks. Women's decisions about the timing of child-bearing are influenced by many factors. In a qualitative study involving women aged 20–48 years, independence, motivation to have a family, declining fertility, chronic health problems and stable relationships were identified as personal influences on decisions about the timing of child-bearing.14 Family influences included partner readiness for child-bearing, financial stability and the influence of extended family.14 Societal influences included increasing acceptability of advanced maternal age, divorce rates and parental-leave policies in the workplace.13 In one of the only studies to explore why men decided to delay having children, influencing factors were similar to those influencing women's decisions and included financial security, partner suitability to parenting and motivation to have children.15 Although this and another population-based study have suggested that men and women are aware of the relation between advanced maternal age and conception difficulties, the studies found that they are generally unaware of other medical risks, including stillbirth, cesarean delivery, multiple births and preterm delivery.15,16 Prepregnancy counselling for patients who delay child-bearing into their late 30s may be too late to inform decisions about preventing pregnancy risks associated with advanced maternal and paternal age. A survey of Canadian obstetricians, gynecologists and family physicians reported many missed opportunities to identify women who are at risk for adverse conception, pregnancy and birth outcomes.17 Although physicians have incorporated discussions of birth control and Papanicolaou smears into their routine care of women,17 screening and providing information about fecundity, nutrition, weight management, alcohol, smoking, mental illness, addictions and stress may increase the chances of optimal reproductive outcomes. Currently, it appears that decisions about the timing of child-bearing are not based on an informed understanding of the risks associated with suboptimal reproductive outcomes.15 Although information alone is insufficient to change behaviours, it may contribute to more informed decisions about the timing of child-bearing.

Finally, an interactive model to assess the risk of stillbirth is needed to guide pregnancy management. Large, prospective studies that include lifestyle and socioeconomic factors are also needed. Given the increasing birth rate among women of advanced maternal age and the resource constraints facing the health care system, increased fetal testing based on advanced maternal age alone may be unfeasible. Prevention of stillbirth may require a broader assessment of risk factors and additional attention to prepregnancy counselling and testing for women and men. Huang and colleagues are to be commended for expanding the awareness of advanced maternal age as one of the risk factors for stillbirth.

Key points of the article

• On average, first-time mothers in Canada are older than women in other developed countries.

• Canadian men and women do not fully understand the link between advanced maternal age and adverse outcomes, such as stillbirth.

• By providing information to all patients of child-bearing age about the medical risks of advanced maternal age, physicians will contribute to more informed decisions about the timing of child-bearing.

@ See related article page 165



Footnotes

This article has been peer reviewed.

Acknowledgement: I thank Dr. Suzanne Tough, Department of Pediatrics, University of Calgary, for reviewing and providing feedback on this commentary.

Competing interests: None declared.



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Related Article


Maternal age and risk of stillbirth: a systematic review
Ling Huang, MD MSc, Reg Sauve, MD MPH, Nicholas Birkett, MD MSc, Dean Fergusson, MHA PhD, and Carl van Walraven, MD MSc
Can. Med. Assoc. J. 2008 178: 165-172. [Abstract] [Full Text

THE MALE BIOLOGICAL CLOCK advancing paternal age leads to schizophrenia and autism and other genetic disorders and diseases

"Paternal age is consistently associated with increased risk of schizophrenia (Brown et al, 2002; Dalman & Allebeck, 2002; Malaspina et al, 2002; Byrne et al, 2003; El-Saadi et al, 2004; Sipos et al, 2004; Tsuchiya et al, 2005). Paternal age is also associated with increased rates of several types of de novo germ-line mutations (Crow, 2003)."

Br J Psychiatry. 2007 Mar ;190 :194-9 17329737 (P,S,E,B,D) Schizophrenia: a common disease caused by multiple rare alleles.

[My paper] Jon M McClellan, Ezra Susser, Mary-Claire King
Department of Psychiatry, Box 356560, University of Washington, Seattle, WA 98195, USA. drjack@u.washington.edu.
Schizophrenia is widely held to stem from the combined effects of multiple common polymorphisms, each with a small impact on disease risk. We suggest an alternative view: that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families. This ;common disease - rare alleles' hypothesis is supported by recent findings in human genomics and by allelic and locus heterogeneity for other complex traits. We review the implications of this model for gene discovery research in schizophrenia.

This Guy is Too Old

Childless couple dedicate lives to helping others have families
Email Printer friendly version Normal font Large font Louise Hall Health ReporteR
March 30, 2008


Happy donors ... Faith Haugh and partner Glenn Watson Shannon.



BETWEEN them, Faith Haugh and her partner Glenn Watson have made 20 babies.

As an egg donor, Ms Haugh is the biological mother of 17 children - 10 girls and seven boys. She has also raised a 19-year-old daughter, Ashlyn, from a previous marriage.

Mr Watson, 44, has one toddler and another baby on the way through sperm donation.

This remarkable couple have dedicated their lives to helping infertile men and women start a family, and many of the donor children form a large, loosely extended family.

But the couple's desire to have a baby of their own has been dashed, as Ms Haugh was recently diagnosed with liver cancer.

The 37-year-old office worker is now freezing her own eggs to prevent her ending up in the same heartbreaking situation as the infertile women she has helped.

"Once I get through this cancer the first thing I'm going to do is try to get pregnant," she said. "But I'm going to freeze an embryo, just in case."

Ms Haugh's decision to become an egg donor first occurred 15 years ago, when she saw an ad in The Age newspaper placed by an infertile couple. Through an IVF clinic at a public hospital she anonymously donated her eggs to them, which led to the birth of twin girls.

Further donations - each requiring her to undergo hormone injections and a stint in hospital - resulted in a second set of twins to another couple, followed by three more babies.

While the donations were to unidentified couples, Ms Haugh is prepared for the donor children to contact her once they turn 18 as her details were recorded on a central register.

These offspring would join the 10 children Ms Haugh has helped procreate to couples she met through classified ads and online infertility networks.

Mr Watson and Ms Haugh have signed agreements with each of the couples they donate to absolving themselves from child support payments or other legal responsibilities.

Ms Haugh's 13-centimetre tumour was discovered by accident while she was undergoing tests to prepare for her next altruistic deed - donating a kidney to a stranger.

As she has successfully donated to 10 different families, the law prevents her from donating any more so she has turned her efforts towards raising awareness about egg donation and linking up potential donors and recipient couples - and hopefully, becoming pregnant herself.

"Glenn says he doesn't mind if we don't have a baby together but I know he'd really like to. He just says we'll get a dog or go overseas," she said.

There are two types of paternal age effects. One relates to the autosomes and the other to the X chromosome

There are two types of paternal age effects. One relates to the autosomes and the other to the X chromosome. New autosomalmutations for dominant conditions show up in the children. Their diseases are due directly to advanced paternal age.

New mutations on the X chromosome are usually not evident in the children. They are transmitted to daughters who are at risk for having sons with X-linked diseases. This is an indirect paternal age effect; it is the effect of the age of the maternal grandfather.

Examples of autosomal dominant conditions associated with advanced paternal age include achondroplasia, neurofibromatosis, Marfan syndrome, Treacher Collins syndrome, Waardenburg syndrome, thanatophoric dysplasia, osteogenesis imperfecta, and Apert syndrome.

Examples of X-linked conditions associated with increased maternal grandfather's age include fragile X, hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), Duchenne muscular dystrophy, incontinentia pigmenti, Hunter syndrome, Bruton-type agammaglobulinemia, and retinitis pigmentosa.

More Schizophrenia More Dizygotic Twinning in Offspring of Older Fathers

1: Br J Psychiatry. 2000 Apr;176:400-1. Links

Comment on:
Br J Psychiatry. 1999 Nov;175:399-401.
Paternal age and schizophrenia in dizygotic twins.Raschka LB.
PMID: 10827898 [PubMed - indexed for MEDLINE]
Raschka LB.Paternal age as a risk factor.Can J Psychiatry. 2002 Nov;47(9):892. No abstract available. PMID: 12500770 [PubMed - indexed for MEDLINE]2: Related Articles, LinksRaschka LB.Paternal age and schizophrenia in dizygotic twins.Br J Psychiatry. 2000 Apr;176:400-1. No abstract available. PMID: 10827898 [PubMed - indexed for MEDLINE]3: Related Articles, LinksRaschka LB.On older fathers.Am J Psychiatry. 1995 Sep;152(9):1404. No abstract available. PMID: 7653708 [PubMed - indexed for MEDLINE]

Risk of Having A Child With De Novo Bi Polar Disorder Rises if Father 51-55 According to Danish Study

risk of schizophrenia found to rise after age 31 increasing with paternal age.

J Clin Psychiatry. 2007 Nov;68(11):1673-81. Links
A comparison of selected risk factors for unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a danish population-based cohort.Laursen TM, Munk-Olsen T, Nordentoft M, Bo Mortensen P.
National Centre for Register-Based Research, University of Aarhus, Denmark. tml@ncrr.dk

OBJECTIVE: Growing evidence of an etiologic overlap between schizophrenia and bipolar disorder has become increasingly difficult to disregard. In this study, we examined paternal age, urbanicity of place of birth, being born "small for gestational age," and parental loss as risk factors for primarily schizophrenia and bipolar disorder, but also unipolar depressive disorder and schizo-affective disorder. Furthermore, we examined the incidence of the disorders in a population-based cohort and evaluated our results in the context of the Kraepelinian dichotomization. METHOD: We established a register-based cohort study of more than 2 million persons born in Denmark between January 1, 1955, and July 1, 1987. Overall follow-up began on January 1, 1973 and ended on June 30, 2005. Relative risks for schizophrenia, bipolar disorder, unipolar depressive disorder, and schizoaffective disorder (ICD-8 or ICD-10) were estimated by survival analysis, using Poisson regression. RESULTS: Differences were found in age-specific incidences. Loss of a parent (especially by suicide) was a risk factor for all 4 disorders. High paternal age and urbanization at birth were risk factors for schizophrenia. Children born pre-term had an excess risk of all disorders except schizophrenia if they were born "small for gestational age." CONCLUSIONS: An overlap in the risk factors examined in this study was found, and the differences between the phenotypes were quantitative rather than qualitative, which suggests a genetic and environmental overlap between the disorders. However, large gender differences and differences in the age-specific incidences in the 4 disorders were present, favoring the Kraepelinian dichotomization.

Multiple genetic glitches disrupt pathways critical for brain development

Public release date: 27-Mar-2008


Contact: Jules Asher
NIMHpress@mail.nih.gov
301-443-4536
NIH/National Institute of Mental Health

Rates of rare mutations soar 3 to 4 times higher in schizophrenia
Multiple genetic glitches disrupt pathways critical for brain development
People with schizophrenia have high rates of rare genetic deletions and duplications that likely disrupt the developing brain, according to studies funded in part by the National Institutes of Health.

These tiny anomalies were found in 15 percent of adult onset schizophrenia patients and 20 percent of child and adolescent onset patients, compared with only 5 percent of healthy participants. Collectively, the mutations carried by patients were significantly more likely than those in healthy participants to disrupt genes involved in brain development -- potentially implicating hundreds of genes in the illness, which affects about 1 percent of adults.

“This is an important new finding in the genetics of schizophrenia,” said NIMH Director Thomas R. Insel, M.D. “Identifying genes prone to harboring these mutations in brain development pathways holds promise for treatment and prevention of schizophrenia, as well as a wide range of other neurodevelopmental brain disorders.”

Two independent teams of researchers report on their combined findings in an article published online in Science Express, March 27, 2008. One team was led by Judith Rapoport, M.D., and Anjene Addington, Ph.D., National Institute of Mental Health (NIMH), Intramural Research Program. The other team was led by Jonathan Sebat, Ph.D., and Shane McCarthy, Ph.D., Cold Spring Harbor Laboratory, and by Jon McClellan, Ph.D., Tom Walsh, Ph.D., and Mary-Claire King, Ph.D., University of Washington. Their research was supported in part by the NIMH, National Institute of Child Health and Human Development, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, and the National Institute on Aging.

The prevailing genetic model of schizophrenia implicates common variants of certain suspect candidate genes, each exerting modest effects, in interaction with each other and environmental factors. This hypothesis holds that risk stems from common variations in the sequence of the genetic code that result in altered protein products.

About a year ago, Sebat, King and colleagues reported evidence strengthening the case for a different kind of genetic risk. Many people with autism were found to have different, spontaneous and individually rare structural variations -- variations in the number of copies of genes. These copy number variations were scattered throughout the genome, suggesting that many different genes could be involved in autism spectrum disorders.

The new findings in schizophrenia echo those in autism, but also broaden their implications. The results suggest a new approach for discovering genes for schizophrenia and other mental disorders, say the researchers. Any mutation in the hundreds of genes involved in brain development could lead to a different set of neurodevelopmental consequences – schizophrenia, autism, mental retardation, or no illness at all. Each person with one of the illnesses could have a different genetic cause for the disorder.

The functional consequences of these structural genetic variations may differ, depending on interactions with other genes or environmental events, say the researchers, making any gene harboring a deleterious structural mutation a “candidate gene.” Any gene harboring one mutation likely contains others. Although each might be individually rare, together such disease-causing variations in one gene could explain a substantial number of illness cases, they suggest.

Among key study findings:

* Genes disrupted in patients, as opposed to healthy participants, were significantly over-represented in pathways critical for brain development. These included genes involved in creating the infrastructure by which neurons communicate -- and for neuronal growth, migration, proliferation, differentiation, and cell death. Among these were genes important for neuronal communications via glutamate and neuregulin, both of which have previously been implicated in schizophrenia.

* The mutations were often specific to single cases or families. Virtually every mutation detected by King, Sebat and colleagues was different in a sample of 150 adults with schizophrenia and 268 healthy controls.

* In families affected by childhood onset schizophrenia, Rapoport and colleagues found that 28 percent (23) of 83 patients harbored mutations, compared with 13 percent (10) of 77 controls. By using the non-transmitted chromosomes of the patients’ parents as controls, the researchers were able to determine if the mutations in their children were likely inherited or spontaneous. The majority turned out to be inherited rather than spontaneous, some from parents unaffected by the illness. Childhood onset schizophrenia is thought to be a more severe and more genetically influenced form of the illness.


###

The research was also funded by the Forrest C. and Frances H. Lattner Foundation, NARSAD, the Simons Foundation, the Stanley Medical Research Foundation, the Howard Hughes Medical Institute.

Rare Structural Variants Distrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Tom Walsh1*, Jon M. McClellan2*#, Shane E. McCarthy3*, Anjene M. Addington4*, Sarah B. Pierce1, Greg M. Cooper5, Alex S. Nord5, Mary Kusenda3, Dheeraj Malhotra3, Abishek Bhandari3, Sunday M. Stray1, Caitlin F. Rippey5, Patricia Roccanova3, Vlad Makarov3, B. Lakshmi3, Robert L. Findling6, Linmarie Sikich7, Thomas Stromberg4, Barry Merriman8, Nitin Gogtay4, Philip Butler4, Kristen Eckstrand4, Laila Noory4, Peter Gochman4, Robert Long4, Amalia Dutra9, Zugen Chen8, Sean Davis10, Carl Baker5, Evan E. Eichler5, Paul S. Meltzer10, Stanley Nelson8, Andrew B. Singleton11, Ming K. Lee1, Judith L. Rapoport4, Mary-Claire King1, 5, Jonathan Sebat3.

1 Department of Medicine, University of Washington, Seattle, WA 98195, USA
2 Department of Psychiatry, University of Washington, Seattle, WA 98195, USA
3 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
4 Child Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA
5 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
6 Department of Psychiatry, Case Medical Center, Cleveland, OH 44106, USA
7 Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA
8 Department of Human Genetics, University of California, Los Angeles, CA 90095, USA
9 Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
10 Cancer Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
11 Neurogenetics Laboratory, National Institute on Aging, NIH, Bethesda, MD 20892, USA

*These authors contributed equally to this work.
#To whom correspondence should be addressed. E-mail: drjack@u.washington.edu

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The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute's Web site at http://www.nichd.nih.gov/.

The National Center for Research Resources (NCRR) provides laboratory scientists and clinical researchers with the environments and tools they need to understand, detect, treat, and prevent a wide range of diseases. Through the CTSA consortium and other collaborations, NCRR supports all aspects of translational and clinical research, connecting researchers with one another, and with patients and communities across the nation. For more information, visit www.ncrr.nih.gov.

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Another ConditionFound in Offspring of Older Fathers ANIRIDIA

Am J Hum Genet. 2002 November; 71(5): 1138–1149.
Published online 2002 October 17. PMCID: PMC385089

Copyright © 2002 by The American Society of Human Genetics. All rights reserved.
Frequent Chromosome Aberrations Revealed by Molecular Cytogenetic Studies in Patients with Aniridia
John A. Crolla1 and Veronica van Heyningen2
1Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom; and 2Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh
Address for correspondence and reprints: Dr. John Crolla, Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, United Kingdom. E-mail: John.Crolla@salisbury.nhs.uk
Received June 17, 2002; Accepted August 21, 2002.
This article has been cited by other articles in PMC.






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Paternal age effect
From Wikipedia, the free encyclopedia
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The paternal age effect describes the influence that a father's age has on the chances of conferring a genetic defect to his offspring. Generally, older men have a greater probability of fathering children with a genetic defect than younger men do.[citation needed] This is seen as likely due to genetic copying errors which may increase in number after repeated spermatogenesis cycles over a man's lifetime.

Contents [hide]
1 Disorders correlated with paternal age
2 See also
3 References
4 External links



[edit] Disorders correlated with paternal age
Achondroplasia (dwarfism); craniofacial disorders such as Apert syndrome and Crouzon Syndrome; mental retardation of unknown etiologies; autism; and 25% of schizophrenia cases are correlated with advanced paternal age.

Other disorders related to advanced paternal age are:

Wilms' tumor
Thanatophoric dysplasia
Retinitis pigmentosa
Osteogenesis imperfecta type IIA
Acrodysostosis
Fibrodysplasia ossificans progressiva
Aniridia
Bilateral retinoblastoma
Multiple exostoses
Marfan Syndrome
Lesch-Nyhan syndrome
Pfeiffer Syndrome
Wardenburg Syndrome
Treacher-Collins Syndrome
Soto’s basal cell nevus
Cleidocranial dysostosis
Polyposis coli
Oculodentodigital syndrome
Costello syndrome
Progeria
Recklinghausen’s neurofibromatosis
Tuberous sclerosis
Polycystic kidney disease
Hemophilia A
Duchenne muscular dystrophy
Athetoid Cerebral Palsy
Dystonic Cerebral Palsy
Congenital Hemiplegia

[edit] See also
Maternal age effect

[edit] References
Crow JF (1997). "The high spontaneous mutation rate: Is it a health risk?". PNAS 94: 8380–6. 
Bertram L, Busch R, Spiegl M, Lautenschlager NT, Müller U, Kurz A (1998). "Paternal age is a risk factor for Alzheimer disease in the absence of a major gene". Neuroscience 1 (4): 277–80. 
Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, Gunnell D (2004). "Paternal age and schizophrenia: a population based (sic) cohort study". BMJ Online. 
DNA repair activity linked to paternal age effect. University of Texas Health Science Center at San Antonio (2000-08-28).
Bray I, Gunnell D, Smith GD (2006). "Advanced paternal age: How old is too old?". Journal of Epidemiology and Community Health 60: 851–3. 
Montgomery SM, Lambe M, Tomas O, Ekbom A (2004). "Paternal age, family size, and risk of multiple sclerosis". Epidemiology 15 (6): 717–23. 
Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E (2006). "Advancing paternal age and autism". Archives of General Psychiatry 63 (9): 1026–32. 
Sanders L (2005). College scientist named Ellison Senior Scholar. University of Southern California College of Letters, Arts & Sciences.
Fisch H, Hyun G, Golden R, Hensle TW, Olsson CA, Liberson GL (2003). "The influence of paternal age on down syndrome (sic)". J Urol 169 (6): 2275–8. PMID 12771769. 
Rami B, Schneider U, Imhof A, Waldhör T, Schober E (1999). "Risk factors for type I diabetes mellitus in children in Austria" 158 (5): 362–6. PMID 10333115. 
Singh NP, Muller CH, Berger RE (2003). "Effects of age on DNA double-strand breaks and apoptosis in human sperm". Fertility and sterility 80 (6): 1420–30. 
Lauritsen MB, Pedersen CB, Mortensen PB (2005). "Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study". J Child Psychol Psychiatry 46 (9): 963–71. PMID 16108999. 
Wohl M, Gorwood P (2007). "Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring". Eur Psychiatry 22 (1): 22–6. PMID 17142012. 
Schizophrenia Research Forum: Current Hypotheses (2006-03-28).
Choi J-Y, Lee K-M, Park SK, Noh D-Y, Ahn S-H, Yoo K-Y, Kang D (2005). "Association of paternal age at birth and the risk of breast cancer in offspring: a case control study". BMC Cancer 5: 143. 
NW Andrology & Cryobank.
Croen LA, Najjar DV, Fireman B, Grether JK (2007). "Maternal and paternal age and risk of autism spectrum disorders". Archives of Pediatrics and Adolescent Medicine 161 (4): 334–40. 
Tarin JJ, Brines J, Cano A (1998). "Long-term effects of delayed parenthood". Human Reproduction 13 (9): 2371–6. 

Indeed, 30% of hemophilia cases are due to new mutations.[5]Older maternal grandfathers. A Paternal Age Effect

Indeed, 30% of hemophilia cases are due to new mutations.[5]

We have a male biological clock, Ask Men. com Here are 5 things you didn't know about men

by Ross Bonander,
Wednesday March 19, 2008
2- Men have their own biological clock
We do indeed have a biological clock of sorts, although instead of one that stops, ours becomes increasingly unreliable over time.

As men age they lose approximately 1% of testosterone every year. The consequence of this deficit is that sperm production decreases, and those that are produced are of a lower quality. For this reason, the older we get the greater the chances that the children we spawn suffer from conditions such as autism, schizophrenia and Down syndrome, to name a few.

To explain why, fertility experts point to cell division: About every 16 days the cells that create sperm and determine their genetic code go through the process of dividing. By the age of 50 that division has happened hundreds and hundreds of times, and each time it did the genetic code was vulnerable to changes that can augment genetic deterioration, making birth defects increasingly likely.

Older Dad's sperm can cause Genetic Disorders Like Autism and Schizophrenia-From 1999 to 2004, the number of new fathers aged 40 or over rose by 1/3

Rates of some cancers, autoimmune disorders, birth defects, Alzhiemer's, etc. also are known to rise with the age of the father at conception or the age of the mother's father at her conception. http://en.wikipedia.org/wiki/Paternal_age_effect


Below are the faces of some of the researchers, living and dead who warn or research about the role of paternal age. Leslie B. Raschka, MD, psychiatrist tried to warn and he could not get published in the major journals. See end of this post for the paper from the Chinese Medical Journal 2000.

Michael Craig Miller, MD psychiatrist

Harry Fisch,MD Male Fertility

Finn Rasmussen Epidemiologist

Avi Abraham Reichenberg, MD Psychiatrist

Dolores Malaspina, MD psychiatrist

James F. Crow geneticist

J.B.S. Haldane geneticist

Lionel Penrose Geneticist

Wilhelm Weinberg Obstetrician, researcher


It was Wilhelm Weinberg in 1912 who noted that paternal age not maternal age was connected with abnormalities in offspring.







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 34 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.
2. Nieschlag E, Lammers U, Freischem C W, et al. Reproductive Functions in Young Fathers and Grandfathers. J Clin Endocrinol Metab 1982; 55: 676.
3. Holstein A F. Spermatid Differentiation In Man During Senescence. In. : Andre J, ed. Proceedings of the Fourth International Symposium on Spermatology; 1982 June; The Hague. Martinus Nijhoff, 1983: 15-18.
4. Homonnai Z T, Fainman N, David M P, et al. Semen Quality and Sex Hormone Pattern of 39 Middle Aged Men. Andrologia 1982; 14(2): 164.
5. Bacetti B, Renieri T, Selmi M G, et al. Sperm Structure and Function in 70 Year Old Humans. In: Andre J, ed. Proceedings of the Fourth International Symposium on Spermatology; 1982 June; The Hague. Martinus Nijhoff, 1983: 19-23.
6. Spira A, Ducot B. Variations physiologiques du spermatogramme. Ann Biol Clin (Paris) 1985; 43: 55.
7. Sternbach H. Age-Associated Testosterone Decline in Men: Clinical Issues for Psychiatry. Am J Psychiatry 1998; 155: 1310.
11
8. Bishop M W H. Aging and Reproduction in the Male. J Reprod Fert 1970; (Suppl. 12): 65.
9. Schwartz D, Mayaux MJ, Spira A, et al. Semen characteristics as a function of age in 833 fertile men. Fertil Steril, 1983; 39: 530.
10. Vogel F. Editorial. A probable sex difference in some mutation rates. Am J Hum Genet, 1977; 29: 312.
11. Haldene J B S. The Mutation Rate of the Gene for Haemophilia and it’s Segregation Ratios in Males and Females. Ann Hum Genet 1947; 13: 261.
12. Vogel F, Motulsky AG. Human Genetics, Problems and Approaches. Berlin: Heidelberg: New York: Springer Verlag, 1979; 282.
13. Crow J F, Denniston C. Mutation in Human Populations. In: Harris H, Hirschhorn K, eds. Advances in Human Genetics. New York: London: Plenum Press, 1985; 14: 59-123.
14. Shimmin L C, Chang B H, Li W. Male-driven evolution of DNA sequences. Nature 1993; 362: 745.
15. Vogel F, Rathenberg R. Spontanious Mutation in Man. In: Harris H, Hirschhorn K, eds. Advances in Human Genetics. New York: London: Plenum Press, 1975; 5: 223-318. 12

16. Evans HJ. Mutation as a cause of genetic disease. Phil Trans R Soc Lond 1988; 319: 325.
17. Berg K, Bochkov N P, Coutelle C, et al. Bull WHO 1986; 64(2): 205.
18. Penrose L S. Parental Age and Mutation. The Lancet 1955; 2: 312.
19. Modell B, Kuliev A. Changing paternal age distribution and the human mutation rate in Europe. Hum Genet 1990; 86:198.
20. Murdoch J L, Walker B A, Hall J G, et al. Achondroplasia-a genetic and statistical survey. Ann Hum Genet 1970; 33: 227.
21. Rogers J G, Danks D M. Birth defects and the father. Med J Austr 1983; 2: 3.
22. Karp L E. Older Fathers and Genetic Mutations. Am J Med Genet 1980; 7: 405.
23. Tunte W. Human Mutations and Paternal Age. Hum Genet 1972; 16: 77.
24. Modell B, Kuliev A. Impact of public health on human genetics. Clin Genet 1989; 36: 286.
　
　
13
25. Carothers A D, McAllion S J, Paterson C R. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986; 23: 227.
26. Jones K L, Smith D W, Sedgwick Harvey M A, et al. Older paternal age and fresh gene mutation: Data on additional disorders. J Ped 1975; 86: 84.
27. Hook EB. Paternal Age and Effects on Chromosomal and Specific Locus Mutations and on Other Genetic Outcomes in Offspring. In: Mastroianni L Jr, Paulsen C A, eds. Aging, Reproduction and the Climacteric. New York and London: Plenum Press, 1986: 117-145.
28. Wilkin D J, Szabo J K, Cameron R, et. al. Mutations in Fibroblast Growth -Factor Receptor 3 in Sporadic Cases of Achendroplansia Occur Exclusively on the Paternally Derived Chromosome. Am J Hum Genet 1998; 63: 711.
29. Orioli J M, Castilla E E, Scarano G, et. al. Effect of Paternal Age in Achondroplasia, Thanatophoric Dysplasia and Osteogenesis Imperfecta. Am J Med Genet 1995; 59: 209.
30. Erickson D, Cohen M M Jr., A Study of parental age effects on the occurrance of fresh mutations for the Apert syndrome. Ann Hum Genet 1974; 38: 89.

14
2. Bordson B L, Leonardo VS. The appropriate upper age limit for semen donors: a review of the genetic effects of paternal age. Fertil Steril 1991; 56: 397.
1. Sankaranarayanan K. Ionizing radiation and genetic risks IX. Estimates of the frequencies of mendelian diseases and spontaneous mutation rates in human populations: a 1998 perspective. Mutat Res 1998; 411: 129.
2. Friedman J M. Genetic Disease in the Offspring of Older Fathers. Obstet Gynecol 1981; 57: 745.
3. Carlson K M, Bracamontes J, Jackson C E, et al. Parent-of-Origin Effects in Multiple Endocrine Neoplasia Type 2B. Am J Hum Genet 1994; 55: 1076.
4. Moloney D M, Slaney S F, Oldridge M, et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 1996; 13: 48.
5. Osborne J P, Fryer A, Webb D. Epidemiology of Tuberous Sclerosis. Ann NY Acad Sci 1991; 615: 125.
6. Schuffenecker I, Ginet N, Goldgan D, et al. Prevalence and Parental Origin of De Novo RET Mutations in Multiple Endocrine Neoplasia Type 2A and Familial Medullary Thyroid Carcinoma. Am J Hum Genet 1997; 60: 233.
　
15
7. Crow J F. How Much Do We Know About Spontaneous Human Mutation Rates? Environ Mol Mutagen 1993; 21: 122.
8. Crow T J. Editorial. Mutation and psychosis: A suggested explanation of seasonality of birth. Psychol Med 1987; 17: 821.
9. Gordon A. The Incidence of Psychotic Disorders in Individuals Whose Parents Married at an Advanced Age. Med Records 1938; 148: 109.
10. Kinnell H G. Parental Age in Schizophrenia. Br J Psychiatry 1983; 142: 204.
11. Hare E H, Moran PAP. Raised Parental Age in Psychiatric Patients: Evidence for the Constitutional Hypothesis. Br J Psychiatry 1979; 134: 169.
12. Raschka L B. Parental Age and Schizophrenia. Magyar Andrologia-Hungarian Andrology 1998/2; III: 47.
13. Bertram L, Busch R, Spiegl M, et al. Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics 1998; 1: 277.
14. Whalley L J, Thomas B M, Starr J M. Epidemiology of Presenile Alzheimer’s Disease in Scotland (1974-88). 11. Exposures to Possible Risk Factors. Br J Psychiatry 1995; 167: 732.
16

3. Urikami K, Adachi Y, Takahashi K. A Community-Based Study of Parental Age in Alzheimer-Type Dementia in Western Japan. Arch Neurol 1988; 45: 375.
http://diabetes.diabetesjournals.org/cgi/content/full/54/2/563

Diabetes age of parents etc risk factor 2005

CMJ_netprints
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Infant Mortality in Remote and Poverty-stricken Areas in China: A ... THE AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS (Leslie B. Raschka M.D.) ...www.aiabeijing.org/netprints/01/02/0102.htm - 14k - Cached - Similar pages

Advanced PARENTAL age and chronic fatigue

J Clin Psychiatry. 1978 Oct;39(10):754-5.Links
Family history of alcoholism in patients with chronic fatigue.Swanson DW, Moore GL, Nobrega FT.
Persistent fatigue is a common functional physical complaint. This study reports a possible relationship between parental alcoholism or advanced parental age at the patient's birth and the functional fatigue syndrome.

But as they delay fatherhood, then their sperm is more likely to carry mistakes and their offspring may be adversely affected by these changes,"

^^ Click to view at full size




Autism risk for delaying dads

Janelle Miles
January 29, 2008 11:00pm
EVIDENCE is mounting that men who become fathers in their 40s or older are more likely to produce children with brain development disorders such as schizophrenia and autism.Queensland researchers have found adult mice born to older fathers have differently shaped brains and are generally more anxious and less adventurous than those fathered by younger animals.
Senior investigator John McGrath, of the Queensland Centre for Mental Health Research, said brain scans of the mice showed those born to older fathers had thicker cerebral cortexes.
Previously, population-based studies have found the children of fathers aged 40 and older have twice the risk of schizophrenia and a six-times increased likelihood of autism than those born to dads in their 20s.
"What we've found in the mice is reminiscent of autism because there's some reasonable evidence about early brain overgrowth in autism," Professor McGrath said.
"The results of this type of research support concern about the impact of advanced paternal age."
Queensland Brain Institute researcher Claire Foldi, who conducted the mice study for her honours thesis, presented her findings to the Australian Neuroscience Society's annual meeting in Hobart this week.
Professor McGrath said the results needed to be replicated to give them scientific validity.
But scientists already suspect older men are more likely to produce sperm containing an increased number of DNA errors, which are passed on to offspring.
"The dads are fine. But as they delay fatherhood, then their sperm is more likely to carry mistakes and their offspring may be adversely affected by these changes," Professor McGrath said.
While public health messages have tended to focus on problems associated with delaying motherhood, Professor McGrath said advanced paternal age might also have implications.
"Ageing mothers have had a lot of attention. But the new results suggest that the fathers also may be needing attention," he said.

Father's Age Feeds Autism Risk, in Blog of Simons Foundation

Father's advanced age feeds autism risk

Helen Pearson 25 February 2008 09:00:00 EST
Children of fathers aged 40 or older are nearly six times more
likely to have autism.
Are older fathers more likely to have children with autism? A series of epidemiological studies is giving credence to the idea, suggesting that, with age, sperm may accumulate damage that increases risk in the next generation.

Advancing age of the father is known to be a significant risk factor for schizophrenia1. These studies — along with anecdotal suggestions that fathers of autistic children tend to be older than average — prompted Avi Reichenberg of Mount Sinai School of Medicine, New York, to launch one of the first thorough epidemiological investigations into a link between the two.

Reichenberg and his colleagues had access to a vast database of health information collected from more than 132,000 Israeli adolescents who underwent draft board assessment, including psychiatric screening, before entering the army. The researchers were able to identify those who were diagnosed with autism spectrum disorders (ASD), along with the age of their parents.

Children of fathers in their 30s are about 1.6 times more likely to have ASD than children of fathers below age 30, the study found2. Compared with the youngest group, children of fathers aged 40 or older were nearly six times more likely to have ASD. “It was much stronger than we had thought,” Reichenberg says.

Since then, a handful of other epidemiology studies have backed the autism-paternal age connection. In one of these3, a team led by Lisa Croen of Kaiser Permanente Northern California Division of Research in Oakland, California, mined a health database of more than 130,000 births and found that each decade of paternal or maternal age increased risk of autism spectrum disorder by around 30%.

Paternal age “is still a relatively small contributor,” Croen says, “but when you see something that keeps coming up in different populations and study designs you start thinking there must be something to this.”

The link may be real, but researchers have yet to explain what causes it. Perhaps, says Croen, older parents are simply more attuned to the development of their children and therefore more likely to get a diagnosis. “It could be an artifact,” she says. “We don’t have enough data yet to really rule that out.”

Genetic origins
Another simple explanation is that fathers who themselves have autism or mild social deficits are likely to marry and have children at a later age than other men, and these children inherit factors putting them at high risk of developing the condition themselves.

But Reichenberg says that in his studies he has found no link between traits such as shyness, sensitivity and aloofness in parents and the age at which they have children. “It’s not definitive but the evidence is definitely against such an explanation,” he says.

Many researchers instead favor a genetic origin for the phenomenon. Male germ cells go through multiple rounds of division to manufacture sperm throughout a man’s life and, according to one idea, they may accumulate DNA damage as the molecule is copied again and again.

Sperm produced by older men are more likely to carry genetic defects, and these defects could boost their children’s risk of autism. Female germ cells divide far fewer times.

It is also possible that older sperm are more likely to acquire epigenetic defects: ones that do not change the DNA sequence itself, but that alter the activity of genes due to structural or chemical changes to DNA such as methylation.

These genetic changes arise in the egg or sperm rather than being inherited from the parents. Both concepts fit with the knowledge that the majority of ASD cases have a genetic cause, even though they are also the first in a family.

For precedent, geneticists point to a condition called achondroplasia, a common cause of dwarfism and the textbook example of a genetic condition associated with paternal age. The risk of sperm carrying a single point mutation in the gene for a growth factor receptor is thought to increase with the age of the father.

“It would be overwhelmingly logical,” for something similar to be going on in some cases of autism, says human geneticist Arthur Beaudet at Baylor College of Medicine in Houston, Texas. Perhaps just one or two of the many genes associated with the disorder are susceptible to detrimental point mutations as the germ cells age.

Beaudet says he would like to see genetic and epigenetic analyses of single sperm to see if mutation rates differ in the fathers of autistic children, and between younger and older men. “That would be the approach I’d be enthusiastic about,” he says. Reichenberg says that he is pursuing such studies.

Because there are few clearly defined genes for autism risk, it’s not yet clear where to look for these increased mutation rates. And genome-wide studies looking for differences in the rates of point mutations in many sperm are still too expensive and laborious.

Copy numbers
Last year, molecular studies showed that mutations called copy number variations (CNVs) — genomic chunks that can be deleted or duplicated from one person to the next — appear to be major contributors to sporadic autism.

A group led by Michael Wigler and Jonathan Sebat at the Cold Spring Harbor Laboratory in New York looked for CNVs that were present in autistic individuals, but not in their parents. They found CNVs in 10% of children with sporadic autism, 2% of those with familial autism and 1% of controls4.

This suggests that many more cases of sporadic autism may be attributable to spontaneous mutations — either CNVs or more subtle mutations — than had been realized.

Sebat has not examined whether the frequency of these CNV mutations increases in aging germ cells — but he suspects it might. “We don’t have data one way or the other,” he says, “but it’s a very tantalizing hypothesis.”

Many of the cellular systems that protect DNA from mutation might begin to fail in aging germ cells, so that their mutation rate increases, Sebat suggests. He is planning to test in a larger group of autistic individuals whether the CNV mutations are more common in children of older parents.

Reichenberg and his colleagues are also testing these hypotheses. In one study, they are trying to compare old and young fathers of autistic children, looking for differences in the rate of new mutations and their association to genetic hotspots previously linked to autism.

They are also doing mouse studies to explore whether offspring of older males tend to suffer more behavioral problems that mimic autism.

There remains some debate about whether the mother’s age is as important a risk factor as that of the father, and studies have differed in their findings. A maternal age effect is harder to tease out, partly because women have children within a more limited age range than men: very few over-40 women have children.

In her study, Croen found that maternal age is just as important and says that other studies have lacked the statistical power to tease this out. “Our data show that maternal age is also in the mix,” she says.

The fact that schizophrenia risk also increases with age leads some researchers to wonder whether some of the same genes may contribute to both disorders – and perhaps to other psychiatric conditions as well.

It’s a “feasible hypothesis”, Reichenberg says, “and I believe a worthwhile one to pursue.”

References:

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

Malaspina D et al. Arch. Gen. Psychiatry 58, 361-367 (2001) PubMed ↩

Reichenberg A. et al. Arch. Gen. Psychiatry 63, 1026-1032 (2006) PubMed ↩

Croen L. et al. Arch. Pediatr. Adolesc. Med. 161, 334-340 (2007) PubMed ↩

Sebat J. et al. Science 316, 445-449 (2007) PubMed ↩
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