Thursday, July 30, 2009

Of 27 translocations, we found 26 to be of paternal origin and only one of maternal origin.

: J Med Genet. 2009 Jul 27. [Epub ahead of print]
De novo apparently balanced translocations in man are predominantly paternal in origin and associated with a significant increase in paternal age.Thomas NS, Morris JK, Baptista J, Ng BL, Crolla JA, Jacobs PA.
Salisbury District Hospital, United Kingdom.

BACKGROUND: Congenital chromosome abnormalities are relatively common in our species and among structural abnormalities the most common class is balanced reciprocal translocations. Determining the parental origin of de novo balanced translocations may provide insights into how and when they arise. While there is a general paternal bias in the origin of non-recurrent unbalanced rearrangements, there are few data on parental origin of non-recurrent balanced rearrangements. METHODS: The parental origin of a series of de novo balanced reciprocal translocations was determined using DNA from flow sorted derivative chromosomes and linkage analysis. RESULTS: Of 27 translocations, we found 26 to be of paternal origin and only one of maternal origin. We also found the paternally derived translocations to be associated with a significantly increased paternal age (p<0.008). CONCLUSION: Our results suggest there is a very marked paternal bias in the origin of all non-recurrent reciprocal translocations and that they may arise during one of the numerous mitotic divisions that occur in the spermatogonial germ cells prior to meiosis.

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Saturday, July 25, 2009

Unlike schizophrenia, the risk of BPAD seems to be associated with both paternal and maternal ages

Psychol Med. 2009 Jul 23:1-9. [Epub ahead of print]
Paternal and maternal ages at conception and risk of bipolar affective disorder in their offspring.
Menezes PR, Lewis G, Rasmussen F, Zammit S, Sipos A, Harrison GL, Tynelius P, Gunnell D.
Department of Preventive Medicine, University of Sao Paulo, Brazil.
BACKGROUND: A consistent association between paternal age and their offspring's risk of schizophrenia has been observed, with no independent association with maternal age. The relationship of paternal and maternal ages with risk of bipolar affective disorders (BPAD) in the offspring is less clear. The present study aimed at testing the hypothesis that paternal age is associated with their offspring's risk of BPAD, whereas maternal age is not.MethodThis population-based cohort study was conducted with individuals born in Sweden during 1973-1980 and still resident there at age 16 years. Outcome was first hospital admission with a diagnosis of BPAD. Hazard ratios (HRs) were calculated using Cox's proportional hazard regression. RESULTS: After adjustment for all potential confounding variables except maternal age, the HR for risk of BPAD for each 10-year increase in paternal age was 1.28 [95% confidence interval (CI) 1.11-1.48], but this fell to 1.20 (95% CI 0.97-1.48) after adjusting for maternal age. A similar result was found for maternal age and risk of BPAD [HR 1.30 (95% CI 1.08-1.56) before adjustment for paternal age, HR 1.12 (95% CI 0.86-1.45) after adjustment]. The HR associated with having either parent aged 30 years or over was 1.26 (95% CI 1.01-1.57) and it was 1.45 (95% CI 1.16-1.81) if both parents were >30 years. CONCLUSIONS: Unlike schizophrenia, the risk of BPAD seems to be associated with both paternal and maternal ages.
PMID: 19627644 [PubMed - as supplied by publisher]
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Paternal age and schizophrenia: a population based cohort study.
BMJ. 2004 Nov 6; 329(7474):1070. Epub 2004 Oct 22.
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» See reviews... » See all...

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Tuesday, July 14, 2009

Data Converges About Older Fathers

Data Converges About Older Fathers
A recent post in the New York Times presents some evidence that men who become fathers at a later age have unhealthier children. It is well recognized that men retain their reproductive potential longer, and lose it in a more gradual manner, than do women. Whereas women's fertility declines sharply after age 35 or so, men retain their ability to father children, albeit to a diminished degree, for several decades longer. Recently, some evidence has been presented in the scientific literature that suggests that children conceived with sperm from an older male may have cognitive or psychological challenges compared to those fathered by younger males. A recent study performed by Australian scientists concluded that older dads have children with slightly lower IQs. Others have shown increased rates of schizophrenia, bipolar disorder, and autism in children fathered by older vs. younger men. This evidence suggests that men are susceptible to age-related effects on reproductive ability. This should not surprise anyone. However, the effects of reproductive ageing appear to be expressed differently in males than in females. Dr. Dolores Malaspina, a professor of psychiatry at New York University Medical Center, puts it this way: “It turns out the optimal age for being a mother is the same as the optimal age for being a father.”
posted by Kathleen, Contributing Editor at 1:00 PM


The ups and downs of mutation frequencies during aging can account for the apert syndrome paternal age effect

: PLoS Genet. 2009 Jul;5(7):e1000558. Epub 2009 Jul 10.
The ups and downs of mutation frequencies during aging can account for the apert syndrome paternal age effect.Yoon SR, Qin J, Glaser RL, Wang Jabs E, Wexler NS, Sokol R, Arnheim N, Calabrese P.
Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America.

Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of ages. The mutation frequencies increase with the age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features.

PMID: 19593369 [PubMed - in process]

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ReviewThe high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A. 1997 Aug 5; 94(16):8380-6.
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Monday, July 13, 2009

Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood

Research Article

Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood

Sukanta Saha1#, Adrian G. Barnett2#, Claire Foldi3, Thomas H. Burne1,3, Darryl W. Eyles1,3, Stephen L. Buka4, John J. McGrath1,3,5*

1 Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, Australia, 2 Institute of Health and Biomedical Innovation and School of Public Health, Queensland University of Technology, Kelvin Grove, Australia, 3 Queensland Brain Institute, The University of Queensland, St. Lucia, Australia, 4 Department of Community Health, Brown University, Providence, Rhode Island, United States of America, 5 Department of Psychiatry, The University of Queensland, St. Lucia, Australia

Abstract Top
Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood.

Methods and Findings
A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures.

The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.

Citation: Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, et al. (2009) Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood. PLoS Med 6(3): e1000040. doi:10.1371/journal.pmed.1000040

Academic Editor: Carol Brayne, University of Cambridge, United Kingdom

Received: September 8, 2008; Accepted: January 15, 2009; Published: March 10, 2009

Copyright: © 2009 Saha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors received no specific funding for this article.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: APA, advanced paternal age; CI, confidence interval; CPP, Collaborative Perinatal Project; WISC, Wechsler Intelligence Scale for Children; WRAT, Wide Range Achievement Test

* To whom correspondence should be addressed. E-mail:

# These authors contributed equally to this work.

Editors' Summary Top
Over the last few decades, changes in society in the developed world have made it increasingly common for couples to wait until their late thirties to have children. In 1993, 25% of live births within marriage in England and Wales were to fathers aged 35–54 years, but by 2003 it was 40%. It is well known that women's fertility declines with age and that older mothers are more likely to have children with disabilities such as Down's syndrome. In contrast, many men can father children throughout their lives, and little attention has been paid to the effects of older fatherhood.

More recent evidence shows that a man's age does affect both fertility and the child's health. “Advanced paternal age” has been linked to miscarriages, birth deformities, cancer, and specific behavioral problems such as autism or schizophrenia.

Rates of autism have increased in recent decades, but the cause is unknown. Studies of twins and families have suggested there may be a complex genetic basis, and it is suspected that damage to sperm, which can accumulate over a man's lifetime, may be responsible. A woman's eggs are formed largely while she is herself in the womb, but sperm-making cells divide throughout a man's lifetime, increasing the chance of mutations in sperm.

Why Was This Study Done?
There is good evidence linking specific disorders with older fathers, but the link between a father's age and a child's more general intelligence is not as clear. A recent study suggested a link between reduced intelligence and both very young and older fathers. The authors wanted to use this large dataset to test the idea that older fathers have children who do worse on tests of intelligence. They also wanted to re-examine others' findings using this same dataset that older mothers have more intelligent children.

What Did the Researchers Do and Find?
The researchers gathered no new data but reanalyzed data on children from the US Collaborative Perinatal Project (CPP), which had used a variety of tests given to children at ages 8 months, 4 years, and 7 years, to measure cognitive ability—the ability to think and reason, including concentration, memory, learning, understanding, speaking, and reading. Some tests included assessments of “motor skills”—physical co-ordination.

The CPP dataset holds information on children of 55,908 expectant mothers who attended 12 university-affiliated hospital clinics in the United States from 1959 to 1965. The researchers excluded premature babies and multiple births and chose one pregnancy at random for each eligible woman, to keep their analysis simpler. This approach reduced the number of children in their analysis to 33,437.

The researchers analyzed the data using two models. In one, they took into account physical factors such as the parents' ages. In the other, they also took into account social factors such as the parents' level of education and income, which are linked to intelligence. In addition, the authors grouped the children by their mother's age and, within each group, looked for a link between the lowest-scoring children and the age of their father.

The researchers found that children with older fathers had lower scores on all of the measures except one measure of motor skills. In contrast, children with older mothers had higher scores. They found that the older the father, the more likely was this result found.

What Do These Findings Mean?
This study is the first to show that children of older fathers perform less well in a range of tests when young, but cannot say whether those children catch up with their peers after the age of 7 years. Results may also be biased because information was more likely to be missing for children whose father's age was not recorded.

Previous researchers had proposed that children of older mothers may perform better in tests because they experience a more nurturing home environment. If this is the case, children of older fathers do not experience the same benefit.

However, further work needs to be done to confirm these findings. Especially in newer datasets, current trends to delay parenthood mean these findings have implications for individuals, couples, and policymakers. Individuals and couples need to be aware that the ages of both partners can affect their ability to have healthy children, though the risks for individual children are small. Policymakers should consider promoting awareness of the risks of delaying parenthood or introducing policies to encourage childbearing at an optimal age.

Additional Information.
Please access these Web sites via the online version of this summary at​000040 .

Mothers 35+ is a UK Web site with resources and information for older mothers, mothers-to-be, and would-be mothers, including information on the health implications of fathering a child late in life

The American Society for Reproductive Medicine published a Patient Information Booklet on Age and Fertility in 2003, which is available online; it contains a small section called “Fertility in the Aging Male,” but otherwise focuses on women

The online encyclopedia Wikipedia has a short article on the “Paternal age effect” (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

In 2005, the UK Office of National Statistics published a booklet entitled “Perpetual postponers? Women's, men's and couple's fertility intentions and subsequent fertility behaviour” looking at data from the British Household Panel Survey

Introduction Top
In recent decades there has been increased attention to health outcomes in the offspring of older fathers. Evidence shows that advanced paternal age (APA) is associated with an increased risk of a wide range of disorders [1]. While not discounting the influence of various age-related psychosocial factors that may translate to differential health outcomes for the offspring of older fathers (e.g., higher socioeconomic status, better education), advances in genomics have refocused attention on the vulnerability of sperm from older fathers to carrying de novo mutations. The development of the germ cell differs between human males and females—there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte [2]. In the female there are 22 mitotic cell divisions that occur in utero. In contrast, after puberty, progenitor sperm stem cells undergo mitotic cell division once every 16 d. By age 20 the progenitor sperm cells have undergone approximately 150 cell divisions. By age 50 this number is 840. Thus, the chance of copy error mutations increases with age in males more dramatically than for females.

Advanced paternal age is associated with increased fetal deaths [3,4] and certain rare congenital syndromes (e.g., achondroplasia) [1,5]. In recent years evidence has accumulated linking APA with a wide range of neurological and neuropsychiatric conditions including Alzheimer's disease [6,7], bipolar disorder [8], dyslexia [9], neural tube defects [10], and epilepsy [11]. A sizeable body of evidence has accumulated linking APA with an increased risk of schizophrenia [12–18]. A recent meta-analysis based on eight studies found that paternal age above 35 was associated with an increased risk of schizophrenia [19]. There is also evidence linking APA to autism spectrum disorders [20–24].

The associations between APA and outcomes such as autism and schizophrenia are of particular interest, as these disorders have recently been associated with genomic structural variation [25–30]. It is feasible that APA-related mechanisms may contribute to genomic structural variation (e.g., copy number variants, microdeletions) [2]. Thus, within the fields of schizophrenia and autism research, there has been an unexpected convergence between epidemiology and molecular biology.

While there is good evidence linking paternal age with several clinically distinct neurodevelopmental disorders, the evidence linking paternal age and other neurocognitive outcomes such as general intelligence is less robust. Earlier studies noted an association between APA and poorer performance on neurocognitive tests [31–34]. This issue has been addressed specifically in a recent study based on male and female Israeli conscripts (age 16–17 y, n = 44,175) [35]. The study found independent effects of paternal age on offspring intelligence with the lowest scores associated with both younger and older fathers (inverted “U”-shaped association). This finding is in contrast to the association between maternal age and offspring intelligence, where most studies have reported a linear association between older maternal age and superior neurocognitive ability [36–39].

The aim of the present study was to explore the association between paternal age and a range of neurocognitive measures using a large, prospective birth cohort: the US-based Collaborative Perinatal Project (CPP). Based on the literature linking increased paternal age with a range of developmental anomalies and neuropsychiatric disorders, we hypothesized that the children of older fathers would have lower scores on various tests used to measure neurocognitive ability when assessed at 8 mo, 4 y, and 7 y. While a study based on this same cohort had previously identified that the offspring of older mothers had superior performance on neurocognitive functioning [36], we also took the opportunity to re-examine this hypothesis in the current analyses.

Methods Top
Sample Selection
The Collaborative Perinatal Project (CPP) recruited pregnant women from 12 university-affiliated hospital clinics in the United States of America from 1959 to 1965. The selection method varied from centre to centre, with between 14% and 100% of the registered pregnant women being invited to participate. At centres with less than 100% sampling, women were selected according to various quasi-random rules (e.g., every nth woman). Of 132,560 eligible pregnancies, 55,908 pregnancies were included, which was a proportion representative of the original sampling frame [40,41].

In order to reduce the impact of prematurity on the neurocognitive outcome measures, we restricted the sample to offspring born after 37 wk gestation. In order to minimize statistical complexities arising from dependent data, we restricted the sample to (a) singleton pregnancies, and (b) one randomly chosen pregnancy for each woman enrolled in the study.

Measures of Neurocognitive Function
Study offspring were assessed at regular intervals until age 7 y. Detailed descriptions of the methods used for cognitive assessments have been published elsewhere [36,42]. At 8 mo of age the Bayley Scales for Infant Development were administered [43,44]. Two scores were available: (a) Mental Scale, which assesses aspects of development including sensory discrimination and eye-hand coordination, and (b) Motor Scale, which assessed various aspects of fine and gross motor coordination. At age 4 y the children were administered (a) the Stanford Binet Intelligence Scale, Form L-M (a measure of general intelligence in young children) [45,46], and (b) the Graham-Ernhart Block Sort Test, which assesses conceptual and perceptual motor ability. This test involves increasingly difficult tasks that range from matching simple like-shaped blocks, to sorting blocks according to one or two dimensions (e.g., colour, shape, size) [47]. At age 7 y the children were administered the widely used Wechsler Intelligence Scale for Children (WISC) [48]. Scores for Full Scale, Verbal, and Performance were available for this study. However, the two WISC subscales (Verbal and Performance) were strongly correlated with WISC Full Scale IQ (Pearson correlation = 0.90 and 0.89, respectively), thus only the WISC Full Scale IQ results are presented. The Wide Range Achievement Test (WRAT) scale was also used at the age 7 y follow-up in order to evaluate academic achievements (e.g., the ability to read words, comprehend sentences, spell, and compute solutions to math problems) [49]. Scores for WRAT Arithmetic, Reading, and Spelling were available in this study. Because the WRAT Reading, Spelling, and Arithmetic scores were all strongly correlated (Pearson correlations of 0.65 to 0.89), only the WRAT Reading is presented.

Statistical Methods
For the primary analyses, we modelled nonlinear associations between parental age and neurocognitive outcomes using a generalized additive model [50]. We used the generalized cross-validation algorithm to select the degree of nonlinearity. To verify the assumptions of the models, we examined the residuals to check (a) their normality and (b) their homoscedasticity (constant variance) against paternal age.

Each parent's age (at the birth of the child) was adjusted for the other parent's age. For the primary analyses, we examined a simple model (Model 1) adjusted for offspring sex, other parent's age, mother's race, weeks of gestation, and child's age at testing (which varied slightly at the 8 mo, 4 y, and 7 y follow-ups). In order to explore if various socioeconomic variables influenced the strength of the association, a second model (Model 2) also included additional adjustments related to maternal marital status, family socioeconomic status and parental mental health. Socioeconomic status was measured by a composite index that averaged centiles derived from maternal and paternal education and occupation, as well as family income [51].

Because maternal and paternal age were strongly correlated (Pearson correlation = 0.80), we checked the models for colinearity using the variance inflation factor [52]. The variance inflation factors were roughly three for paternal and maternal age in all models. This value is well below the suggested threshold of ten [52], and hence we modelled both ages together.

The results of the primary analyses are displayed graphically, with the nonlinear model fitted for both maternal and paternal age (and 95% confidence intervals [CIs]). The variance explained (adjusted R-squared) and the p-values for each of the primary analyses are also shown in tabular form. Nonlinear models do not lend themselves to simple quantitative descriptions (e.g., statements such as “the outcome variable falls by a certain number of units for every additional 5 years of paternal age” cannot be made for nonlinear relationships). In order to facilitate interpretation of the primary analyses, we also provided estimates (and 95% CIs) for each outcome variable at two paternal ages (20 and 50 y).

As secondary analyses, we examined the association between paternal age and offspring neurocognition according to various strata of maternal age. This removes widely diverse effects due to maternal age on neurocognitive outcomes by estimating the effect of paternal age in subgroups where mother's ages were highly comparable. We identified cohort members where maternal ages fell within roughly 5 y age strata: <20, 20–24, 25–29, 30–34, 35–39, 40+. For these secondary analyses, we also chose a more stringent test of the association between the variables of interest. For each of the neurocognitive variables, we stratified the sample by sex, age, and race and then dichotomized the sample into a low-achievers group, defined as the lowest 10% of scores in each sex, age, and race group, versus the remaining 90% of the group. We calculated the adjusted odds ratio for being in the low achievers group for a 5 y increase in paternal age using conditional logistic regression.

All p-values were two-sided and statistical significance was set at 0.05. We used the mgcv library in R to fit the generalized additive models [53] and SAS PROC PHREG for the conditional logistic regression [54].

Results Top
There were 55,740 singleton pregnancies. Of these, 12,297 children were excluded because of (a) missing maternal and/or paternal age (1,542), (b) having indeterminate or unspecified sex (1,050), or (c) gestational age that was missing or less than 37 wk (9,705). After randomly selecting one live-born offspring per study mother, this left a total of 33,437 study offspring (17,148 males) available for the main analyses. Of these, 51% of the mothers were white, 39% black, and the remaining 10% were Asian and other racial groups. Finally, 6,355 children were missing information about age at testing at 8 mo, while 9,930 were missing age at testing at 4 y, and 9,109 were missing age at testing at 7 y. Those with missing paternal age were significantly more likely to have missing outcome variables at 8 mo, 4 y, and 7 y (each p < 0.001).

Table 1 shows descriptive statistics for paternal and maternal age and differences in parental age. On average, fathers were 3 to 4 y older than mothers, but the differences in parental age varied widely. Concerning the primary analyses, there was a statistically significant association between advanced paternal age and inferior performance on all neurocognitive tests (all p < 0.001) except for Bayley Motor score (Model 2, p = 0.104) (see Table 2). Concerning the influence of maternal age, there were statistically significant associations between advanced maternal age and superior performance on all measures. Figures 1 and 2 show the mean adjusted score for paternal and maternal age for the outcome variables based on Models 1 and 2 respectively. Apart from the direction of the association between maternal and paternal age, the association between maternal age and the outcome variables at ages 4 and 7 y was curvilinear (generally steep at younger ages, then less steep at older ages), in contrast to the near-linear association with paternal age. Post-hoc analyses examining the goodness-of-fit of nonlinear versus linear models indicated that two of the variables were adequately capture by simple linear models (Bayley Mental score and Graham Ernhart Block Sort Test), but that nonlinear models were best suited for all other variables (unpublished data). Table 3 shows the estimated scores (and 95% CIs) for two paternal ages (20 and 50 y) based on the nonlinear modelling used in the primary analyses. For Model 2, the adjusted R-squared ranged from 2.4% (Bayley Motor) to 29.5% (WISC Full Scale IQ).

Table 1.

Descriptive Statistics of Maternal and Paternal Age, and Parental Age Difference (n = 33,437)

doi:10.1371/journal.pmed.1000040.t001Table 2.

Primary Analyses: Summary Table for the Nonlinear Model Fits for Models 1 and 2

doi:10.1371/journal.pmed.1000040.t002Figure 1. Primary Analyses: Model 1—Adjusted for Other Parent's Age, Mother's Race, Gestational Age, and Child Gender

Solid lines ranging from 15 to 45 y for maternal age, dotted lines ranging from 15 to 65 y for paternal age. Nonlinear model fit with 95% CIs.

doi:10.1371/journal.pmed.1000040.g001Figure 2. Primary Analyses: Model 2—Adjusted for Other Parent's age, Mother's Race, Gestational Age, and Child Gender, Socioeconomic Index, Marital Status, and Maternal and Paternal Mental Illness

Solid lines ranging from 15 to 45 y for maternal age, dotted lines ranging from 15 to 65 y for paternal age. Nonlinear model fit with 95% CIs.

doi:10.1371/journal.pmed.1000040.g002Table 3.

Primary Analyses: Estimates for Two Paternal Ages Based on the Nonlinear Model Fits for Models 1 and 2

Concerning the secondary analyses, the odds ratio (Model 2) for being in the lowest decile for each neurocognitive variable was significantly associated with elevated paternal age for three of the neurocognitive measures (Bayley Motor, Graham Ernhart Block Sort Test, WISC Full Scale IQ), with trend level association identified for the other three measures (Bayley Mental, Stanford Binet Intelligence Scale, WRAT Reading) (Table 4).

Table 4.

Secondary Analyses: Associations between Increasing Paternal Age and Neurocognitive Measures in Children, Results from Logistic Regression Analyses Using Subgroups of Women with Similar Ages

Discussion Top
We report, to our knowledge for the first time, that the offspring of older fathers show impairments on a range of neurocognitive tasks during infancy and childhood. The pattern of findings was relatively consistent across ages and across neurocognitive domains, with near-linear declines found in most of the measures. When the data were examined with a more stringent definition of cognitive impairment (scores in the lowest 10%), a significant relationship between APA and impaired neurocognition was found for three of the six outcome variables, with trend level associations found for the remaining three variables. These findings persisted after adjustment for a range of socioeconomic variables and for parental mental health. In striking contrast to the findings for APA, the association between advanced maternal age and performance on neurocognitive tasks was in the opposite direction.

The findings differ somewhat from those reported by Malaspina et al. [35], who reported on four different measures related to cognitive ability in teenagers (age 16–17y). In that study the offspring of both younger (<20 y) and older fathers (>40 y) had impaired neurocognitive performance compared to those with fathers in the other age strata. However, differences between the Malaspina et al. study and the current study with respect to the psychometric measures and the age of the offspring make direct comparisons difficult. As expected, the current study also identified an association between advanced maternal age and superior performance on the neurocognitive tests, in keeping with some [36–39] but not all studies [35].

The association between APA and reduced neurocognitive ability may have important implications for clinical outcomes previously linked to APA. While not all individuals with autistic spectrum disorders have impaired intelligence, many have specific learning disabilities and/or intellectual handicap [55]. With respect to schizophrenia, systematic reviews and meta-analyses have shown a reliable, medium-sized impairment in premorbid intelligence associated with this disorder [56,57]. For example, Woodberry et al. [57] reported that years before the onset of psychotic symptoms, individuals who later developed schizophrenia had IQ scores that, on average, were approximately one-half of a standard deviation below that of healthy comparison participants. Consistent with these findings, a systematic review of the antecedents of schizophrenia based on prospective birth cohorts [58] provided robust evidence that individuals who later develop schizophrenia show deviation during childhood on a range of cognitive measures related to intelligence, motor development, speech and language, and educational outcomes. In particular, cohort members who later developed schizophrenia, as a group, achieved lower scores on intelligence tests in childhood and adolescence than their peers [59–61].

The findings from this study linking APA and impaired cognition may be best conceptualized within the notion of impaired cognitive reserve [62,63]. Just as superior cognitive capacity appears to provide a buffer against dementia [64,65], subtle APA-related impairments in neurocognitive ability may contribute to an increased risk of a diverse range of adverse neurological and neuropsychiatric health outcomes.

The study has several caveats. Nonrandom sample attrition and missing data may influence the generalisability of the findings [41]. Those with missing data on paternal age were more likely to be lost to follow-up. It will be important to examine the variables of interest in cohorts with optimal participant retention and minimal missing data. More importantly, the cohort members were born in the United States during the 1960s, thus the generalisability of the findings with respect to more contemporary cohorts needs to be examined. While it is feasible that various economic and psychosocial factors that can influence childhood developmental trajectories may have changed in recent decades, there is no reason to suspect that the putative biological processes linking APA and adverse health outcome would have varied over this time frame. Finally, it is important to note that these analyses investigated neurocognitive outcomes only until age 7 y, and it is feasible that the offspring of older fathers “catch up” during later childhood. How the subtle neurocognitive features associated with APA translate into later educational and mental health outcomes across the lifespan remains to be determined.

With respect to the mechanism of action underpinning these findings, several hypotheses warrant further scrutiny. While twin studies have demonstrated that cognitive ability and brain structure are heritable [66,67], studies based on sibships within the CPP have also confirmed that socioeconomic factors play a role in mediating the heritable aspects of intelligence [68]. With respect to paternal age, a broad range of socioeconomic factors improve with increasing age, thus most commentators believe that the offspring of older parents would have better access to health and educational services compared to the offspring of younger parents (who tend to have lower education and poorer income) [69]. For example, Fergusson and Lynsky [38] found that offspring of younger mothers tended to be born into relatively poorly educated and socially disadvantaged families. These authors commented that children born to young mothers were exposed to less nurturing and more changeable home environments. One would expect that such mechanisms would also operate with respect to paternal age. Clearly, our findings linking APA with impaired neurocognitive development cannot be readily explained by these social mechanisms.

Mechanisms related to the development of the male germline warrant consideration [70]. Each time the cell divides, the replication of the genome introduces the possibility of copy error mutations. In humans it has been confirmed that sperm from older men have significantly more mutations [2,71,72]. Levels of DNA proofreading and repair enzymes also decline as a function of APA [16] and DNA fragmentation increases [73], further compromising the integrity of gene replication. Apart from genetic changes (i.e., changes in DNA basepair sequence), APA may also involve abnormal epigenetic mechanisms [74–76].

Unravelling the molecular mechanisms underlying the association between APA and adverse health outcomes will be a substantial task for the biomedical research community. The precise location and nature of these mechanisms will probably vary substantially from offspring to offspring. It is unlikely that they will “map” neatly to a few loci, nor probably to one mechanism (e.g. genetic, epigenetic). With respect to genetic mechanisms, these may include single nucleotide mutations, or various types of genomic rearrangements (e.g., microdeletions, tandem and trinucleotide repeat expansions, microduplication or higher order expansions, aneuploidy). Animal experiments based on inbred rodent strains may provide the most efficient way to explore genetic and epigenetic factors mediating APA and brain development. Comparable to “forward genetics” platforms based on chemical mutagens [77,78], rodent-based APA models could provide an age-related mutagenesis experiment that has epidemiological face validity [79].

The observation linking APA with risk of schizophrenia has led to the hypothesis that APA-related mechanisms are contributing de novo mutations, which could explain the persistence of schizophrenia in the population in spite of reduced fertility and/or fecundity associated with this disorder [80]. APA-related mechanisms could accumulate over several generations, with the full clinical phenotype “breaking through” only after a critical threshold of certain mutations have accumulated [81,82]. In light of secular trends related to delayed parenthood [83], and in light of the potential for APA-related mechanisms to accumulate over several generations, the association between APA and subtle deficits in neurocognitive outcomes warrants closer scrutiny. While most of the neurocognitive differences were small at the individual level, these could have important implications from a public health perspective [84].

Acknowledgments Top
Computational resources and services used in this work were provided by the High Performance Computing and Research Support Unit, Queensland University of Technology, Brisbane, Australia.

Author Contributions Top
The overall study was designed and supervised by JJM. The dataset was prepared by SLB and the statistical analyses were conducted by SS, AGB, and JJM. All authors contributed to the interpretation of the data and writing up of the manuscript.

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Saturday, July 11, 2009

Older Fathers, more mental illness?

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De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin

1: J Med Genet. 2009 Jul 8. [Epub ahead of print]
De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin.
Heron SE, Scheffer IE, Iona X, Zuberi SM, Birch R, McMahon JM, Bruce CM, Berkovic SF, Mulley JC.
Women's and Children's Hospital, Adelaide, Australia.
BACKGROUND: Dravet syndrome is a severe infantile epileptic encephalopathy caused in approximately 80% of cases by mutations in the voltage-gated sodium channel subunit gene SCN1A. The majority of these mutations are de novo. The parental origin of de novo mutations varies widely among genetic disorders and the aim of this study was to determine this for Dravet syndrome. METHODS: Ninety-one patients with de novo SCN1A mutations and their parents were genotyped for single-nucleotide polymorphisms (SNPs) in the region surrounding their mutation. Allele-specific PCR based on informative SNPs was used to separately amplify and sequence the paternal and maternal alleles to determine in which parental chromosome the mutation arose. RESULTS: We established the parental origin of SCN1A mutations in 44 patients for whom both parents were available and SNPs were informative. The mutations were of paternal origin in 33 cases and of maternal origin in the remaining 11 cases. De novo mutation of SCN1A most commonly, but not exclusively, originates from the paternal chromosome. The average age of parents originating mutations did not differ from that of the general population. CONCLUSIONS: The greater frequency of paternally derived mutations in SCN1A is likely to be due to the greater chance of mutational events during the increased number of mitoses which occur during spermatogenesis compared to oogenesis and greater susceptibility to mutagenesis of the methylated DNA characteristic of sperm cells.


Friday, July 03, 2009

Facing Autism in New Brunswick: Autism and Vaccine Safety - Has the Scientific Method Been Abandoned?

Facing Autism in New Brunswick: Autism and Vaccine Safety - Has the Scientific Method Been Abandoned?

Thursday, July 02, 2009

Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination

Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination
Authors: Belloc, Stéphanie1; Cohen-Bacrie, Paul1; Benkhalifa, Moncef2; Cohen-Bacrie, Martine2; De Mouzon, Jacques3; Hazout, André4; Ménézo, Yves1
Source: Reproductive BioMedicine Online, Volume 17, Number 3, September 2008 , pp. 392-397(6)
Publisher: Reproductive Healthcare Ltd

Abstract:More than 17,000 intrauterine insemination (lUI) cycles were analysed retrospectively with respect to outcome according to differing aetiologies of infertility. The quantity and motility of spermatozoa in the final preparation used for insemination had a positive effect on the outcome, as classically observed in the past. It was found that advanced maternal age had a negative effect on the pregnancy rate and was associated with increased miscarriage rate. More interestingly, an exactly parallel effect was found for paternal age. The impact of increased age on necrospermia and sperm DNA structure is discussed as a probable direct cause of this paternal effect.
Document Type: Research article
Affiliations: 1: Laboratoire d'Eylau, 55 rue Saint Didier, 75116 Paris, France; Unité AMP Eylau La Muette, 46-48 rue Nicolo 75116, Paris, France; Unité AMP Eylau Cherest, 5 Rue Pierre Cherest 92200 Neuilly sur Seine, France 2: Laboratoire d'Eylau, 55 rue Saint Didier, 75116 Paris, France 3: Unité INSERM 822, 82 rue General Leclerc, 94276 Le Kremlin Bicetre, France 4: Unité AMP Eylau La Muette, 46-48 rue Nicolo 75116, Paris, France


Older fathers were also linked with autism with every additional five years increasing the risk by 3.6 per cent

Children of older parents at increased risk of autism
Children born to older parents or whose mother suffered complications during pregnancy are at increased risk of developing autism, a review of research has found.

By Rebecca Smith, Medical Editor Published: 7:00AM BST 01 Jul 2009
Harvard researchers examined 64 studies which looked at various factors such as order or birth, parents' age, and complications such as bleeding during pregnancy and the subsequent risk of the child developing autism.
The strongest links were found with mothers over the age of 30, bleeding during pregnancy, developing diabetes while pregnant, using medication while pregnant and being first born.

The research discovered that developing diabetes during pregnancy increase the risk of autism two-fold, bleeding during pregnancy increased the risk by 81 per cent and maternal medication use by 46 per cent.
Becoming a mother over the age of 30 increased the risk of autism by between 27 per cent to 106 per cent according to different studies included in the review. Older fathers were also linked with autism with every additional five years increasing the risk by 3.6 per cent.
Age is probably linked with autism because of greater damage to eggs and sperm as parents age, which in turn affects the quality of the embryo and developing foetus.
The analysis also found that being first-born increased the risk of autism by 61 per cent compared with children born third or later.
However the research, published in the British Journal of Psychiatry, said there was no one factor which could be singled out as most important. They said complications in pregnancy in general appeared to increase the risk of having a child with autism.
The researchers also suggested that the reason for this may be that there is a common cause for both the complications and the autism, rather than the complications themselves being responsible for the condition.
The researchers said there was "insufficient evidence" to point to any one prenatal factor as being particularly significant. However, they said: "There is some evidence to suggest that exposure to pregnancy complications in general may increase the risk of autism."
The review found there was strong evidence that several factors did not increase the risk of autism including previous miscarriage, high blood pressure and pre-eclampsia and swelling.
There are thought to be 588,000 people in Britain with autism spectrum disorder, including Asperger syndrome, which is a developmental disability that affects the way a person communicates and relates to people around them. People with autism have difficulties with everyday social interaction.
Fear of the condition was behind a dramatic fall in the number of children being given the triple jab for measles, mumps and rubella, following discredited research which linked it to bowel disease and autism.
A spokesman for The National Autistic Society said: "The causes of autism are not yet understood but there is evidence to suggest that autism can be caused by a variety of genetic, physical and environmental factors which affect brain development, although as yet we don't fully understand how or why this happens.
"Research into the causes of autism can cause concern and worry amongst parents of children with autism, and potential anxiety for expectant mothers or new parents. Particularly, as there is much confusion over the various theories put forward.
"Whilst research continues, it is crucial that parents have access to appropriate advice and support, as well as the services to enable them to cope with living with autism in their daily lives."