What is the stunning new finding about autism? Spontaneous Germ Line Mutations in autism are not a new find

Aug 15, 2007 11:20 pm US/Central

N.Y. Scientist Claims Stunning Find About Autism
(CBS) COLD SPRING HARBOR, N.Y. Behind the walls of a laboratory in Cold Spring Harbor, N.Y., may lie the beginnings of a scientific breakthrough.

Michael Wigler is a molecular geneticist, whose research is slowly unraveling the secrets of autism, and what causes it.

"It has all kinds of scientific implications," Wigler said. "It has a really hopeful message.".........................................

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


http://www.autismspeaks.org/inthenews/wrights_cold_spring_harbor.php


http://adventuresinautism.blogspot.com/search/label/Autism%20Eugenics

Why does Dr. Wigler not let the press know that it is clearly advancing paternal, not maternal age that is implicated in de novo autism??? If men knew, at least some would choose not to father later in life and have their children in their 20s and early 30s.
What is the hopeful message?



Maybe that it is a great idea to father all babies before 33-35? and also it is best for women to conceive their children by 33-35. Maybe that ones twenties are the best time to have children. This age doesn't guarantee children without genetic disorders if they are already in the family. This will not be the message however.



NW Sperm Bank--Sperm Donor Between 18 and 35 to minimize age related genetic abnormalities

Donor Standards

Our donors are recruited from the Northwest US. Most of our donors are either starting, currently involved with, or have finished their higher education at the time of their participation in our donor program. All donors are between 18 and 35 years of age in order to minimize age related genetic abnormalities. All donors are frozen in very limited quantities in order to guarantee that the number of pregnancies created from any one donor are limited. We stop further sales to new clients at 10 reported successes. Although all donor histories are reviewed to provide you with donors that should give you a great chance of concieving a healthy and normal baby, there is of course no way to guarantee such an outcome. As all donor family histories will present with their own unique positive and negative attributes, we encourage all clients to review donor information thoroughly prior to purchase and use of specimens.

All of our donors are commercial anonymous donors. We do not provide the identity of any of our donors to clients. All of our donors are asked if they are willing to meet with, or be contacted by, legal aged children that could be produced through their donations. If the donor expresses that he is willing to entertain future contact by legal aged children, then the child must approach the Cryobank to initiate the potential donor contact.
Our donor screening meets or exceeds the standards set forth by the FDA, AATB, ASRM. (Food and Drug Administration, American Association of Tissue Banks, American Society for Reproductive

"The older the mother, the more likely she has acquired spontaneous mutations in [her chromosomes]," and will transmit them at conception, Wigler said. Less frequently, but just as likely, Wigler said, fathers can transmit autism traits as well.


Are CNVs really less likely in the male germ line?

Children born to fathers of advancing age are at significantly higher risk of developing autism compared with children born to younger fathers, according a comprehensive study published yesterday that offers surprising new insight into one of the most feared disorders of the brain.


Reichenberg's study from September 2006:
With every decade of advancing age starting with men in their teens and twenties, the new study found, older fathers pose a growing risk to their children when it comes to autism -- unhappy evidence that the medical risks associated with late parenthood are not just the province of older mothers, as much previous research has suggested.

Of special concern is the finding that the risk for autism not only increases with paternal age but also appears to accelerate.

When fathers are in their thirties, children have about 1 1/2 times the risk of developing autism of children of fathers in their teens and twenties. Compared with the offspring of the youngest fathers, children of fathers in their forties have more than five times the risk of developing autism, and children of fathers in their fifties have more than nine times the risk
Labels: autism, paternal age




Sunday, March 18, 2007
Paternal age and intelligence: implications for age-related genomic changes in male germ cells.

Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY.
New York State Psychiatric Institute and Columbia University, New York, NY 10032, USA. dm9@columbia.edu

BACKGROUND: A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence.............................


The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children.




I cannot find the evidence that older fathers are less likely to have mutations in their germ line. What is the basis for this statement? I hope it isn't the incidence of Down Syndrome. Dr. Harry Fisch can provide the information that paternal age is a major, major factor in the incidence of Down syndrome for offspring of women over 35. By age 40 fathers age is responsible 50% of the time.

Dr Fisch and his colleagues found that the rate of Down syndrome steadily increased with advancing paternal age for the maternal age group of 35 to 39 years. The greatest increase, however, was seen in the maternal age group of 40 years and older with increasing paternal age. "The rate of Down syndrome for both maternal and paternal age greater than 40 years is approximately 60 per 10,000 births, which is a six-fold increase compared with maternal and paternal ages less than 35 years of age. In this age group, the paternal contribution to Down syndrome was 50 percent. Men over age 40 were twice as likely to have a Down syndrome child than men less than 20 years old," notes Dr Fisch.


1: Haemophilia. 2003 Nov;9(6):717-20. Links
Germ-line origin of intron 1 inversion in two haemophilia A families.Acquila M, Pasino M, Santoro C, Lanza T, Molinari AC, Bottini F, Bicocchi MP.
Haemostasis and Haemophilia Laboratory, IV Paediatric Department, G Gaslini Institute, Genova, Italy. mauraacquila@ospedale-gaslini.ge.it

Factor VIII gene inversion of intron 1 has recently been reported to be the mutation responsible for haemophilia A in about 5% of severe cases. In our series of patients, which is made up of 77 Italian cases negative for intron 22 inversion, the mutation was found in three sporadic and in one familial patients, with an overall frequency of 5.2%. The carrier status of the patients' female relatives was assessed by mutation analysis and showed that only two-thirds of cases could be considered truly sporadic. The germ-line origin of the mutation was investigated in the two sporadic families by haplotype analysis on genomic DNA of the patients' maternal grandparents. These studies indicated that both mutation events had occurred in the germ cell lines of the patients' healthy grandfather, suggesting that, as already demonstrated for the inversion of intron 22, the male germ cell line is more susceptible to the intrachromosome recombination which leads to the inversion of intron 1.

PMID: 14750938 [PubMed - indexed for MEDLINE


http://archpedi.ama-assn.org/cgi/content/abstract/161/4/326

The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.



1: Fertil Steril. 2007 May;87(5):1077-86. Epub 2007 Apr 11. Links
Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age.Sloter ED, Marchetti F, Eskenazi B, Weldon RH, Nath J, Cabreros D, Wyrobek AJ.
Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.

OBJECTIVE: To investigate the association between male age and the frequency of sperm with de novo structural chromosomal abnormalities. DESIGN: Semen specimens collected from two groups of 10 healthy, nonsmoking men, aged 22-28 and 65-80 years, were analyzed with the use of a multicolor fluorescence in situ hybridization assay for detecting breaks, segmental duplications and deletions, and aneuploidy and diploidy involving chromosome 1. SETTING: Healthy volunteer workers and retirees from a government research environment. MAIN OUTCOME MEASURE: Sperm carrying numerical and structural chromosomal abnormalities. RESULT(S): We detected significant increases in the frequency of sperm carrying breaks and segmental duplications and deletions of chromosome 1 among older men compared with younger men. Older men carried twice the frequency of sperm with segmental duplications and deletions of chromosome 1. The frequency of sperm carrying breaks within the 1q12 fragile-site region nearly doubled in older men. In contrast to female gametes, there was no effect of age on the frequency of sperm with numerical chromosomal abnormalities. CONCLUSION: Our findings suggest that advancing male age is associated with a gradual and significant increase in the risk of fathering children with various chromosomal defects such as segmental aneusomy syndromes.






If autism increases with paternal age why isn't Dr. Wigler mentioning that men over 34, 35 can have multiple autistic or schizophrenic children.
In 1988 there was a paper advocating that men complete their families by 35.


"The issue is that the older man will have sperm that has undergone more divisions and therefore had more chances to have mutations. The COMPLEXITY of the myelination process makes it more vulnerable to mutations. I am not talking of one specific mutation. Many things could MANIFEST in the myelination or myelin breakdown process because it is so vulnerable - something going slightly wrong will impact it while it will not impact bone growth or the heart. A good example is ApoE4 - whatever else it may affect, it manifests in the reduced capacity of myelin repair and earlier onset of AD." George Bartzokis M.D.

A DIRECT CAMPAIGN FOR FATHERS TO COMPLETE THEIR FAMILIES BEFORE THE AGE OF 35 MAY HAVE A MEASUREABLE EFFECT IN THE PREVENTION OF DOMINANT MUTATIONS
1: Am J Med Genet. 1988 Dec;31(4):845-52. Links Prevalence of dominant mutations in Spain: effect of changes in maternal age distribution.Martinez-Frias ML, Herranz I, Salvador J, Prieto L, Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Estudio Colaborativo Espanol de Malformaciones Congenitas (ECEMC), Facultad de Medicina, Universidad Complutense, Madrid, Spain.We studied the birth prevalence of autosomal dominant mutations in Spain and estimated how a decrease in maternal age distribution may lead to reduction in dominant mutations. The data were collected by the Estudio Colaborativo Espanol de Malformaciones Congenitas from April, 1976, to December, 1985. Among 553,270 liveborn infants monitored during the period, 66 infants with autosomal dominant conditions were identified. These included Apert, Crouzon, Hay-Wells, Treacher-Collins, Robinow, Stickler, Adams-Oliver, and the blepharophimosis syndromes, achondroplasia, cleidocranial dysostosis, and thanatophoric dysplasia. The overall rate of autosomal dominant conditions was 1.2 per 10,000 liveborn infants. Thirteen (20%) had an affected relative, and 52 (79%) had a negative family history. One case was excluded because of insufficient family data. The rate of autosomal dominant mutations was 0.9 per 10,000 liveborn infants, or 47 per 1 million gametes. A reduction in the maternal age distribution of mothers age 35 years and older from the current 10.8% to 4.9%, as in Atlanta, Georgia, would reduce the rate of Down syndrome in Spain by 33% and through a change in parternal age distribution may lead to a reduction in dominant mutations of about 9.6%. This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.





Researchers: New understanding of autism is near There is something fishy about this new theory of autism. How old are the fathers of autistic children on average?

"As people age, their genes increasingly acquire mutations that are not fixed through DNA repair mechanisms. That's why a spontaneous strike can lead to Down syndrome. And that is also why autism can similarly occur through CNVs, Wigler said." What he fails to mention is the amount of research that attributes spontaneous mutations to rising paternal age past 32 and the great increase in average paternal age since 1980.


"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." Dolores Malaspina



1: J Child Psychol Psychiatry. 2005 Sep;46(9):963-71.
Links
Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.
Lauritsen MB, Pedersen CB, Mortensen PB.
Centre for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Denmark. mbl@psykiatri.aaa.dk
BACKGROUND: The etiology of autism is unknown. A strong genetic component has been detected but non-genetic factors may also be involved in the etiology. METHODS: We used data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity. RESULTS: A total of 943,664 children younger than ten years were followed from 1994 to 2001; of those, 818 children developed autism. The highest risks of autism were found in siblings of children with autism, or Asperger's syndrome and other pervasive developmental disorders (PDDs), with relative risks of 22 and 13, respectively. The relative risk of autism in the child was about twice as high if the mother had been diagnosed with a psychiatric disorder. The risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age. An increased relative risk of 1.4 was found if the mother was born outside Europe, and in children of parents who were born in different countries. CONCLUSIONS: The highest risk of autism was found in families with a history of autism, or Asperger's syndrome and other PDDs in siblings, supporting the commonly accepted knowledge that genetic factors are involved in the etiology of autism.
PMID: 16108999 [PubMed - indexed for MEDLINE]


Hum Reprod. 1989 Oct;4(7):794-7. Links Paternal age and mental functions of progeny in man.Auroux MR, Mayaux MJ, Guihard-Moscato ML, Fromantin M, Barthe J, Schwartz D. Biologie de la Reproduction et du Developpement, CHU Bicetre, Le Kremlin-Bicetre, France.Hum Reprod. 1989 Oct;4(7):794-7. LinksPaternal age and mental functions of progeny in man.Auroux MR, Mayaux MJ, Guihard-Moscato ML, Fromantin M, Barthe J, Schwartz D.Biologie de la Reproduction et du Développement, CHU Bicêtre, Le Kremlin-Bicêtre, France.The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.PMID: 2606957 [PubMed - indexed for MEDLINE]................................................................................"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." The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age. A variant of schizophreniaA persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).






There has been a strong linkage of autism with older fathers for many, many years.





In 1980 Christopher Gillberg found that autism was found in children with older mother and much older fathers. The mean average age of the fathers of the children with autism was 34 which was much older than in the general population.





The Fathers Too, Were Much Older Than Average --A study of classical autism in 1980
1: J Autism Dev Disord. 1980 Sep;10(3):293-7. Links Maternal age and infantile autism.Gillberg C.In a total population survey of childhood psychosis in the region of Goteborg, 20 children (2 in every 10,000) fulfilled the diagnostic criteria for infantile autism formulated by Rutter. There was a male preponderance with 15 boys and 5 girls. Eighty-five percent of the mothers were older than average. Mean maternal age in the autistic sample was 30.7 years, compared with 26.0 years in the general population. The difference is statistically significant at the .1% level. There was a strong tendency toward increasing risk of autism in the child with increasing maternal age. The fathers too were much older than average.PMID: 6927656 [PubMed - indexed for MEDLINE



Hum Reprod. 1989 Oct;4(7):794-7. Links Paternal age and mental functions of progeny in man.Auroux MR, Mayaux MJ, Guihard-Moscato ML, Fromantin M, Barthe J, Schwartz D. Biologie de la Reproduction et du Developpement, CHU Bicetre, Le Kremlin-Bicetre, France.Hum Reprod. 1989 Oct;4(7):794-7. LinksPaternal age and mental functions of progeny in man.Auroux MR, Mayaux MJ, Guihard-Moscato ML, Fromantin M, Barthe J, Schwartz D.Biologie de la Reproduction et du Développement, CHU Bicêtre, Le Kremlin-Bicêtre, France.The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.PMID: 2606957 [PubMed - indexed for MEDLINE]................................................................................"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." The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father's age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age. A variant of schizophreniaA persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).


J Child Psychol Psychiatry. 2005 Sep;46(9):963-71.
Links
Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.
Lauritsen MB, Pedersen CB, Mortensen PB.
Centre for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Denmark. mbl@psykiatri.aaa.dk
BACKGROUND: The etiology of autism is unknown. A strong genetic component has been detected but non-genetic factors may also be involved in the etiology. METHODS: We used data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity. RESULTS: A total of 943,664 children younger than ten years were followed from 1994 to 2001; of those, 818 children developed autism. The highest risks of autism were found in siblings of children with autism, or Asperger's syndrome and other pervasive developmental disorders (PDDs), with relative risks of 22 and 13, respectively. The relative risk of autism in the child was about twice as high if the mother had been diagnosed with a psychiatric disorder. The risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age. An increased relative risk of 1.4 was found if the mother was born outside Europe, and in children of parents who were born in different countries. CONCLUSIONS: The highest risk of autism was found in families with a history of autism, or Asperger's syndrome and other PDDs in siblings, supporting the commonly accepted knowledge that genetic factors are involved in the etiology of autism.
PMID: 16108999 [PubMed - indexed for MEDLINE]

Eur J Paediatr Neurol. 2007 Jul;11(4):223-31. Epub 2007 Mar 7.
Links
Newborns at risk for special education placement: a population-based study.
Mannerkoski MK, Aberg LE, Autti TH, Hoikkala M, Sarna S, Heiskala HJ.
Department of Child Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland. minna.mannerkoski@hus.fi
OBJECTIVES: To establish the contributions of birth weight (BW), gender, socioeconomic status (SES), and parental age on risks for special education (SE) placements in school-age children. METHODS: A population-based sample of 900 school-age children attending the following full-time SE groups: at level 1, children had isolated neurodevelopmental, physical, or other impairments; at level 2, borderline to mild intellectual disability (ID); and at level 3, moderate to severe ID. Three hundred and one children enrolled in mainstream education formed the control group (level 0). For all children with siblings, we defined familiar forms of learning disorders as having a sibling in one of the SE groupings. We performed our analysis for the entire cohort as well as comparing risk factors within the familial and non-familial types of SE groupings. RESULTS: In multinomial logistic regression analysis, age of father 40 years, low BW Parental ages at birth of children with pervasive developmental disorders are higher than those of children in the general population.
Koyama T, Miyake Y, Kurita H.
Department of Mental Health Administration, National Institute of Mental Health, National Center for Neurology and Psychiatry, Kodaira, Tokyo, Japan. tomok@ncnp.go.jp
To examine whether parental ages at birth of children with pervasive developmental disorders (PDD) are elevated, maternal/paternal ages at birth of 309 PDD children born in 1993-2003 (mean age, 8.4 years) were compared with those of children in the Japanese national statistics (general population). The mean maternal/paternal ages (years) at birth of PDD children of 31.7/34.6 were significantly higher even than the highest mean maternal/paternal ages at birth of children of 31.2/33.6 in the national statistics in 2003. This first Japanese study to report elevated parental ages at birth of PDD children underscores the need of further extensive studies.
PMID: 17362441 [PubMed - indexed for MEDLINE]



Letter to the Editor
Molecular Psychiatry (2007) 12, 419–421. doi:10.1038/sj.mp.4001966

Paternal age and autism are associated in a family-based sample
R M Cantor1,2,3, J L Yoon1, J Furr4 and C M Lajonchere3,4,5

1Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
2Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
3AGRE Consortium, Los Angeles, CA, USA
4Autism Genetic Resource Exchange, Cure Autism Now, Los Angeles, CA, USA
5Department of Pediatrics, Keck School of Medicine, University of Southern California, CA, USA
Correspondence: RM Cantor, E-mail: rcantor@mednet.ucla.edu


PMID: 17453057 [PubMed - as supplied by publisher]

The paternal age distribution of the AGRE fathers, whose first child is autistic differs significantly from that of the 'control' sample (P=0.005). A 2 goodness-of-fit test with 2 degrees of freedom was conducted using percents in the 'control' group age categories to calculate the expected values in the AGRE sample. The shift toward higher paternal ages in those with an affected first-born is seen most dramatically in the group of AGRE fathers who are 30–39 years inclusive, which is 54.7% of the distribution compared with the 41.9 % that is expected. We interpret this shifted age distribution to provide support for the recently reported finding by Reichenberg and co-workers that autism risk is associated with advancing paternal age.



The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.