Childhood Schizophrenia is Now Called Autism and Risk Rises with Age of the Father

Genetic underpinnings of schizophrenia revealed
Thu Mar 27, 2008
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By Will Dunham

WASHINGTON (Reuters) - The devastating mental illness schizophrenia may be caused by many different mutations in many different genes that disrupt biological pathways vital to normal brain development, scientists said on Thursday.

Schizophrenia is a complex disorder marked by delusions, hallucinations and disordered thinking that appears in about 1 percent of all adults. Experts long have struggled to grasp its causes and the role of genetics and environmental factors.

Two teams of researchers published new genetic insights in the journal Science. Their findings suggest that instead of one crucial gene or a handful, a myriad of different glitches in many genes could be responsible for schizophrenia.

DNA deletions and duplications that disrupt genes are far more common in schizophrenics, the researchers found.

These disrupted genes often are related to pathways critical for brain development. They involve creating the infrastructure in which neurons communicate, as well as such functions as neuronal growth and migration and cell death.

"You're basically screwing up the way that the regulation of brain growth occurs," said Dr. Jon McClellan of the University of Washington in Seattle, one of the researchers.

Researchers at the University of Washington and Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, looked at DNA from 150 schizophrenics and from 268 healthy people. These genetic deletions and duplications were present in 15 percent of schizophrenics and only 5 percent of healthy people.

A team of researchers from the U.S. National Institutes of Health came up with similar results looking at another group of schizophrenics who developed the disease as children. The tiny genetic glitches were seen in about 20 percent of them. Continued...

Advancing Paternal Age and the Risk of Schizophrenia

Third, schizophrenia is associated with older paternal age, and older paternal age is associated with increased rates of de novo germline mutations. Thus, new individually rare severe mutations in genes related to brain functioning or neural development may be responsible for a portion of cases of schizophrenia.
Any gene harboring one disease-related mutation is likely to harbor more than one mutation



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Vol. 58 No. 4, April 2001 Archives






Advancing Paternal Age and the Risk of Schizophrenia
Dolores Malaspina, MD; Susan Harlap, MBBS; Shmuel Fennig, MD; Dov Heiman, MPH; Daniella Nahon, BA; Dina Feldman, MA; Ezra S. Susser, MD, PhD


Arch Gen Psychiatry. 2001;58:361-367.

Background A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines.

Method We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry.

Results Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age.

Conclusions These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.


From the Department of Psychiatry/New York State Psychiatric Institute, Columbia University, New York (Drs Malaspina and Susser); Department of Obstetrics and Gynecology, New York University School of Medicine, New York (Dr Harlap); Shalvata Mental Health, Ministry of Mental Health, Even-Yehuda, Israel (Dr Fennig and Mr Heiman); and Mental Health Services Section, Israel Ministry of Health, Tel Aviv (Mss Nahon and Feldman).

Corresponding author: Dolores Malaspina, MD, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY 10032 (e-mail: dm9@Columbia.edu)


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Nat Rev Genet. 2000 Oct;1(1):40-7.Related Articles, Links
The origins, patterns and implications of human spontaneous mutation.

Crow JF.

Genetics Department, University of Wisconsin, Madison, Wisconsin 53706, USA. jfcrow@facstaff.wisc.edu

The germline mutation rate in human males, especially older males, is generally much higher than in females, mainly because in males there are many more germ-cell divisions. However, there are some exceptions and many variations. Base substitutions, insertion-deletions, repeat expansions and chromosomal changes each follow different rules. Evidence from evolutionary sequence data indicates that the overall rate of deleterious mutation may be high enough to have a large effect on human well-being. But there are ways in which the impact of deleterious mutations can be mitigated.

Publication Types:
Review

PMID: 11262873 [PubMed - indexed for MEDLINE]
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http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15918152

IntroductionSegmental duplications (also termed “low-copy repeats”) are blocks of DNA that range from 1 to 400 kb in length, occur at more than one site within the genome, and typically share a high level of (>90%) sequence identity (reviewed by Eichler [2001]). Both in situ hybridization and in silico analyses have shown that ~5% of the human genome is composed of duplicated sequence (Cheung et al. 2001; Bailey et al. 2002; Cheung et al. 2003; She et al. 2004a), and many studies have noted a significant association between the location of segmental duplications and regions of chromosomal instability or evolutionary rearrangement (Ji et al. 2000; Samonte and Eichler 2002; Armengol et al. 2003; Locke et al. 2003a, 2003b; Bailey et al. 2004). Indeed, segmental duplications have been implicated as the probable mediators of >25 recurrent genomic disorders (reviewed by Stankiewicz and Lupski [2002]). Molecular studies have shown that the presence of large, highly homologous flanking repeats predisposes these regions to recurrent rearrangement by nonallelic homologous recombination, resulting in deletion, duplication, or inversion of the intervening sequence (Chance et al. 1994; Shaw et al. 2002).

A growing body of evidence now suggests that the duplication architecture of the genome may also mediate normal variation. The existence of large genomic polymorphisms, originally termed “heteromorphisms” or “euchromatic variants,” has been recognized since the advent of high-resolution cytogenetic banding techniques (summarized at the Chromosome Anomaly Register Web site). With the use of more-targeted molecular analyses, a number of submicroscopic polymorphic rearrangements between homologous blocks of sequence have been identified in the normal population (Siniscalco et al. 2000; Sprenger et al. 2000; Giglio et al. 2001; Osborne et al. 2001; Gimelli et al. 2003; Skaletsky et al. 2003). Recently, the use of methods such as array comparative genomic hybridization (array CGH) and representational oligonucleotide microarray analysis (ROMA) have revealed the presence of numerous copy-number polymorphisms (CNPs) in the human genome and have suggested an enrichment of segmental duplications associated with these variants (Iafrate et al. 2004; Sebat et al. 2004). However, these studies used arrays with either limited genomic coverage or limited resolution with respect to regions of segmental duplication, and even current tiling-path arrays with >30,000 BAC clones (Ishkanian et al. 2004) do not achieve complete coverage of regions rich in segmental duplications (Z.C. and E.E.E., unpublished data).

Because regions flanked by segmental duplications are susceptible to rearrangement by nonallelic homologous recombination, we hypothesized that these regions represent potential hotspots of genomic instability that are prone to copy-number variation. It has been shown that several factors—including the length, sequence identity, and orientation of and the distance between duplications—influence the probability of meiotic misalignment (Stankiewicz and Lupski 2002). Most of the blocks of duplicated sequence that have been implicated in known genomic disorders are large (10–400 kb in size) and have >96% sequence identity. This level of sequence sharing between intrachromosomal sites provides ample substrate for aberrant recombination, on the basis of the estimated minimal efficient-processing segment length (Waldman and Liskay 1988). In general, the larger and more homologous the block of duplicated sequence is, the more frequently sporadic segmental aneusomy events occur. For example, the most frequently occurring microdeletion syndrome (velocardiofacial and DiGeorge syndromes; frequency 1/3,000) occurs between blocks of duplications that are in excess of 300 kb in length and that share 99.7% sequence identity (Edelmann et al. 1999; Shaikh et al. 2000).

Thus, a review of the recurrent genomic disorders characterized to date suggests a strategy for the identification of novel regions of genomic instability. With a focus on regions flanked by intrachromosomal duplications that are >10 kb in length, share >95% sequence identity, and span from 50 kb to 10 Mb of intervening sequence (Stankiewicz and Lupski 2002), novel sites of genomic variation may be uncovered. On the basis of these criteria, in silico analysis of the human genome defines a map of potential rearrangement hotspots (Bailey et al. 2002). In total, 130 regions—covering 274 Mb, or ~10% of the entire genome—are flanked by intrachromosomal duplications whose characteristics suggest a potential predisposition to genomic instability. Whereas 25 of these regions are associated with known genomic disorders, the remainder represent novel sites whose genomic architecture is susceptible to either polymorphic or disease-causing rearrangement. We have constructed a custom BAC array, termed the “segmental duplication microarray” (SD microarray), specifically targeted to these rearrangement hotspots, and we used it to investigate copy-number variation in a panel of ethnically diverse normal individuals. We report the discovery of numerous novel CNPs distributed throughout the human population and demonstrate an enrichment of copy-number variation in regions of the genome flanked by segmental duplications.
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King MC, Ahsan H, Susser E. Designs for the genomic era. In: Susser E, Schwartz S, Morabia A, Bromet EJ, eds. Psychiatric Epidemiology: Searching for the Causes of Mental Disorders. New York, NY: Oxford University Press; 2006

Older paternal age was linked to a higher miscarriage risk

Miscarriage risk climbs with dad's age
Reuters
Tuesday, 1 August 2006



The latest study provides more evidence that men, like women, have a biological clock (Image: iStockphoto)
The risk of a miscarriage appears to rise along with the father's age, regardless of how old the mother is, researchers report.

Their study looked at nearly 14,000 women who were pregnant in the 1960s and 70s.

The researchers found that the risk of miscarriage was 60% greater when the father was age 40 or older than when he was 25-29 years old.

What's more, age made a difference even for men in their 30s. Miscarriage risk was about three times greater when the man was 35-39 years of age than if he were younger than 25.

These risks were all independent of the mother's age, a well-known factor in miscarriage, the researchers report in the latest issue of the journal Obstetrics & Gynecology.

The findings add to evidence showing that, like women, men have a biological clock.

Although men continually produce new sperm and can father children late in life, research shows that their fertility gradually declines starting at a relatively young age.

Also, as with women, older fathers are more likely to have children with birth defects.

One recent study found that a man's ability to have a child fades after the age of 40, similar to a woman's fertility decline after age 35.

Another confirmed that genetic abnormalities in sperm steadily become more common as men age.

Why does it happen?

Miscarriages, particularly those in the first trimester, often occur because of genetic anomalies in the foetus, which may explain the risk tied to paternal age.

The current findings strengthen the belief that people planning a family should consider not only the woman's age, but the man's as well, according to the study authors.

"As child-bearing is increasingly delayed in Western societies, this study provides important information for people who are planning their families," write the researchers, led by Dr Karine Kleinhaus, who was with the Columbia University School of Public Health in New York at the time of the study.

Back in the 60s and 70s

The findings are based on data from a large study of women in Jerusalem who were pregnant between 1964 and 1976, about 1500 of whom suffered a miscarriage.

These women were compared with the more than 12,000 study participants who delivered a baby.

Older paternal age was linked to a higher miscarriage risk, regardless of both the woman's age and a range of other factors that contribute to miscarriage, such as smoking during pregnancy and maternal diabetes.

Still, the researchers point out, despite this generally higher miscarriage rate, older paternal age may only slightly raise the risk to any one couple.

5 Things You Didn't Know: Men From Ross Bonander Ask Men. com

"2- Men have their own biological clock
We do indeed have a biological clock of sorts, although instead of one that stops, ours becomes increasingly unreliable over time.

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

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

I would guess that our study is just the tip of the iceberg. Father's and autism and schizophrenia

While older women run a higher risk of having babies with birth defects, it has long been presumed that men could have healthy children at any age. Think again. A new (2001, there have been 10 studies by 2007) study now shows that older fathers are far more likely to have children with schizophrenia, while the age of the mother appears to have no influence on the likelihood of her offspring developing this devastating disease.

The study showed a strong, steady increase in the risk of having children with the disease as men aged. Men aged 45 to 49 were twice as likely to have children with schizophrenia as men under the age of 25 who became fathers, while the risk tripled for men over the age of 50, according to an analysis of a large population of over 85,000 people by researchers from New York University School of Medicine, Columbia University College of Physicians & Surgeons, and Israel's Ministry of Health.

"Women are often made to feel responsible for problems occurring during pregnancy, especially if anything goes wrong with their children's health, but this new study shows that men also contribute," says Susan Harlap, M.D., Research Professor of Epidemiology in the Department of Obstetrics and Gynecology at NYU School of Medicine and an author of the new study.

"There has been some previous research showing that men contribute to rare genetic abnormalities in their offspring. Schizophrenia, by comparison, is common, affecting 1% of all populations worldwide," says Dr. Harlap. "I would guess that our study is just the tip of the iceberg. Eventually it would seem that the father's sperm is going to turn out to be just as important as the mother's egg."

Father's advanced age feeds autism risk by Helen Pearson

Father's advanced age feeds autism risk
Helen Pearson
25 February 2008 09:00:00 EST

Children of fathers aged 40 or older are nearly six times morelikely to have autism.

Are older fathers more likely to have children with autism? A series of epidemiological studies is giving credence to the idea, suggesting that, with age, sperm may accumulate damage that increases risk in the next generation.
Advancing age of the father is known to be a significant risk factor for schizophrenia1. These studies — along with anecdotal suggestions that fathers of autistic children tend to be older than average — prompted Avi Reichenberg of Mount Sinai School of Medicine, New York, to launch one of the first thorough epidemiological investigations into a link between the two.
Reichenberg and his colleagues had access to a vast database of health information collected from more than 132,000 Israeli adolescents who underwent draft board assessment, including psychiatric screening, before entering the army. The researchers were able to identify those who were diagnosed with autism spectrum disorders (ASD), along with the age of their parents.
Children of fathers in their 30s are about 1.6 times more likely to have ASD than children of fathers below age 30, the study found2. Compared with the youngest group, children of fathers aged 40 or older were nearly six times more likely to have ASD. “It was much stronger than we had thought,” Reichenberg says.
Since then, a handful of other epidemiology studies have backed the autism-paternal age connection. In one of these3, a team led by Lisa Croen of Kaiser Permanente Northern California Division of Research in Oakland, California, mined a health database of more than 130,000 births and found that each decade of paternal or maternal age increased risk of autism spectrum disorder by around 30%.
Paternal age “is still a relatively small contributor,” Croen says, “but when you see something that keeps coming up in different populations and study designs you start thinking there must be something to this.”
The link may be real, but researchers have yet to explain what causes it. Perhaps, says Croen, older parents are simply more attuned to the development of their children and therefore more likely to get a diagnosis. “It could be an artifact,” she says. “We don’t have enough data yet to really rule that out.”
Genetic origins
Another simple explanation is that fathers who themselves have autism or mild social deficits are likely to marry and have children at a later age than other men, and these children inherit factors putting them at high risk of developing the condition themselves.
But Reichenberg says that in his studies he has found no link between traits such as shyness, sensitivity and aloofness in parents and the age at which they have children. “It’s not definitive but the evidence is definitely against such an explanation,” he says.
Many researchers instead favor a genetic origin for the phenomenon. Male germ cells go through multiple rounds of division to manufacture sperm throughout a man’s life and, according to one idea, they may accumulate DNA damage as the molecule is copied again and again.
Sperm produced by older men are more likely to carry genetic defects, and these defects could boost their children’s risk of autism. Female germ cells divide far fewer times.
It is also possible that older sperm are more likely to acquire epigenetic defects: ones that do not change the DNA sequence itself, but that alter the activity of genes due to structural or chemical changes to DNA such as methylation.
These genetic changes arise in the egg or sperm rather than being inherited from the parents. Both concepts fit with the knowledge that the majority of ASD cases have a genetic cause, even though they are also the first in a family.
For precedent, geneticists point to a condition called achondroplasia, a common cause of dwarfism and the textbook example of a genetic condition associated with paternal age. The risk of sperm carrying a single point mutation in the gene for a growth factor receptor is thought to increase with the age of the father.
“It would be overwhelmingly logical,” for something similar to be going on in some cases of autism, says human geneticist Arthur Beaudet at Baylor College of Medicine in Houston, Texas. Perhaps just one or two of the many genes associated with the disorder are susceptible to detrimental point mutations as the germ cells age.
Beaudet says he would like to see genetic and epigenetic analyses of single sperm to see if mutation rates differ in the fathers of autistic children, and between younger and older men. “That would be the approach I’d be enthusiastic about,” he says. Reichenberg says that he is pursuing such studies.
Because there are few clearly defined genes for autism risk, it’s not yet clear where to look for these increased mutation rates. And genome-wide studies looking for differences in the rates of point mutations in many sperm are still too expensive and laborious.
Copy numbers
Last year, molecular studies showed that mutations called copy number variations (CNVs) — genomic chunks that can be deleted or duplicated from one person to the next — appear to be major contributors to sporadic autism.
A group led by Michael Wigler and Jonathan Sebat at the Cold Spring Harbor Laboratory in New York looked for CNVs that were present in autistic individuals, but not in their parents. They found CNVs in 10% of children with sporadic autism, 2% of those with familial autism and 1% of controls4.
This suggests that many more cases of sporadic autism may be attributable to spontaneous mutations — either CNVs or more subtle mutations — than had been realized.
Sebat has not examined whether the frequency of these CNV mutations increases in aging germ cells — but he suspects it might. “We don’t have data one way or the other,” he says, “but it’s a very tantalizing hypothesis.”
Many of the cellular systems that protect DNA from mutation might begin to fail in aging germ cells, so that their mutation rate increases, Sebat suggests. He is planning to test in a larger group of autistic individuals whether the CNV mutations are more common in children of older parents.
Reichenberg and his colleagues are also testing these hypotheses. In one study, they are trying to compare old and young fathers of autistic children, looking for differences in the rate of new mutations and their association to genetic hotspots previously linked to autism.
They are also doing mouse studies to explore whether offspring of older males tend to suffer more behavioral problems that mimic autism.
There remains some debate about whether the mother’s age is as important a risk factor as that of the father, and studies have differed in their findings. A maternal age effect is harder to tease out, partly because women have children within a more limited age range than men: very few over-40 women have children.
In her study, Croen found that maternal age is just as important and says that other studies have lacked the statistical power to tease this out. “Our data show that maternal age is also in the mix,” she says.
The fact that schizophrenia risk also increases with age leads some researchers to wonder whether some of the same genes may contribute to both disorders – and perhaps to other psychiatric conditions as well.
It’s a “feasible hypothesis”, Reichenberg says, “and I believe a worthwhile one to pursue.”
References:
Malaspina D et al. Arch. Gen. Psychiatry 58, 361-367 (2001) PubMed ↩
Reichenberg A. et al. Arch. Gen. Psychiatry 63, 1026-1032 (2006) PubMed ↩
Croen L. et al. Arch. Pediatr. Adolesc. Med. 161, 334-340 (2007) PubMed ↩
Sebat J. et al. Science 316, 445-449 (2007) PubMed ↩
posted by ApoorvaMandavilli

Maternal age of 40 years and over was found to be suggestively associated with a higher risk of Alzheimer's disease (overall relative risk = 1.7; 95%

Later research found the father's advanced age and not the mother's age associated with a greater risk of Alzheimer's. See Bertram:

(Paternal age is a risk factor for Alzheimer disease in the absence of a major gene
Journal neurogenetics
Publisher Springer Berlin / Heidelberg
ISSN 1364-6745 (Print) 1364-6753 (Online)
Issue Volume 1, Number 4 / August, 1998
Category Original article
DOI 10.1007/s100480050041
Pages 277-280
Subject Collection Biomedical and Life Sciences
SpringerLink Date Thursday, February 19, 2004



Authors
L. Bertram1, R. Busch2, M. Spiegl1, N. T. Lautenschlager1, U. Müller3, A. Kurz1
1Department of Psychiatry, Technical University Munich, Möhlstrasse 26, D-81675 Munich, Germany
2Department of Medical Statistics and Epidemiology, Technical University, Munich, Germany
3Department of Human Genetics, Justus-Liebig University, Giessen, Germany


Abstract

We compared the parental age at birth of patients with Alzheimer disease (AD) with that of cognitively healthy control subjects. Within 206 carefully diagnosed AD patients, two groups were distinguished according to the likelihood of carrying a major gene for AD (MGAD). This likelihood was calculated by applying a Bayesian approach which incorporates data on aggregation of the disease, age at onset, and "censoring" ages within the family. All AD patients were ranked by MGAD probability. According to the sample's quartiles, two subgroups were defined representing the 52 individuals with the lowest and the 52 with the highest MGAD probability. Age at onset of dementia, education, and apolipoprotein E )v4 allele frequencies were not statistically different between the two groups. Fathers of patients with a low MGAD probability were significantly older (35.7-8.1 years) than fathers of both other groups (high MGAD probability 31.3-6.9 years, P=0.004; controls 32.6-6.8 years, P=0.04, n=50). The differences for mothers were less pronounced and not statistically significant. These findings suggest that increased paternal age is a risk factor for AD in the absence of a major gene, whereas increased maternal age and AD are associated only weakly and independently of genetic disposition.)


Maternal age of 40 years and over was found to be suggestively associated with a higher risk of Alzheimer's disease (overall relative risk = 1.7; 95%








1: Int J Epidemiol. 1991;20 Suppl 2:S21-7. Links
Maternal age and Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.Rocca WA, van Duijn CM, Clayton D, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, et al.
SMID Centre, Florence, Italy.

To investigate the possible association between Alzheimer's disease and late maternal age at index birth, we conducted a collaborative re-analysis of existing case-control data sets. Of the 11 studies participating in the EURODEM project, four were included in the analyses regarding maternal age. In all four studies, cases were matched to controls by age and gender, and only population controls were considered. Analyses were conducted on the individual data sets, on the pooled sample, and on subgroups defined by gender, age at onset, and familial aggregation of dementia. Maternal age of 40 years and over was found to be suggestively associated with a higher risk of Alzheimer's disease (overall relative risk = 1.7; 95% confidence intervals: 1.0-2.9). In subgroup analyses, the association was statistically significant for women and for sporadic cases. Adjustments for education or analyses restricted to case-control pairs matched by type of respondent did not modify these results noticeably. The association was confirmed by a test of consistency with the Down's syndrome risk model; results of this test were again more definite for sporadic Alzheimer's disease. In addition, three of the four studies also suggested an increased risk for maternal age at index birth between 15 and 19 years (overall relative risk = 1.5; 95% confidence intervals: 0.8-3.0). Although consistency across studies was not always complete, only some of the increased relative risks reached statistical significance, and information regarding maternal age obtained through a next-of-kin interview may have limitations, our study suggests that both early and late maternal age should be further investigated as possible risk factors for Alzheimer's disease.