Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.

The British Journal of Psychiatry (2008) 193: 316-321. doi: 10.1192/bjp.bp.107.045120
© 2008 The Royal College of Psychiatrists


Paternal age at birth and high-functioning autistic-spectrum disorder in offspring
Kenji J. Tsuchiya, MD, PhD
Osaka Hamamatsu Joint Research Center for Child Mental Development, and Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Kaori Matsumoto, MA and Taishi Miyachi, MD, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

Masatsugu Tsujii, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, and Faculty of Sociology, Chukyo University, Nagoya, Japan

Kazuhiko Nakamura, MD, PhD, Shu Takagai, MD, PhD, Masayoshi Kawai, MD, PhD, Atsuko Yagi, MD, PhD, Kimie Iwaki, MD and Shiro Suda, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Genichi Sugihara, MD, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

Yasuhide Iwata, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Hideo Matsuzaki, MD, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

Yoshimoto Sekine, MD, PhD and Katsuaki Suzuki, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Toshirou Sugiyama, MD, PhD

Aichi Children's Health and Medical Center, Obu, Japan

Norio Mori, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Nori Takei, MD, PhD, MSc

Osaka Hamamatsu Joint Research Center for Child Mental Development and Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan, and Division of Psychological Medicine, Institute of Psychiatry, London, UK

Correspondence: Nori Takei, Osaka Hamamatsu Joint Research Center for Child Mental Development (OHJRC–CMD), Hamamatsu University School of Medicine, Handayama 1 Higashiku, Hamamatsu 431-3192, Japan. Email: ntakei@hama-med.ac.jp

Declaration of interest

None. Funding detailed in Acknowledgements.

Background

Previous studies have reported the association between advanced paternal age at birth and the risk of autistic-spectrum disorder in offspring, including offspring with intellectual disability.

Aims

To test whether an association between advanced paternal age at birth is found in offspring with high-functioning autistic-spectrum disorder (i.e. offspring without intellectual disability).

Method

A case–control study was conducted in Japan. The participants consisted of individuals with full-scale IQ70, with a DSM–IV autistic disorder or related diagnosis. Unrelated healthy volunteers were recruited as controls. Parental ages were divided into tertiles (i.e. three age classes). Odds ratios and 95% confidence intervals were estimated using logistic regression analyses, with an adjustment for age, gender and birth order.

Results

Eighty-four individuals with autistic-spectrum disorder but without intellectual disability and 208 healthy controls were enrolled. Increased paternal, but not maternal, age was associated with an elevated risk of high-functioning autistic-spectrum disorder. A one-level advance in paternal age class corresponded to a 1.8-fold increase in risk, after adjustment for covariates.

Conclusions

Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.




Related articles in BJP:


Highlights of this issue
Kimberlie Dean
BJP 2008 193: A14. [Full Text]

Older fathers are almost twice as likely to have autistic children as younger men, research has found.

Father age link to autism in children
Older fathers are almost twice as likely to have autistic children as younger men, research has found.

By Rebecca Smith, Medical Editor
Last Updated: 12:31AM BST 01 Oct 2008

A small study of children with autism spectrum disorder, the umbrella term for a range of similar conditions, found they were more likely to have been fathered by men over the age of 33.

There was no link with the condition and the mother's age, the Japanese study found.

The research involved 84 children with high-functioning autism spectrum disorders, meaning they had the social impairments of the condition but had normal intelligence, and 208 children without the disorder.

Children whose fathers were over 33 were 1.8 times more likely to have autism than those fathers were under 29. Men who fathered children between the age of 29 and 32 were 30 per cent more likely to have an autistic child.

The research is published in the British Journal of Psychiatry.

This is the first study to explore the effect of paternal age on the risk of high-functioning autistic spectrum disorder. Its findings correspond with previous studies which have shown a link between older fathers and a low IQ in children.

Benet Middleton, director of communications at The National Autistic Society, said: "The causes of autism are still being investigated. Many experts believe that the pattern of behaviour from which autism is diagnosed may not result from a single cause. Autism affects around one in 100 people in the UK and does not solely affect children of older parents.

"Members of the NAS are made up of parents of children from a variety of ages and backgrounds; in addition there is evidence to suggest that complex genetic factors are responsible for some forms of autism."

Some experts have argued that the measles, mumps and rubella vaccination is linked to the development of autism but this has been widely discredited and other studies have failed to find any link.

Autism Doc claims government led witch hunt against him

Autism Doc claims government led witch hunt against him
Sep 28 2008 by Phil Doherty, Sunday Sun

THE man at the centre of the triple jab controversy has accused the Government of conducting a witch hunt against him.

Dr Andrew Wakefield has been pilloried by the medical establishment after he voiced fears 10 yeas ago the Measles Mumps and Rubella inoculation could cause autism in some kids it was given to.

Now working in the USA, he was called back to appear before a General Medical Council disciplinary hearing earlier this year to answer charges of serious professional misconduct.

Speaking for the first time since the hearing was adjourned in July, he said: “What the establishment does is throw stuff at you continuously and then tie you up for years with things like the GMC.

“It is not a question of not vaccinating. I’m not against vaccinations. I don’t know for sure vaccines cause autism but I suspect they do. The opposition just states categorically it does not. But they don’t know either.”

Dr Wakefield and two other colleagues professor Simon Murch and Professor John Walker-Smith, were summoned to the GMC disciplinary hearing over allegations that research they conducted on children breached ethical codes.

If found guilty they face being struck off the medical register.

This follows years of being reviled in parts of the medical world after they published a scientific paper in the Lancet that said there could be a link between the MMR vaccine, and autism and bowel disease.

At a Press conference in 1998 Dr Wakefield said while further research was conducted to see if there was a link, parents should have the single inoculations instead of the triple jabs. At the time of the research it was claimed he had been paid to carry out another study to find out if parents who said their children were damaged by the MMR had a case.

The Lancet said this was a potential conflict of interest and if they had known they would have rejected the research paper.

Dr Wakefield said: “I was accused of going beyond the science when I suggested that parents should have single jabs until the MMR had been properly assessed for risk.

“I had assessed the data and the safety study relied upon by the Department of Health and it was derisory. It was no way as good as the research into the single jabs.

“Bernadine Healy, the former head of the US National Institute for Health, admitted they had altered evidence on the epidemiological studies conducted by the US Government to suit the official line. She admitted the evidence both the US and UK relies on is useless.

“The UK Government has a big dirty secret that it doesn’t want the public to know . . . they agreed to under write any compensation claims for the MMR. This is why they can’t and won’t let their position fail.

“It was inevitable I was going to be dragged in front of the GMC because I dared to question big business. They always come after those who don’t toe their line.”

A Department of Health spokesman said: “We believe that the vaccine has an excellent safety record and studies have confirmed this belief.

“Neither population-based studies or studies in individual children have confirmed a link between MMR vaccine and autism.”

A Brief Overview of the Criteria For Diagnosing Adults with Autism

A Brief Overview of the Criteria For Diagnosing Adults with Autism
September 28th, 2008 by admin | Filed under Uncategorized.
Currently, there is no one single medical test that will definitively diagnose audlts with autism. Instead, the diagnosis is made on the basis of observable characteristics of the individual.
Here is an overview of some of the different diagnostic standards:

I. Autism Diagnostic Interview-Revised (ADI-R)

The Autism Diagnostic Interview-Revised (ADI-R) is a clinical diagnostic instrument for assessing autism in children and adults. The ADI-R is a semi-structured instrument for diagnosing autism in children and adults with mental ages of 18 months and above. The instrument has been shown to be reliable and to successfully differentiate young children with autism from those with mental retardation and language impairments. The ADI-R focuses on behavior in three main areas and contains 111 items which specifically focuses on behaviors in three content areas - they are:

Quality of social interaction, (e.g., emotional sharing, offering and seeking comfort, social smiling and responding to others);

Communication and language (e.g., stereotyped utterances, pronoun reversal, social usage of language); and…

Behavior (e.g., unusual preoccupations, hand and finger mannerisms, unusual sensory interests).

(ADI-R) Scoring

The interview generates scores in each of the three content areas. Elevated scores indicate problematic behavior. For each item, the clinician gives a score ranging from 0 to 3. A score of 0 is given when “behavior of the type specified is probably present but defining criteria are not fully met”; a score of 2 indicates “definite abnormal behavior”; and a score of 3 is reserved for “extreme severity” of the specified behavior.

ICD 10 (World Health Organisation 1992) Diagnostic Criteria

Diagnosis requires that single words should have developed by two years of age or earlier and that communicative phrases be used by three years of age or earlier. Self-help skills, adaptive behaviour and curiosity about the environment during the first three years should be at a level consistent with normal intellectual development. However, motor milestones may be somewhat delayed and motor clumsiness is usual (although not a necessary diagnostic feature). Isolated special skills, often related to abnormal preoccupations, are common, but are not required for diagnosis.

Diagnosis requires demonstrable abnormalities in at least 3 out of the following 5 areas:

1. Failure adequately to use eye-to-eye gaze, facial expression, body posture and gesture to regulate social interaction;

2. Failure to develop (in a manner appropriate to mental age, and despite ample opportunities) peer relationships that involve a mutual sharing of interests, activities and emotions;

3. Rarely seeking and using other people for comfort and affection at times of stress or distress and/or offering comfort and affection to others when they are showing distress or unhappiness;

4. Lack of shared enjoyment in terms of vicarious pleasure in other people’s happiness and/or a spontaneous seeking to share their own enjoyment through joint involvement with others;

5. A lack of socio-emotional reciprocity as shown by an impaired or deviant response to other people’s emotions; and/or lack of modulation of behavior according to social context, and/or a weak integration of social, emotional and communicative behaviours.

Diagnosis also requires demonstrable abnormalities in at least 2 out of the following 6 areas:

1. An encompassing preoccupation with stereotyped and restricted patterns of interest;

2. Specific attachments to unusual objects;

3. Apparently compulsive adherence to specific, non-functional, routines or rituals;

4. Stereotyped and repetitive motor mannerisms that involve either hand/finger flapping or twisting, or complex whole body movement;

5. Preoccupations with part-objects or non-functional elements of play materials (such as their odor, the feel of their surface/ or the noise/vibration that they generate);

6. Distress over changes in small, non-functional, details of the environment.

Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Diagnostic Criteria

A. Qualitative impairment in social interaction, as manifested by at least two of the following:

1. Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction;

2. Failure to develop peer relationships appropriate to developmental level;

3. A lack of spontaneous seeking to share enjoyment, interests or achievements with other people (eg: by a lack of showing, bringing, or pointing out objects of interest to other people);

4. Lack of social or emotional reciprocity.

B. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:

1. Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus;

2. Apparently inflexible adherence to specific, non-functional routines or rituals;

3. Stereotyped and repetitive motor mannerisms (eg: hand or finger flapping or twisting, or complex whole-body movements);

4. Persistent preoccupation with parts of objects

C. The disturbance causes clinically significant impairment in social, occupational, or other important areas of functioning.

D. There is no clinically significant general delay in language (eg: single words used by age 2 years, communicative phrases used by age 3 years).

E. There is no clinically significant delay in cognitive development or in the development of age-appropriate self-help skills, adaptive behavior (other than social interaction), and curiosity about the environment in childhood.

F. Criteria are not met for another specific Pervasive Developmental Disorder, or Schizophrenia.

International Classification of Diseases (ICD-10) issued by the World Health Organization

DIAGNOSTIC CRITERIA FOR AUTISM DISORDER (ICD-10) (WHO 1992)

At least 8 of the 16 specified items must be fulfilled.

a. Qualitative impairments in reciprocal social interaction, as manifested by at least three of the following five:

1. failure adequately to use eye-to-eye gaze, facial expression, body posture and gesture to regulate social interaction.

2. failure to develop peer relationships.

3. rarely seeking and using other people for comfort and affection at times of stress or distress and/or offering comfort and affection to others when they are showing distress or unhappiness.

4. lack of shared enjoyment in terms of vicarious pleasure in other peoples’ happiness and/or spontaneous seeking to share their own enjoyment through joint involvement with others.

5. lack of socio-emotional reciprocity.

b. Qualitative impairments in communication:

1. lack of social usage of whatever language skills are present.

2. impairment in make-believe and social imitative play.

3. poor synchrony and lack of reciprocity in conversational interchange.

4. poor flexibility in language expression and a relative lack of creativity and fantasy in thought processes.

5. lack of emotional response to other peoples’ verbal and non-verbal overtures.

6. impaired use of variations in cadence or emphasis to reflect communicative modulation.

7. lack of accompanying gesture to provide emphasis or aid meaning in spoken communication.

c. Restricted, repetitive and stereotyped patterns of behavior, interests and activities, as manifested by ate least two of the following six:

1. encompassing preoccupation with stereotyped and restricted patterns of interest.

2. specific attachments to unusual objects.

3. apparently compulsive adherence to specific, non-functional routines or rituals.

4. stereotyped and repetitive motor mannerisms.

5. preoccupations with part-objects or non-functional elements of play material.

6. distress over changes in small, non-functional details of the environment.

d. Developmental abnormalities must have been present in the first three years for the diagnosis to be made

To see more on this topic see autismtoday.com/” target=”_new autismtoday.com/.

About The Author
Born in Oklahoma, in 1951, Karen L Simmons had her first book published in 1996. The book, Little Rainman, Autism Through The Eyes of A Child was written to raise awareness about the early detection signs of autism and has sold over 10,000 copies worldwide to parents and educators of these special children.
For more information see AutismToday.com” target=”_new www.AutismToday.com

Economists Against The Paulson Plan

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Economists Against The Paulson Plan

To the Speaker of the House of Representatives and the President pro tempore of the Senate:

26/09/09 As economists, we want to express to Congress our great concern for the plan proposed by Treasury Secretary Paulson to deal with the financial crisis. We are well aware of the difficulty of the current financial situation and we agree with the need for bold action to ensure that the financial system continues to function. We see three fatal pitfalls in the currently proposed plan:

1) Its fairness. The plan is a subsidy to investors at taxpayers’ expense. Investors who took risks to earn profits must also bear the losses. Not every business failure carries systemic risk. The government can ensure a well-functioning financial industry, able to make new loans to creditworthy borrowers, without bailing out particular investors and institutions whose choices proved unwise.

2) Its ambiguity. Neither the mission of the new agency nor its oversight are clear. If taxpayers are to buy illiquid and opaque assets from troubled sellers, the terms, occasions, and methods of such purchases must be crystal clear ahead of time and carefully monitored afterwards.

3) Its long-term effects. If the plan is enacted, its effects will be with us for a generation. For all their recent troubles, America's dynamic and innovative private capital markets have brought the nation unparalleled prosperity. Fundamentally weakening those markets in order to calm short-run disruptions is desperately short-sighted.

For these reasons we ask Congress not to rush, to hold appropriate hearings, and to carefully consider the right course of action, and to wisely determine the future of the financial industry and the U.S. economy for years to come.



Signed (updated at 9/25/2008 8:30AM CT)

Acemoglu Daron (Massachussets Institute of Technology)
Adler Michael (Columbia University)
Admati Anat R. (Stanford University)
Alexis Marcus (Northwestern University)
Alvarez Fernando (University of Chicago)
Andersen Torben (Northwestern University)
Baliga Sandeep (Northwestern University)
Banerjee Abhijit V. (Massachussets Institute of Technology)
Barankay Iwan (University of Pennsylvania)
Barry Brian (University of Chicago)
Bartkus James R. (Xavier University of Louisiana)
Becker Charles M. (Duke University)
Becker Robert A. (Indiana University)
Beim David (Columbia University)
Berk Jonathan (Stanford University)
Bisin Alberto (New York University)
Bittlingmayer George (University of Kansas)
Boldrin Michele (Washington University)
Brooks Taggert J. (University of Wisconsin)
Brynjolfsson Erik (Massachusetts Institute of Technology)
Buera Francisco J. (UCLA)
Camp Mary Elizabeth (Indiana University)
Carmel Jonathan (University of Michigan)
Carroll Christopher (Johns Hopkins University)
Cassar Gavin (University of Pennsylvania)
Chaney Thomas (University of Chicago)
Chari Varadarajan V. (University of Minnesota)
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Coleman John (Duke University)
Constantinides George M. (University of Chicago)
Crain Robert (UC Berkeley)
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Da Zhi (University of Notre Dame)
Davis Morris (University of Wisconsin)
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Faulhaber Gerald (University of Pennsylvania)
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Fox Jeremy T. (University of Chicago)
Frank Murray Z.(University of Minnesota)
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Gao Paul (Notre Dame University)
Garicano Luis (University of Chicago)
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Glomm Gerhard (Indiana University)
Goettler Ron (University of Chicago)
Goldin Claudia (Harvard University)
Gordon Robert J. (Northwestern University)
Greenstone Michael (Massachusetts Institute of Technology)
Guadalupe Maria (Columbia University)
Guerrieri Veronica (University of Chicago)
Hagerty Kathleen (Northwestern University)
Hamada Robert S. (University of Chicago)
Hansen Lars (University of Chicago)
Harris Milton (University of Chicago)
Hart Oliver (Harvard University)
Hazlett Thomas W. (George Mason University)
Heaton John (University of Chicago)
Heckman James (University of Chicago - Nobel Laureate)
Henderson David R. (Hoover Institution)
Henisz, Witold (University of Pennsylvania)
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Hite Gailen (Columbia University)
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Hopenhayn Hugo (UCLA)
Hurst Erik (University of Chicago)
Imrohoroglu Ayse (University of Southern California)
Isakson Hans (University of Northern Iowa)
Israel Ronen (London Business School)
Jaffee Dwight M. (UC Berkeley)
Jagannathan Ravi (Northwestern University)
Jenter Dirk (Stanford University)
Jones Charles M. (Columbia Business School)
Kaboski Joseph P. (Ohio State University)
Kahn Matthew (UCLA)
Kaplan Ethan (Stockholm University)
Karolyi, Andrew (Ohio State University)
Kashyap Anil (University of Chicago)
Keim Donald B (University of Pennsylvania)
Ketkar Suhas L (Vanderbilt University)
Kiesling Lynne (Northwestern University)
Klenow Pete (Stanford University)
Koch Paul (University of Kansas)
Kocherlakota Narayana (University of Minnesota)
Koijen Ralph S.J. (University of Chicago)
Kondo Jiro (Northwestern University)
Korteweg Arthur (Stanford University)
Kortum Samuel (University of Chicago)
Krueger Dirk (University of Pennsylvania)
Ledesma Patricia (Northwestern University)
Lee Lung-fei (Ohio State University)
Leeper Eric M. (Indiana University)
Leuz Christian (University of Chicago)
Levine David I.(UC Berkeley)
Levine David K.(Washington University)
Levy David M. (George Mason University)
Linnainmaa Juhani (University of Chicago)
Lott John R. Jr. (University of Maryland)
Lucas Robert (University of Chicago - Nobel Laureate)
Luttmer Erzo G.J. (University of Minnesota)
Manski Charles F. (Northwestern University)
Martin Ian (Stanford University)
Mayer Christopher (Columbia University)
Mazzeo Michael (Northwestern University)
McDonald Robert (Northwestern University)
Meadow Scott F. (University of Chicago)
Mehra Rajnish (UC Santa Barbara)
Mian Atif (University of Chicago)
Middlebrook Art (University of Chicago)
Miguel Edward (UC Berkeley)
Miravete Eugenio J. (University of Texas at Austin)
Miron Jeffrey (Harvard University)
Moretti Enrico (UC Berkeley)
Moriguchi Chiaki (Northwestern University)
Moro Andrea (Vanderbilt University)
Morse Adair (University of Chicago)
Mortensen Dale T. (Northwestern University)
Mortimer Julie Holland (Harvard University)
Muralidharan Karthik (UC San Diego)
Nanda Dhananjay (University of Miami)
Nevo Aviv (Northwestern University)
Ohanian Lee (UCLA)
Pagliari Joseph (University of Chicago)
Papanikolaou Dimitris (Northwestern University)
Parker Jonathan (Northwestern University)
Paul Evans (Ohio State University)
Pejovich Svetozar (Steve) (Texas A&M University)
Peltzman Sam (University of Chicago)
Perri Fabrizio (University of Minnesota)
Phelan Christopher (University of Minnesota)
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Ruud Paul (Vassar College)
Safford Sean (University of Chicago)
Sandbu Martin E. (University of Pennsylvania)
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Seru Amit (University of Chicago)
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Shimer Robert (University of Chicago)
Shore Stephen H. (Johns Hopkins University)
Siegel Ron (Northwestern University)
Smith David C. (University of Virginia)
Smith Vernon L.(Chapman University- Nobel Laureate)
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Spiegel Matthew (Yale University)
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Strahan Philip (Boston College)
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Taylor Alan M. (UC Davis)
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Williamson Samuel H. (Miami University)
Witte Mark (Northwestern University)
Wolfers Justin (University of Pennsylvania)
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Zingales Luigi (University of Chicago)
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The potential public health consequences of delayed parenting were emphasized.

The Male Biological Clock - Does It Exist?
Main Category: Urology / Nephrology
Also Included In: Men's health; Endocrinology; Fertility
Article Date: 26 Sep 2008 - 4:00 PDT

His comprehensive review was recently published in an article entitled "Declining Worldwide Sperm Counts: Disproving a Myth," in Male Infertility: Current Concepts and Controversies, edited by Harris M. Nagler, Urologic Clinics of North America (2008).

However, Dr Fisch presented data indicating the decline in male fertility is associated with age. Dr Fisch presented his data on the impact of paternal age on Down syndrome (Fisch et al., "The Influence of Paternal Age on Down Syndrome". J.Urol 2003) There are a large number of entities that have been reported to be associated with advanced paternal age. One potential explanation for the increased incidence of some of these entities may be a recognized increase in sperm acneuploidy with increasing age.

The incidence of schizophrenia has also been reported as having a correlation to increasing paternal age ("Advancing Paternal Age and the Risk of Schizophrenia," D. Malaspina, et al., Arch Gen Psychiatry.158:758, 2001).

The potential public health consequences of delayed parenting were emphasized.

Mental Disorders in Parents may be Linked to Autism in Children

http://autisminformation.blogspot.com/2008/09/mental-disorders-in-parents-may-be.html

Wednesday, September 24, 2008

Mental Disorders in Parents may be Linked to Autism in Children
According to a recent study, parents of children with autism were roughly twice as likely to have been hospitalized for a mental disorder, such as schizophrenia, than parents of other children."We are trying to determine whether autism is more common among families with other psychiatric disorders. Establishing an association between autism and other psychiatric disorders might enable future investigators to better focus on genetic and environmental factors that might be shared among these disorders," said study author Julie Daniels, Ph.D., an assistant professor in the UNC School of Public Health's epidemiology and maternal and child health departments.
"Earlier studies have shown a higher rate of psychiatric disorders in families of autistic children than in the general population," she said. "We wanted to see if the parents of autistic children were more likely to be diagnosed with mental disorders.
"Our research shows that mothers and fathers diagnosed with schizophrenia were about twice as likely to have a child diagnosed with autism. We also saw higher rates of depression and personality disorders among mothers, but not fathers," Daniels said.
The study examined 1,237 children born between 1977 and 2003 who were diagnosed with autism before age 10, and compared them with 30,925 control subjects matched for gender, year of birth and hospital. The large sample size enabled researchers to distinguish between psychiatric histories of mothers versus fathers in relation to autism. The association was present regardless of the timing of the parent's diagnosis relative to the child's diagnosis.
This is another step closer to finding where the disorder is coming from and why. Maybe someday, scientists will be able to block the disorder even before it comes out.
posted by Natural Health Sites at 10:48 PM
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One Man's Opinion on Bipolar Disorder

The Last Psychiatrist
Updated Tuesdays and FridaysWovon man nicht sprechen kann, daruber muss man schweigen

September 22, 2008


Advancing Paternal Age And Bipolar DisorderThere is considerable evidence that advanced paternal age raises the risk of autism. It appears that the same is true in schizophrenia.Bipolar disorder, however, is an entirely different matter.

Radio waves from cellphones damage sperm, study says

Radio waves from cellphones damage sperm, study says
11:50 AM, September 19, 2008
Attention male cellphone users of reproductive age: Take that phone out of your pocket. Information published today suggests that the radio-frequency energy released by cellphones decreases sperm quality in men.
Last year, researchers from the Cleveland Clinic released a study showing that men who used their cellphones for more than four hours a day had significantly lower sperm quality than men who used their phones for less time. That study, however, did not reveal what might be causing this association. The new study by the same research group, published online today in Fertility & Sterility, took sperm samples from 32 men and divided the samples into two parts for a test group and a control group. The test group specimens were placed an inch from a 850 MHz cellphone that was in talk mode. Measurements taken after the one-hour exposure showed that the sperm exposed to the cellphone contained higher levels of harmful free radicals and a decreased amount of protective antioxidants compared with the unexposed sperm. These factors caused a decline in the sperm's function and motility and in the overall health of the sperm. However, there was no significant difference in damage to the DNA of the exposed cells.
For now, the amount of radio-frequency energy released from cellphones is considered safe. But there are looming questions about the long-term and heavy use of cellphones. Links between brain cancer and cellphones have been suggested, for example. And a recent study found a link between women who used a cellphone in pregnancy and later behavior problems in their children. See this recent L.A. Times Health section story on cellphones and the risk of disease.
Further studies are needed to determine if the results seen in the laboratory sperm samples hold true in men. Many men put their phones in a trouser pocket when using a hands-free device. In the lab, the sperm and cellphone were placed side-by-side. But in real life, the phone and the male reproductive organs are separated by several layers of tissue. Still, men who are planning a family may want to play it safe and keep the active phone a safe distance from their reproductive parts.
"Since many people are now using hands-free sets with their cellphones for various health and safety reasons, it's important that we continue studying this topic to gain a better understanding of the true impact these devices are having on every part of the body," said Dr. Edmund Sabanegh, director of the Center for Male Fertility for the Glickman Urological and Kidney Institute at the Cleveland Clinic.
-- Shari Roan
Photo: More people than ever are using hands-free phone devices or headsets and placing their phones on a belt or in a pocket. Credit: Annie Wells /Los Angeles Times

Journal of Epidemiology and Community Health 2006;60:851-853; doi:10.1136/jech.2005.045179
Copyright © 2006 by the BMJ Publishing Group Ltd.



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SHORT REPORT

Advanced paternal age: How old is too old?
Isabelle Bray, David Gunnell, George Davey Smith

Department of Social Medicine, University of Bristol, UK


Correspondence to:
Correspondence to:
Dr I Bray
Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK; Issy.Bray@bristol.ac.uk


Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. This commentary aims to contribute to such a debate. Accumulated chromosomal aberrations and mutations occurring during the maturation of male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers, and schizophrenia. Adverse health outcomes should be weighed up against advantages for children born to older parents, mindful that these societal advantages are likely to change over time.



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Keywords: paternal age; DNA damage; fertility; abnormalities; schizophrenia

Older Dads Cause Around One Third of All Schizophrenia, As More Older Men Father Babies Maybe More

Schizophrenia Risk and the Paternal Germ Line
By 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 findings
We 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 evidence
This 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 plausibility
We 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 schizophrenia
A 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).

New Mutations for Huntington's Disease Only Through the Paternal Germline with Advanced Paternal Age

Comment in:
Nat Genet. 1993 Nov;5(3):215.

Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects.

Goldberg YP, Kremer B, Andrew SE, Theilmann J, Graham RK, Squitieri F, Telenius H, Adam S, Sajoo A, Starr E, et al.

Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

Huntington's disease (HD) is associated with expansion of a CAG repeat in a novel gene. We have assessed 21 sporadic cases of HD to investigate sequential events underlying HD. We show the existence of an intermediate allele (IA) in parental alleles of 30-38 CAG repeats in the HD gene which is greater than usually seen in the general population but below the range seen in patients with HD. These IAs are meiotically unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for HD are more frequent than prior estimates and indicate a previously unrecognized risk of inheriting HD to siblings of sporadic cases of HD and their children.Publication Types:
Research Support, Non-U.S. Gov't

PMID: 8252043 [PubMed - indexed for MEDLINE]

Younger Fathers Have Offspring With Fewer New Genetic Problems

1: Am J Med Genet A. 2008 Sep 15;146A(18):2385-9. Links
The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, Pearson K, Romitti PA, Shaw GM, Hecht JT.
Houston Health Science Center, The University of Texas, Houston, Texas 77030, USA. kim.waller@uth.tmc.edu

There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records. Copyright 2008 Wiley-Liss, Inc.

PMID: 18698630 [PubMed - indexed for MEDLINE]

Where does genetic disease come from?

"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." Leslie B. Raschka, MD 2000
　

End fathering before 35 and Impact Public Health and Well-Being

Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl'>http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Wohl%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus">Wohl M, Gorwood'>http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gorwood%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus">Gorwood P.INSERM U675, 16 rue Henri Huchard 75018 Paris, France.BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.PMID: 17142012 [PubMed - indexed for MEDLINE]

Time CNN-- Men Have a Biological Clock Too For The Mental and Physical Health of Offspring

A Biological Clock for Dads Too
Tuesday, Sep. 09, 2008 By ELIZABETH HOWTON Turns out women aren't the only ones with an expiration date on their fertility. An emerging body of research is showing that men, too, have a "biological clock."


Not only do men become less fecund as they age, but their fertility begins to decline relatively early — around age 24, six years or so before women's. Historically, infertility has been seen as a female issue, as has the increased risk of Down syndrome and other birth defects, but studies now also link higher rates of autism, schizophrenia and Down syndrome in children born to older fathers. A recent paper by researchers at Sweden's Karolinska Institute found that the risk of bipolar disorder in children increased with paternal age, particularly in children born to men age 55 or older.

It used to be that "if you had hair on your chest, it was your wife's problem," says Barry Behr, an associate professor of obstetrics and gynecology at the Stanford Medical School and director of Stanford's in vitro fertilization laboratory. Even now, he said, though about half of infertility cases are caused by male factors, such as low sperm count or motility, there are many more tests to evaluate a woman's fertility than a man's.

To some degree, that bias is rooted in biology. Women are born with as many eggs as they'll ever have — about a million. That number steadily diminishes, and "the best eggs are ovulated first," Behr says. The ones that remain — after age 35 or so, on average — are vulnerable to toxins, radiation and other insults that may degrade their quality and viability.

By contrast, men make new sperm about every 90 days, Behr says, so the logic has been that there should not be that much difference between a young man's sperm and an old man's. Indeed, men as old as 94 have been known to father children.

Still, the research suggests it gets harder with age. A French study published in the current issue of Reproductive BioMedicine Online found that in couples undergoing infertility treatment, the father's age had as much effect as the mother's on rates of pregnancy and miscarriage — the older either parent was, the less likely they were to get pregnant, and the more likely to miscarry. Other studies have found similar trends: on average, it will take longer than a year to conceive for 8% of couples in which the man is younger than 25; that percentage nearly doubles, to 15%, in couples with men 35 or older. Data have also suggested that couples whose partners are the same age, or in which the man is younger than the woman, are more likely to conceive within a year, compared with couples in which men are at least five years older than their partners.

There are many possible explanations for the decline in male fertility, from a decrease in the number of sperm and their motility, to lower testosterone levels, to the effects of other age-related diseases such as diabetes, which is associated with erectile dysfunction and lower levels of testosterone. But researchers think that genetic factors may be behind the link between paternal age and risk of bipolar disorder and other psychiatric disorders, like autism and schizophrenia, whose origins are increasingly being attributed to DNA. Although sperm may be no more than 90 days old, the cells that make sperm may be subject to increasing DNA mutations as men age, affecting the quality of the sperm they produce.

In the Swedish study, published Sept. 1 in the Archives of General Psychiatry, researchers found that risk of developing bipolar disorder began to increase in children born to fathers around age 40. The highest risk, however, occurred in men 55 and older; their offspring were 37% more likely to develop the disorder than children born to men in their 20s. Children of older men were also twice as likely to develop early-onset disease — before age 20 — which studies suggest has a strong genetic component.

What does all this mean for would-be older dads? While women are used to seeing grim statistics about their decreasing chances of achieving pregnancy and the increasing risks of Down syndrome as they age, men have typically believed they had all the time in the world. Perhaps now, men in the mid-30s will start sharing the same "now or never" pressure to conceive that women have long endured.

When older men father children, Behr says, the traditional response has been to "pat them on the back and buy them a beer." He has seen patients that he felt were too old to become fathers, but "plenty of people make decisions about parenthood that I wouldn't," he says. "Our responsibility is to educate patients with the facts, and they decide."

(

Seven Years Ago We Knew and No Public Health Warnings

April 12, 2001


Father's Age Linked to Risk of Schizophrenia

By ERICA GOODE





Expanded Coverage

Health: Psychology





Join a Discussion on Mental Health and Treatment





he risk of having a child with schizophrenia may increase with a father's advancing age, researchers reported yesterday.

The researchers, who examined the relationship between the fathers' ages and schizophrenia among 87,907 Israelis born from 1964 through 1976, found that the older the father, the more likely he was to have a child who suffered from schizophrenia, a devastating mental illness.

Men who were 45 through 49, for example, were twice as likely to have offspring with schizophrenia or a related disorder as were men under 25, the researchers found. The overall risk of having a child with the illness, however, remained small.

"The finding is a very strong association of schizophrenia risk and father's age," said Dr. Delores Malaspina, an associate professor of clinical psychiatry at the Columbia University College of Physicians and Surgeons and the lead author of the report, which appears in this month's issue of the journal Archives of General Psychiatry.

Other scientists were more skeptical. They noted that confirmation through other studies was needed before such a link could be said to be established, and they cautioned that in the history of schizophrenia research, many apparent associations had eventually proved spurious or impossible to replicate.

If the results of the study hold up to scrutiny, Dr. Malaspina said, "The next question is, `What might explain that finding?' " One possibility, the researchers argue in their report, is that some cases of schizophrenia are a result of genetic abnormalities in sperm cells that become more likely as a man ages.

Stem cells in the testicles divide throughout a man's life in a process that leads to the production of sperm. Each cell division carries the chance for copying errors in reproducing the DNA. By the age of 40, research suggests, about 660 such divisions have taken place. Genetic mutations can also occur from exposure to radiation or chemicals over a man's life.

In contrast, the divisions of cells that produce a woman's eggs occur only before birth.

A number of physical illnesses and birth defects have been linked to genetic mutations during sperm production in older fathers, including Apert syndrome, a rare congenital deformity of the skull, fingers and toes, and achondroplasia, the most common form of dwarfism.

Some cases of schizophrenia, the researchers suggested, might be associated with similar mutations.

The illness runs in families, and is known to have a strong genetic component, though efforts to identify the specific gene or genes that predispose a person to schizophrenia have so far been inconclusive. The disease affects 1 of every 100 Americans and is more common in men. Full-blown symptoms often first appear in late adolescence or early adulthood.

In some cases, people who do not have a family history of schizophrenia also develop the illness. Dr. Malaspina said that the findings of her study "suggest that relevant mutations are there" in such sporadic cases "as well as in familial cases."

Dr. James F. Crow, a professor emeritus of genetics at the University of Wisconsin, said, "I think this is very strong evidence for a mutation component to schizophrenia, but it's quite an open question as to how much of a component."

But other scientists cautioned that other explanations beside spontaneous genetic mutation could also account for the study's results.

For example, said Dr. Ann Pulver, director of the epidemiology and genetics program in psychiatry at Johns Hopkins University, "It may be that the fathers of schizophrenics have unusual characteristics that delay reproduction."

"I think this is an interesting contribution to the epidemiological literature, that paternal age may be a risk factor for a subgroup of schizophrenic patients," Dr. Pulver said. "And it may be that advanced paternal age is associated with a mutation. But that is a hypothesis and one would need to test it.

In the study, Dr. Malaspina and her colleagues took advantage of the Jerusalem Perinatal Study, a research archive that includes information about all births in one area of Jerusalem. Records from the study were correlated with those of a national registry of psychiatric illness kept by the Israeli government.

The researchers found that in 1,337 people admitted to psychiatric hospitals before 1998, the fathers' ages were strongly associated with a diagnosis of schizophrenia or a related disorder. The risk of schizophrenia increased steadily with the father's increasing age. Advancing age of the fathers, the investigators reported, accounted for 26 percent of the cases of schizophrenia in the study; for fathers over 50, two out of every three cases of the illness could be attributed to the father's age.

Should Older Men Father Babies What is considered older? 34 and over?

Do Jonathan Sebat and Michael Wigler study paternal age and autism??


Health & Science
Cause of Autism Narrowed Down to 100 Genes
by Jon Hamilton

Listen Now [3 min 30 sec] add to playlist


“There may in fact be many genes -- I would speculate 100 or more -- that play some role in cognitive development, and when they are altered, could cause autism.”
Jonathan Sebat, Geneticist, Cold Spring Harbor Laboratory



All Things Considered, March 15, 2007 · A new study links autism to subtle changes in a wide range of genes. The finding, published in the journal Science, suggests that autism has many causes, and that whatever triggers autism usually occurs long before birth.

The study, led by Jonathan Sebat, a geneticist at Cold Spring Harbor Laboratory in New York, examined the genes of 264 families. Some families had members with autism, others did not.

Sebat says the goal was to compare the genes of autistic children with the genes of their parents.

"By comparing the two," he says, "we could find a mutation in the child that was not inherited from either parent."

It turned out that children with autism were much more likely than other kids to have these "spontaneous" mutations. The mutations affected bits of genetic code that tend to appear more than once, like duplicate copies of certain pages of a book.

In many children with autism, some of the duplicates were deleted.

For example, Sebat says one child in the study was missing a copy of the gene for oxytocin – a hormone that seems to influence social behavior.

"That child has one copy of oxytocin instead of the normal two copies," Sebat says, "and that may have resulted in the corresponding decrease in the levels of oxytocin."

It's a change that could have affected normal social development.

But Sebat says that in other children with autism, the deletions affected other genes.

"There may in fact be many genes — I would speculate 100 or more — that play some role in cognitive development, and when they are altered, could cause autism," Sebat says.

That's many more than researchers have found involved in inherited autism.

Sebat's research is causing a lot of excitement among autism researchers, including Ezra Susser, an epidemiologist at the Mailman School of Public Health at Columbia University and the New York State Psychiatric Institute.

"It changes our thinking about what kind of genetic causes are important," he says, "and knowing that changes our thinking about what kinds of environmental causes are important. Because I think everybody believes that there is an interplay of genes and environment in most diseases, and that would be true for autism, too."

The sort of mutations found in the study tend to occur in eggs or sperm before conception or in the earliest stages of an embryo's development, Susser says.

The finding suggests that things such as exposure to vaccines after birth probably aren't the main causes of autism.

Susser also says the study suggests a new direction for researchers seeking the causes of autism.

"It doesn't mean that we should stop looking for [early-life] exposures," he says. "It does not mean that we should stop looking for early life exposures. But it does mean we should start looking for exposures that might be preconceptional also."

Susser has already shown that older fathers are more likely to have genetic mutations in their sperm, and more likely to have a child who is autistic. He says scientists need to ask whether a parent's exposure to certain chemicals has a similar effect.

In the meantime, Sebat says, the new research offers at least one practical application. Parents who already have a child with autism could undergo genetic tests to see what sort of mutations are present. If the mutations are spontaneous, rather than inherited, future children would have no special risk for autism.

Disorder age link

Disorder age link
Sep 8 2008 by Helen Rae, Evening Chronicle

OLDER fathers are more likely to have children with bipolar disorder, research suggests.

The risk goes up when men are older than 29 before they start their family, and is highest if they are over 55.

Increasing paternal age has already been linked with schizophrenia and autism, but not bipolar disorder, formerly known as manic depression.

The Swedish study, in Archives of Psychiatry, suggests the risk may, in part, be explained by ageing sperm.

For the study, they identified 13,428 patients in Swedish registers with a diagnosis of bipolar disorder.

After controlling for other factors like age of the individual's mother, number of siblings and family history of mental health problems, they found a clear link between risk of bipolar disorder and father's age.

The older an individual's father, the more likely he or she was to have bipolar disorder.

It is HYPOCRITICAL of the Autism Charities Not to WARN about Advancing Paternal Age and Autism

The charities rake in the money for autism research and yet do not warn the public. It is also true that type 1 diabetes, Muscular Dystrophy, MS, Alzheimer's disease, breast cancer, prostate cancer, schizophrenia, and bipolar disorder for starters increase in offspring of older fathers.Wa

"The age of the father is an important determinant of the health of future generations."

Leslie B. Raschka, MD: "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. The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations."


THE AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS

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.
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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.
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Diabetes age of parents etc risk factor 2005

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Labels: Alzheimer's, DNA, Mutations, Schizophrenia, Sperm

PUBLIC HEALTH WARNINGS ABOUT THE RISKS OF OLDER MEN FATHERING BABIES ARE OVERDUE

More Harsh Reality: Aging Fathers and Bipolar Children
4 September, 2008 (21:54) | Health, Psychology

Like depression, bipolar disorder has been romanticized as an affliction that confers hidden benefits. It may, but evidence is accumulating that suggests manic-depression results from the sorts of genetic disruption that contribute to other severe afflictions, such as schizophrenia and autism.
Readers of this blog may recall that schizophrenia and autism have been linked to “de novo” mutations, new abnormal genes that develop in the parent’s sperm line and have not passed a Darwinian, evolutionary test of fitness. The amino acid sequences are simply disrupted. Readers who have looked at yet earlier columns will recall that problems in gene regulation — epigenetic “scarring” — can also give rise to mental illness. Scientists are now suggesting that both of these mechanisms, new mutations and gene dysregulation, may be implicated in bipolar disorder.
Emma Frans and other researchers at the Karolinska Institute in Stockholm looked at a sample of over seven million Swedes and identified over 13,000 patients who had been hospitalized at least twice for bipolar disorder. The epidemiologists compared these subjects to over 70,000 matched controls. The investigators found that older fathers are more likely (the increase is on the order of 37%) to have offspring with manic depression. Older mothers had more bipolar children, too, but the association was less marked.
More, when the investigators looked at subjects with early-onset bipolarity, the association was very high. Compared with men in their early twenties, men over 55 were more than two-and-a-half times as likely to father a child who would go on be hospitalized for manic depression before age 20.
As with schizophrenia, some manic depression is familial and hereditary, caused in part by genes that have been passed down for generations. Conceivably, as well as doing harm, those genes may confer some adaptive fitness in sufferers or their relatives. Theorists have suggested that high energy and decisiveness, if not frank mania, may be the traits selected for over time. But the association between paternal age and mental illness points in a different direction.
Part of what distinguishes older fathers from older mothers is the nature of the gene line. Women’s eggs go through 23 replications and then are held in the uterus (or expelled) throughout life; the eggs’ genes may deteriorate, but they are much less vulnerable to “gene copy errors.” In contrast, the cells that make sperm have gone through 200 divisions by age 20; by age 40, the number of divisions is up to 660. The sperm of older men is much more likely to have acquired mistakes through faulty replication. On a separate basis, altered genetic regulation in offspring has been related to paternal age. The Karolinska researchers speculate that these two mechanisms may explain why older fathers have more bipolar offspring. Either way, the influence is via “one-off” events, new abnormalities that changes the offsprings’ brain development.
Other interpretations of the data are possible. Perhaps older fathers simply do a worse job of parenting. Here is where the question of early onset comes into play. Early-onset bipolar disorder is more heritable and less related to environmental factors. The fact that manic depression in the teenage years was so much more common in the children of older father speaks toward genetic transmission.
Interestingly, very young (teenaged) fathers also have more children who go on to experience early-onset bipolarity. It may be that “immature sperm” also give rise to de novo genetic disorders; or environment may play a role, via drug and alcohol abuse in the fathers, poor prenatal care on the part of young mothers, epigenetic problems in parents who themselves have been stressed, and then the additional disruption in the early lives of children born to parents who are poor and who (studies show) may demonstrate conduct disorders.
Of course, the association with paternal age proves nothing. It is easy to conjure up epigenetic evolutionary mechanisms that might explain the same data. Perhaps nature has arranged for the sperm of aging parents to be reconfigured to favor manic depression in a sort of “Boy Named Sue” strategy. If the parents may well die early, bipolarity could be a sort of double-or-nothing bet, in which low-level mania gives orphaned offspring a better shot at survival.
But the Karolinska researchers read the results differently. For now, bipolarity is another on a list of mental illnesses that seem to arise from random changes in genes or gene expression — which is to say: syndromes that have long been categorized as mental illness look like just that, expressions of frank biological pathology.

Advancing Paternal Age and Bipolar Disorder

Advancing Paternal Age and Bipolar Disorder
Emma M. Frans, MMedSc; Sven Sandin, MSc; Abraham Reichenberg, PhD; Paul Lichtenstein, PhD; Niklas Långström, MD, PhD; Christina M. Hultman, PhD


Arch Gen Psychiatry. 2008;65(9):1034-1040.

Context Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders.

Objectives To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately.

Design A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders.

Setting Identification of 7 328 100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register.

Participants A total of 13 428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case.

Main Outcome Measure Bipolar disorder based on ICD codes at discharge from hospital treatment.

Results An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (<20 years) cases, the effect of paternal age was much stronger (odds ratio, 2.63; 95% CI, 1.19-5.81), whereas no statistically significant maternal age effect was found.

Conclusions Advanced paternal age is a risk factor for BPD in the offspring. The results are consistent with the hypothesis that advancing paternal age increases the risk for de novo mutations in susceptibility genes for neurodevelopmental disorders.


Author Affiliations: Department of Medical Epidemiology and Biostatistics (Ms Frans, Mr Sandin, and Drs Lichtenstein and Hultman) and Center for Violence Prevention (Dr Långström), Karolinska Institutet, Stockholm, Sweden; and Institute of Psychiatry, King's College, London, England (Dr Reichenberg).

Harry Firsch says "The message here for men is: don't wait too long."

Friday, September 5, 2008
Older Men Are More Likely To Father Children With Bipolar Disorder
Recent research brings to light more bad news for older fathers. This Swedish study showed that children born to fathers 55 years or older were 1.37 times more likely to go on to be diagnosed with the mental illness bipolar disorder than those of men aged 20 to 24. The study examined 13,428 people diagnosed with bipolar disorder and took into account family history and socioeconomic status. Bipolar disorder is often a cyclic condition with which people periodically exhibit elevated (manic) and depressive episodes.

Harry Fisch, MD, a male infertility expert and the author of "The Male Biological Clock", states "We're finding that as the father's age increases, there's an increased chance not just of infertility or Down's syndrome, but also schizophrenia, autism-related disorders and bipolar, too." He says "The message here for men is: don't wait too long."

More Harsh Reality: Aging Fathers and Bipolar Children

Psychology Today Blog By Dr. Peter D. Kramer


Peter D. Kramer is a psychiatrist and author. His books include Against Depression and Listening to Prozac.




More Harsh Reality: Aging Fathers and Bipolar Children
By Peter D. Kramer on September 04, 2008 in In Practice
Like depression, bipolar disorder has been romanticized as an affliction that confers hidden benefits. It may, but evidence is accumulating that suggests manic-depression results from the sorts of genetic disruption that contribute to other severe afflictions, such as schizophrenia and autism.

Readers of this blog may recall that schizophrenia and autism have been linked to “de novo” mutations, new abnormal genes that develop in the parent’s sperm line and have not passed a Darwinian, evolutionary test of fitness. The amino acid sequences are simply disrupted. Readers who have looked at yet earlier columns will recall that problems in gene regulation — epigenetic “scarring” — can also give rise to mental illness. Scientists are now suggesting that both of these mechanisms, new mutations and gene dysregulation, may be implicated in bipolar disorder.

Emma Frans and other researchers at the Karolinska Institute in Stockholm looked at a sample of over seven million Swedes and identified over 13,000 patients who had been hospitalized at least twice for bipolar disorder. The epidemiologists compared these subjects to over 70,000 matched controls. The investigators found that older fathers are more likely (the increase is on the order of 37%) to have offspring with manic depression. Older mothers had more bipolar children, too, but the association was less marked.

More, when the investigators looked at subjects with early-onset bipolarity, the association was very high. Compared with men in their early twenties, men over 55 were more than two-and-a-half times as likely to father a child who would go on be hospitalized for manic depression before age 20.

As with schizophrenia, some manic depression is familial and hereditary, caused in part by genes that have been passed down for generations. Conceivably, as well as doing harm, those genes may confer some adaptive fitness in sufferers or their relatives. Theorists have suggested that high energy and decisiveness, if not frank mania, may be the traits selected for over time. But the association between paternal age and mental illness points in a different direction.

Part of what distinguishes older fathers from older mothers is the nature of the gene line. Women’s eggs go through 23 replications and then are held in the uterus (or expelled) throughout life; the eggs’ genes may deteriorate, but they are much less vulnerable to “gene copy errors.” In contrast, the cells that make sperm have gone through 200 divisions by age 20; by age 40, the number of divisions is up to 660. The sperm of older men is much more likely to have acquired mistakes through faulty replication. On a separate basis, altered genetic regulation in offspring has been related to paternal age. The Karolinska researchers speculate that these two mechanisms may explain why older fathers have more bipolar offspring. Either way, the influence is via “one-off” events, new abnormalities that changes the offsprings’ brain development.

Other interpretations of the data are possible. Perhaps older fathers simply do a worse job of parenting. Here is where the question of early onset comes into play. Early-onset bipolar disorder is more heritable and less related to environmental factors. The fact that manic depression in the teenage years was so much more common in the children of older father speaks toward genetic transmission.

Interestingly, very young (teenaged) fathers also have more children who go on to experience early-onset bipolarity. It may be that “immature sperm” also give rise to de novo genetic disorders; or environment may play a role, via drug and alcohol abuse in the fathers, poor prenatal care on the part of young mothers, epigenetic problems in parents who themselves have been stressed, and then the additional disruption in the early lives of children born to parents who are poor and who (studies show) may demonstrate conduct disorders.

Of course, the association with paternal age proves nothing. It is easy to conjure up epigenetic evolutionary mechanisms that might explain the same data. Perhaps nature has arranged for the sperm of aging parents to be reconfigured to favor manic depression in a sort of “Boy Named Sue” strategy. If the parents may well die early, bipolarity could be a sort of double-or-nothing bet, in which low-level mania gives orphaned offspring a better shot at survival.

But the Karolinska researchers read the results differently. For now, bipolarity is another on a list of mental illnesses that seem to arise from random changes in genes or gene expression — which is to say: syndromes that have long been categorized as mental illness look like just that, expressions of frank biological pathology.

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