Copy number variations and rare de novo mutations may also be a risk factor for schizophrenia

"This class of mutation, it turns out, is more likely to occur in people who have children late in their 30s and 40s—a segment of the population that has been growing in recent years. Copy number variations and rare de novo mutations may also be a risk factor for schizophrenia."





Biology of Mental Disorder
By Eric Kandel NEWSWEEK
Published Jun 27, 2009
From the magazine issue dated Jul 13, 2009


Understanding the biology of mental illness would be a paradigm shift in our thinking about mind. It would not only inform us about some of the most devastating diseases of humankind but, because these are diseases of thought and feeling, it would also tell us more about who we are and how we function. I naively thought we were on the verge of such a paradigm change in 1983, when James Gusella and Nancy Wexler were tracking down the gene that causes Huntington's disease. I expected that within 10 years we would have found the major genes that contribute to schizophrenia, depression, and autism. Since then, there has been a lot of enthusiasm about genes and mental illness and some false starts, but surprisingly little progress.

In the past few years, however, certain advances in genetics have given us new reasons for optimism. Now that we can look at the whole human genome, there is a logic to it that we could not appreciate when looking at genes in isolation. As a result, there is reason to believe that the next 10 to 20 years will be more fruitful than the past two decades have been.

One major advance has been the discovery that there is much more variability in the genome than had been anticipated, and that this takes the form of copy number variation (CNV). These are duplications or deletions of segments of a chromosome, often involving several or tens of genes, that enhance or depress the actions of specific genes. A well-known example of a CNV is the extra copy of chromosome 21 resulting in Down syndrome. It has recently been discovered that this type of variation is extremely common in everyone's genome.

A specific type of CNV—called de novo mutations—may be relevant to autism. De novo mutations occur in only one tissue of the body—the sperm or egg—and may crop up relatively late in life (during reproduction), appearing only in the next generation. This fits the pattern of autism, a genetic disease that occasionally emerges in families in which the mother doesn't have autism, the father doesn't have it, and the other sibling doesn't have it. A mother and father could pass this mutation down to one of their children, even though the mutation would not appear in their chromosomes but only in their sperm or eggs. The children would now have the mutation and could pass it on from generation to generation. De novo CNVs may explain the rise in the true incidence of autism in recent years. (Autism cases have also risen in part because of better diagnostic criteria.) This class of mutation, it turns out, is more likely to occur in people who have children late in their 30s and 40s—a segment of the population that has been growing in recent years. Copy number variations and rare de novo mutations may also be a risk factor for schizophrenia.

Overcome Infertility - Understanding the Male Biological Clock

Overcome Infertility - Understanding the Male Biological Clock
By Kyle J Norton

Infertility is defined as the inability of a couple to conceive after 12 months of unprotected sexual intercourse or the cannot carry the pregnancy full term. It effects over 5 million couples alone in the U. S. and many times more in the world. Because of an unawareness of treatments, only 10% seek help from professional specialists. In fact, about 35% of infertility is caused by the male's inability to fertilize. 35% is caused by the female's inability to conceive, 10% attributes to both, and 10 % is considered a failure with an unknown cause.

Even though the sperm in the male reproductive organ do not change much, the quality and quantity of sperm may be reduced by low levels of testosterone due to ageing. Therefore, you can see why a couple in their late 20's is easier to conceive than a couple with a wife in her 20's and a husband at the age of 40 and more. Study shows that the odds of male fertility rate decreases at an alarming rate of 11% every year and the chance for his partner to conceive declines even further.

According to the study of European Society of Human Reproduction and Embryology, the rate of miscarriage also increases substantially when the father was over the age of 35.
1. Nearly 17 percent if the father was over 34 years old.
2. Around 20 percent if the father was between the ages of 35 and 39.
3. Over 32 percent if the father was older than 44.

Most couple delay unwanted conception by having the female partner take contraceptive pill or by using condoms, or other methods. Unfortunately, by the time they think that they are ready to have children, they are in their mid thirties and according to the above statistics, the rate of fertility is low and the risk of miscarriage is increased substantially, not counting the risk of giving birth to a child with a defection, including chromosomal abnormalities. Like an old car, no matter how much money which you spend each year to fix it, it will never work like when it was new.

It is wise for a couple to conceive no later then the age of late 20's and early 30's to prevent any unnecessary stress caused by infertility within 12 months after they decide to have a baby.

For the best pregnancy self help program review, please visit http://bestfertility.blogspot.com/
For series of Infertility Articles, please visit http://fertility-infertility.blogspot.com/

All rights reserved. Any reproducing of this article must have the author name and all the links intact.
"Let Take Care Your Health, Your Health Will Take Care You" Kyle J. Norton
I have been studying natural remedies for disease prevention for over 20 years and working as a financial consultant since 1990. Master degree in Mathematics, teaching and tutoring math at colleges and universities before joining insurance industries. Part time Health and entertainment Article Writer.

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

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

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


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

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

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

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

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

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

And why are older fathers not told of the risks?

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

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

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

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

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

CONCLUSIONS: The risk of an adverse pregnancy outcome is highest if both partners are advanced in age.

Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study
Authors: Elise de La Rochebrochard1; Patrick Thonneau2

Source: Human Reproduction, Volume 17, Number 6, June 2002 , pp. 1649-1656(8)

Publisher: Oxford University Press


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Abstract:

BACKGROUND: It is well known that miscarriage risk increases with age. However, studies usually investigate only maternal age effects. We investigated both maternal age and paternal age effects on miscarriage risk to provide insight into this frequent reproductive failure. METHODS: The last planned pregnancies (n = 3174) that ended in a birth or miscarriage were analysed in a retrospective population-based study on women aged 25–44 years in Denmark, Germany, Italy and Spain. Maternal and paternal ages were analysed together, using a single variable `couple age' in a multivariate logistic regression analysis, with couples composed of a woman and a man both aged 20–29 years forming the reference group. RESULTS: After adjustment for various factors (e.g. reproductive history, country), we found that the risk of miscarriage was higher if the woman was aged 35 years, as has already been reported in a number of studies. However, the increase in risk was much greater for couples composed of a woman aged 35 years and of a man aged 40 years. Potential source of bias (especially `reproductive compensation') are discussed. CONCLUSIONS: The risk of an adverse pregnancy outcome is highest if both partners are advanced in age.
Keywords: ageing; fetal death; maternal age; paternal age; spontaneous abortion

Document Type: Research article

Affiliations: 1: INED (National Demographic Studies Institute), 75020 Paris and 2: Research Group in Human Fertility, INSERM, La Grave Hospital, 31052 Toulouse, France

Father's Sperm Delivers Much More Complex Material Than Previously Thought

Father's Sperm Delivers Much More Complex Material Than Previously Thought
ScienceDaily (June 15, 2009) — It was long believed that conception does not involve a meeting of equals. The egg is a relatively large, impressive biological factory compared with the tiny sperm, which delivers to the egg one copy of the father's genes. However, a new study from Huntsman Cancer Institute (HCI) at the University of Utah reveals that the father's sperm delivers much more complex genetic material than previously thought. The findings could lead to a diagnostic test to help couples deal with infertility.

Researchers discovered particular genes packaged in a special way within the sperm, and that may promote the development of the fetus.

"Our findings show that the father plays an active role in packaging his genome to help ensure a healthy baby," says study co-leader Brad Cairns, Ph.D., investigator with HCI and the Howard Hughes Medical Institute, and professor of oncological sciences at the University of Utah. "However, they also raise the possibility that a man's aging, health and lifestyle may alter this packaging and negatively affect fertility and embryo development."

During fetal development, certain genes make decisions about organ and tissue development. The new research shows that in sperm, these genes are wrapped in special packaging materials called 'modified histones.' These modified histones appear to be key factors in ensuring genes are activated or repressed at the right level, place and time, which helps the fertilized egg develop properly.

Chromosomes are long strands of DNA containing thousands of genes, and their packaging helps determine which genes turn on and off. Understanding how these genes are activated or repressed leads to a better understanding of how disorders like birth defects and cancer develop.

"Genes have on-and-off switches, and understanding them allows us to target them, leading to possible treatments, cures or prevention strategies," says Cairns. "That's the good news."

The study is set for publication June 14 – a week before Father's Day – in the online edition of the journal Nature. The research involved collaboration between Cairns' lab at HCI and the University of Utah's in vitro fertilization (IVF) and andrology lab led by Doug Carrell – along with their joint graduate student, Sue Hammoud.

An implication of this study is that factors such as genetic mutations, age or lifestyle may affect sperm chromosome packaging, leading to infertility. "We are hopeful that this work will soon lead to a clinical diagnostic test that will help couples with infertility problems make better informed decisions regarding their prospects for a healthy child. We will also be testing if aspects of a man's lifestyle – such as age, diet or health – affect proper packaging and fertility," says Cairns. Other future work includes how decision-making genes are packaged in eggs, which remains a major mystery.

Fathers’ Age and Autism

Fathers’ Age and Autism
Fathers’ Age as Contributor to Risk for Autism
Leslie Feldman
The average age of fatherhood is increasing in the US and in Western Europe. Some research shows that offspring of older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. [The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent (Malaspina et al., 2006).] Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladottir and colleagues (2007) reported increased diagnoses of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age. Crow said, the evidence suggested that the greatest mutational health hazard in the population is fertile old men.

A study by Reichenberg et al. (2006) found a strong connection between cases of autism and advancing paternal age. Reichenberg and colleagues, who found more autism as paternal age increased, also found that the ratio of girls to boys in this cohort was 1:1, suggesting that this was a special subset of autism, maybe de novo rather than familial autism.

What might be the mechanism that produces higher rates of disorders among children of older fathers? The DNA in a 20 year-old male has been copied approximately100 times but in a 50 year-old father it has been copied over 800 times. Singh and colleagues (2003) studied differences in the sperm of older and younger men. Men over age 35 have sperm with lower motility and more highly damaged DNA in the form of double-strand breaks. The older group also had fewer apoptotic cells, an important discovery. (Apoptosis is form of cell death that protects the parent organism from problems or that permits differentiation, as in resorption of a tadpole’s tail.) A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage, as most other cells do. As a result, the only way to avoid passing DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age. Singh is quoted in Science Blog (Sullivan, 2002) as explaining that, “In older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated.”

Sources

The following list of sources is for works cited in this document or for other studies finding a connection between age of fathers at conception and various disorders. Access to some of the Web-based resources may be limited because of the policies of the publishers.

Atladottir, H. O., Parner, E. T., Schendel, D., Dalsgaard, S., Thomsen, P. H., & Thorsen, P. (2007). Time trends in reported diagnoses of childhood neuropsychiatric disorders. Arch Pediatr Adolesc Med., 161, 193-198. Link

Brown et al. (2002): Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry, 159, 1528-1533. Link

Bray, I., Gunnell, D., & Smith, G. D. (2006). Advanced paternal age: How old is too old? Journal of Epidemiology and Community Health, 60, 851-853. Link

Burd et al., (1999). Prenatal and perinatal risk factors for autism. J. Perinatal. Med., 27, 441-450. Link

Byrne, M., Agerbo, E., Ewald, H., Easton, W. W., & Mortensen, P. D. (2003). Parental age and risk of schizophrenia, A case control study. Arch Gen Psychiatry, 60, 673-678. Link

Centers for Disease Control, (2006). How common are Autism Spectrum Disorders (ASD)? Link

Centers for Disease Control. (2002). Prevalence of the Autism Spectrum Disorders (ASDs) in multiple areas of the United States, 2000 and 2002. Atlanta, GA: Author. Link

Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. USA, 94, 8380-8386. Link

Dalman, C., & Allebeck, D. (2002). Paternal age and schizophrenia: Further support for an association. Am J Psychiatry, 159, 1591-1592. Link

Gillberg, C. (1980). Maternal age and infantile autism. J. Autism and Developmental Disorders, 10, 293-297. Link

Lauritsen M. B., Pedersen, C. B., & Mortensen, P. B. (2005) Effect of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychology and Psychiatry, 46, 963-971. Link

Miller, M. C. (2006) A new key to Autism. Aetna IntelliHealth, September 25. Link

Malaspina, D., et al. (2001): Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry, 58, 361-367. Link

Malaspina, D. (2006). In session with Dolores Malaspina, MD, MSPH: Impact of childhood trauma on psychiatric illness (interview by N. Sussman). Primary Psychiatry, 13(7), 33-36. Link

Malaspina, D. (2006). Schizophrenia risk and the paternal germ line. Schizophrenia Research Forum. Link

Rasmussen, F. (2006) Paternal age, size at birth, size in young adulthood&mdashrisk factors for schizophrenia. Eur Journal of Endocrinology, 155 Suppl 1:S65-69. Link

Reichenburg, A., Gross, R., Weiser, M. Bresnahan, M., Silverman, J. Harlap, S., et al. (2006). Advancing paternal age and autism. Arch Gen Psychiatry, 63, 1026-1032. Link

Singh, N. P., Muller, C. H., & Burger, R. E. (2003). Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertility and Sterility, 80, 1420-1430. Link

Sipos, A., Rasmussen, R., Harrison, G., Tynelius, P., Lews, G., Leon, D. A., et al. (2004). Paternal age and schizophrenia: A population based cohort study. BMJ, 329, 1070. Link

Sullivan, B. J. (2002). Research reveals a cellular basis for a male biological clock. Science Blog, 2002-11-25 22:31. Link

Tarin, J. J., Brines, J., & Cano, A. (1998). Long-term effects of delayed parenthood. Human Reproduction, 13, 2371-2376. Link

Tsuchiya, K. J., Takagai, S., Kawai, M., Matsumoto, H., Nakamura, K., Minabe, Y., et al. (2005). Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophrenia Research, 76, 337-342. Link

Wohl, M. & Gorwood, P. (2006). Paternal ages below or above 35 are associated with a different risk for schizophrenia in offspring. Eur. Psychiatry, Dec 1 [Epub ahead of print]. Link

Zammit, S., Allebeck, P., Dalman, C., Lundgerg, I., Hemming, T., Owen, M. J., et al. (2003). Paternal age and risk for schizophrenia. Br. J. Psychiatry, 183, 405-408. Link