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Parental immigration has been suggested as a possible risk factor for autism spectrum disorders (ASD), but findings have been inconsistent. Very few studies have focused specifically on Asperger's syndrome. The aim of this study was to examine the association between maternal and paternal immigration and the diagnosis of Asperger's syndrome in offspring. The study was a nested case-control study based on a national birth cohort in Finland. Children born in 1987-2005 and diagnosed with Asperger's syndrome by the year 2007 were identified from the Finnish Hospital Discharge Register ( N = 1,783). Four matched controls for each case were selected from the Finnish Medical Birth Register ( N = 7,106). Information on maternal and paternal country of birth and mother tongue was collected from the Finnish Central Population Register. The study showed that children whose parents are both immigrants have a significantly lower likelihood of being diagnosed with Asperger's syndrome than those with two Finnish parents [adjusted odds ratio (aOR) 0.2, 95 % confidence interval (CI) 0.1-0.4]. No significant associations were found between having only one immigrant parent and the diagnosis of Asperger's syndrome. A regional analysis showed a significantly decreased likelihood of the diagnosis of Asperger's syndrome in children whose mother (aOR 0.1, 95 % CI 0.01-0.5) or father (aOR 0.2, 95 % CI 0.05-0.5) was born in Sub-Saharan Africa. The findings may help in identifying risk factors for different ASD subtypes. On the other hand, they might reflect service use of immigrant families in Finland. [ABSTRACT FROM AUTHOR]

Increasing paternal age is known to be associated with a great variety of psychiatric disorders such as schizophrenia or autism. Hence the factor “age” may be taken as strategic tool to analyse specific scientific hypotheses. Additionally, this finding also needs to be addressed in rather pragmatically performed breeding protocols of model organisms, since otherwise artefacts may challenge the validity of the results. Our study was performed to investigate influences of advanced age of mouse dams (30 vs. 16 weeks) on maternal- and offspring behaviour. Adult offspring of both sexes was analysed in a test battery comprising paradigms for exploration, anxiety and depressive-like behaviours. Final blood sampling was conducted for stressphysiological analysis. Interestingly, advanced age of the mothers was associated with increased nest-building quality while maternal activity was unaffected. Moreover “maternal (mice) age” (MA) affected emotionality in the offspring, which became apparent in the dark–light box and the social recognition paradigm. These findings not only emphasize MA to model a potent risk factor with regard to emotional stability, but also underscore the vast necessity to include information about breeding protocols into the methods section of any animal study. [ABSTRACT FROM AUTHOR]

We examined trends in autism spectrum disorders (ASD) and the association of ASD with parental age among young New York City (NYC) children. Children born in NYC to resident mothers from 1994-2001 were identified through vital statistics records (N = 927,003). Records were linked to data from NYC Early Intervention (EI) Program through 2004. The independent parental age-specific odds of having an ASD before 36 months of age were estimated using multiple logistic regression controlling for risk factors. The increase in ASD attributable to changes in parental age at birth was examined. Births to mothers and fathers 35 years or older increased 14.9 and 11.5 %, respectively, between 1994 and 2001. ASD prevalence in EI increased significantly from 1 in 3,300 children born in 1994 to 1 in 233 children born in 2001. Children born to mothers ages 25-29, 30-34 and 35 or older had significantly greater odds of being diagnosed with ASD than children of mothers younger than 25 years (OR 1.5, 1.6, and 1.9, respectively). Children born to fathers ages 35 or older (OR 1.4) had greater odds of ASD than children of fathers younger than 25. The change in parental age accounted for only 2.7 % of the increase in ASD prevalence. Older paternal age and maternal age were independently associated with increased risk of ASD. However, while parental age at birth increased between the 1994 and 2001 birth cohorts in NYC, it did not explain the increase in number of ASD cases. [ABSTRACT FROM AUTHOR]

Objective: Multiple etiological and prognostic factors have been implied in schizophrenia and its outcome. Advanced paternal age has been reported as a risk factor in schizophrenia. Whether this may affect schizophrenia outcome was not previously studied. We hypothesized that advanced paternal age may have a negative effect on the outcome of relapse in schizophrenia. Method: We interviewed 191 patients with first-episode schizophrenia and their relatives for parental ages, sociodemographic factors at birth, birth rank, family history of psychotic disorders, and obstetric complications. The outcome measure was the presence of relapse at the end of the first year of treatment. Results: In the 1-year follow-up period, 42 (22%) patients experienced 1 or more relapses. The mean paternal age was 34.62 years (SD 7.69). Patients who relapsed had significantly higher paternal age, poorer medication adherence, were female, and were hospitalized at onset, compared with patients who did not relapse. A multivariate regression analysis showed that advanced paternal age (OR 1.05, 95% CI 1.01 to 1.10), medication nonadherence (OR 2.37, 95% CI 1.12 to 4.99), and female sex (OR 2.44, 95% CI 1.14 to 5.24) independently contributed to a higher risk of relapse. Analysis between different paternal age groups found a significantly higher relapse rate with paternal age over 40. Conclusions: Advanced paternal age is found to be modestly but significantly related to more relapses, and such an effect is the strongest at a cut-off of paternal age of 40 years or older. The effect is less likely to be mediated through less effective parental supervision or nonadherence to medication. Other possible biological mechanisms need further explorations. [ABSTRACT FROM AUTHOR]

BackgroundAdvanced paternal age is associated with increased risk of schizophrenia. This study aimed to explore whether older paternal age is associated with earlier onset among co-affected schizophrenia sib-pairs with the same familial predisposition.MethodA total of 1297 patients with schizophrenia from 630 families, which were ascertained to have at least two siblings affected, throughout Taiwan were interviewed using the Diagnostic Interview for Genetic Studies. Both inter-family comparisons, a hierarchical regression model allowing for familial dependence and adjusting for confounders, and within-family comparisons, examining the consistency between onset order and birth order, were performed.ResultsAn inverted U shape was observed between paternal age and onset of schizophrenia. Affected offspring with paternal age of 20–24 years had the oldest onset. As paternal age increased over 25 years, older paternal age exhibited a linear decrease in the onset of schizophrenia. On average, the onset was lowered by 1.5 years for paternal age of 25–29 years and by 5.5 years for paternal age ⩾50 years (p = 0.04; trend test). The proportion of younger siblings with earlier onset (58%) was larger than that of older siblings with earlier onset (42%) (p = 0.0002).ConclusionsThese findings indicate that paternal age older than 25 years and younger than 20 years were both associated with earlier onset among familial schizophrenia cases. The associations of advanced paternal age with both increased susceptibility to schizophrenia and earlier onset of schizophrenia are consistent with the rate of increases in spontaneous mutations in sperm as men age. [ABSTRACT FROM PUBLISHER]

Between 2% and 12% of adults in the general population report experiencing psychotic-like symptoms, and there is suggestive evidence that these symptoms are associated with risk of schizophrenia and other forms of psychopathology. Older parental age is an established risk factor for schizophrenia, however few studies have attempted to extend this relationship to psychotic-like symptoms. Data come from the National Comorbidity Survey—Replication and analysis is restricted to a subset of respondents who completed questions on psychosis ( N = 924). Lifetime occurrence of six psychotic-like symptoms (i.e., see a vision others couldn't see, hear voices others couldn't hear) was assessed by self-report. These symptoms were combined into a single binary (any vs. none) variable and analyzed using logistic regression, accounting for the complex survey design. Models were adjusted for age, sex, race/ethnicity, socioeconomic status, marital status, birth order, and history of mood, anxiety, and substance use disorders. Approximately 9% ( n = 103) of respondents reported at least one psychotic-like symptom. In fully-adjusted models, paternal age was significantly associated with experiencing psychotic-like symptoms ( χ 2 = 13.34, p = .010). Relative to respondents whose fathers were aged 25 to 29 at the time of their birth, those with fathers aged > 35 had 2.12 times higher odds (95% confidence interval: 1.08–4.16) of psychotic-like symptoms. There was no relationship between maternal age (younger or older) and psychotic-like symptoms ( χ 2 = 0.54, p = .909). Older paternal, but not maternal, age at birth is associated with psychotic-like symptoms in adult offspring. [ABSTRACT FROM AUTHOR]

The proportion of parents aged ≥35 years at the birth of their child continues to increase, but long-term health consequences for these children are not fully understood. A recent prospective study of 110,999 adult women showed an association between paternal—but not maternal—age at birth and sporadic hematological cancer risk. To further investigate this topic, we examined these associations in women and men in the American Cancer Society Cancer Prevention Study-II Nutrition Cohort. Among 138,003 Cancer Prevention Study-II participants, 2,532 incident hematological cancers were identified between 1992 and 2009. Multivariable-adjusted hazard ratios and 95% confidence intervals were computed by using Cox proportional hazards regression. There was no clear linear trend in the risk of hematological malignancies by either paternal or maternal age. However, there was a strong, positive association with paternal age among participants without siblings. In that group, the hazard ratio for fathers aged ≥35 years compared with <25 years at birth was 1.63 (95% confidence interval: 1.19, 2.23), and a linear dose-response association was suggested (Pspline = 0.002).There were no differences by subtype of hematological cancer. Results of this study support the need for further research to better understand the association between paternal age at birth and hematological malignancies. [ABSTRACT FROM AUTHOR]

Our study is the first investigation of the effects of advanced paternal age ( APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice ( C57BL/ 6J) across postnatal development ( N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age-related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring. [ABSTRACT FROM AUTHOR]

Over the last decade, there has been a significant increase in average paternal age when the first child is conceived, either due to increased life expectancy, widespread use of contraception, late marriages and other factors. While the effect of maternal ageing on fertilization and reproduction is well known and several studies have shown that women over 35 years have a higher risk of infertility, pregnancy complications, spontaneous abortion, congenital anomalies, and perinatal complications. The effect of paternal age on semen quality and reproductive function is controversial for several reasons. First, there is no universal definition for advanced paternal ageing. Secondly, the literature is full of studies with conflicting results, especially for the most common parameters tested. Advancing paternal age also has been associated with increased risk of genetic disease. Our exhaustive literature review has demonstrated negative effects on sperm quality and testicular functions with increasing paternal age. Epigenetics changes, DNA mutations along with chromosomal aneuploidies have been associated with increasing paternal age. In addition to increased risk of male infertility, paternal age has also been demonstrated to impact reproductive and fertility outcomes including a decrease in IVF/ICSI success rate and increasing rate of preterm birth. Increasing paternal age has shown to increase the incidence of different types of disorders like autism, schizophrenia, bipolar disorders, and childhood leukemia in the progeny. It is thereby essential to educate the infertile couples on the disturbing links between increased paternal age and rising disorders in their offspring, to better counsel them during their reproductive years. [ABSTRACT FROM AUTHOR]

Gender dysphoria (GD) and autism spectrum disorder (ASD) are associated. In 49 GD children (40 natal males), we examined ASD risk factors (i.e., birth weight, parental age, sibling sex ratio) in relation to autistic traits. Data were gathered on autistic traits, birth weight, parents' ages at birth, sibling sex ratio, gender nonconformity, age, maternal depression, general behavioral and emotional problems, and IQ. High birth weight was associated with both high gender nonconformity and autistic traits among GD children. Developmental processes associated with high birth weight are, therefore, likely to underlie the GD-ASD link either directly or indirectly. The present study is the first to provide quantitative data bearing on possible mechanisms that lead GD and ASD to co-occur. [ABSTRACT FROM AUTHOR]

Two modes of inheritance have been proposed in autism spectrum disorder, transmission though pre-existing variants and de novo mutations. Different modes may lead to different symptom expressions in affected individuals. De novo mutations become more likely with advancing paternal age suggesting that paternal age may predict phenotypic differences. To test this possibility we measured IQ, adaptive behavior, and autistic symptoms in 830 probands from simplex families. We conducted multiple linear regression analysis to estimate the predictive value of paternal age, maternal age, and gender on behavioral measures and IQ. We found a differential effect of parental age and sex on repetitive and restricted behaviors. Findings suggest effects of paternal age on phenotypic differences in simplex families with ASD. [ABSTRACT FROM AUTHOR]

Introduction: Our aim is to investigate the prevalence of comorbidity of anxiety disorders (AD) among patients newly diagnosed with attention deficit hyperactivity disorder (ADHD) and to compare symptom severity of ADHD and sociodemographic parameters between patients with and without AD. Methods: Among 1683 children and adolescents admitted to Kocaeli University Medical Faculty, Child and Adolescent Mental Health Outpatient Clinic, 447 children and adolescents, who were preliminarily diagnosed as ADHD by clinical interview based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), were invited to participate in the second phase of the study. Kiddie Schedule for Affective Disorder and Schizophrenia, Present and Lifetime-Turkish Version were applied to children and adolescents with ADHD and one of their parents to support the diagnoses of both ADHD and AD. Mothers, fathers, and teachers of the children were asked to complete DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale. Results: Our study group comprised 170 children and adolescents diagnosed with ADHD of whom 19.4% were girls and 80.6% were boys; 27.6% of patients diagnosed with ADHD showed AD comorbidity. Age of the parents at birth of the patients with AD was significantly lower than that of patients without AD. Conclusion: In line with the previous studies, the comorbidity rate of AD was found to be higher among patients with ADHD than general population and clinical sample without ADHD. The possibility of comorbidity of AD in patients with ADHD should be considered because higher rates of AD are observed in ADHD and comorbidities of AD. [ABSTRACT FROM AUTHOR]

Extensive research defines the impact of advanced maternal age on couples' fecundity and reproductive outcomes, but significantly less research has been focused on understanding the impact of advanced paternal age. Yet it is increasingly common for couples at advanced ages to conceive children. Limited research suggests that the importance of paternal age is significantly less than that of maternal age, but advanced age of the father is implicated in a variety of conditions affecting the offspring. This review examines three aspects of advanced paternal age: the potential problems with conception and pregnancy that couples with advanced paternal age may encounter, the concept of discussing a limit to paternal age in a clinical setting, and the risks of diseases associated with advanced paternal age. As paternal age increases, it presents no absolute barrier to conception, but it does present greater risks and complications. The current body of knowledge does not justify dissuading older men from trying to initiate a pregnancy, but the medical community must do a better job of communicating to couples the current understanding of the risks of conception with advanced paternal age. [ABSTRACT FROM AUTHOR]

The influence of paternal age on the risk for sporadic forms of Mendelian disorders is well known, but a burgeoning recent literature demonstrates, in addition, a paternal age effect for complex neuropsychiatric conditions, including schizophrenia, autism, bipolar disorder, and even for learning potential, expressed as intelligence. Mental illness is costly to patients, their family, and the public health system, accounting for the largest portion of disability costs in our economy. The delayed onset of neuropsychiatric conditions and lack of physical manifestations at birth are common frequencies in the population that have obscured the recognition that a portion of the risks for mental conditions is associated with paternal age. Identification of these risk pathways may be leveraged for knowledge about mental function and for future screening tests. However, only a small minority of at-risk offspring are likely to have such a psychiatric or learning disorder attributable to paternal age, including the children of older fathers. [ABSTRACT FROM AUTHOR]

Uncovering sources of variation in gorilla infant mortality informs conservation and life history research efforts. The international studbook for the western lowland gorilla provides information on a sample of captive gorillas large enough for which to analyze genetic, maternal, and various other effects on early life mortality in this critically endangered species. We assess the importance of variables such as sex, maternal parity, paternal age, and hand rearing with regard to infant survival. We also quantify the proportions of variation in mortality influenced by heritable variation and maternal effects from these pedigree and survival data using variance component estimation. Markov chain Monte Carlo simulations of generalized linear mixed models produce variance component distributions in an animal model framework that employs all pedigree information. Two models, one with a maternal identity component and one with both additive genetic and maternal identity components, estimate variance components for different age classes during the first 2 years of life. This is informative of the extent to which mortality risk factors change over time during gorilla infancy. Our results indicate that gorilla mortality is moderately heritable with the strongest genetic influence just after birth. Maternal effects are most important during the first 6 months of life. Interestingly, hand-reared infants have lower mortality for the first 6 months of life. Aside from hand rearing, we found other predictors commonly used in studies of primate infant mortality to have little influence in these gorilla data. Am. J. Primatol. 77:666-678, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives Mutation-selection balance theory proposes that a balance of forces between constantly arising mildly harmful mutations and selection causes variation in genetic configuration and phenotypic condition. As mutations are predominantly deleterious, the entry of variation due to mutations is kept at low frequencies by selection. It has recently been demonstrated that nearly all de novo mutation are caused by paternal age. Methods We examined on basis of the Wisconsin Longitudinal Study ( n = 6,182) whether a subject's probability of having ever married as well as having ever reproduced is associated with that subject's father's age at subject's birth. Results We find that advanced paternal but not maternal age at subject's birth predicts a lower chance of ever being married and a higher chance of childlessness, even controlling for various confounders. Conclusions As marriage is a prerequisite of reproduction in this sample, we discuss that mate choice may provide a mechanism to prevent too high mutation load in the progeny. Am. J. Hum. Biol. 27:339-343, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Studies have shown an increased head circumference and the absence of the head tilt reflex as possible risk factors for autism spectrum disorder, allowing for early detection at 12 months in typically developing population of infants. Our aim was to develop a screening tool to identify infants prior to 12 months at risk for autism spectrum disorder and developmental learning delay, not affected by literacy or primary parental language, and provide immediate determination of risk for autism spectrum disorder. An abrupt head circumference acceleration and the absence of head tilt reflex by 9 months were used to identify infants at risk for autism spectrum disorder. Stability of early findings was then investigated when compared to comprehensive standardized neurodevelopmental assessment results and complete neurological and genetics evaluations. A total of 1024 typically developing infants were enrolled by 9 months, with 14 identified as at risk for autism spectrum disorder and 33 for developmental learning delay. There was a good positive predictive value for the identification of autism spectrum disorder prior to 12 months. This study demonstrates an efficient means to identify infants at risk for autism spectrum disorder by 9 months of age and serves to alert primary care providers of infants who are vulnerable for autism spectrum disorder before symptoms are discernible by clinical judgment of primary care providers, parental concerns, or by screening questionnaires. [ABSTRACT FROM PUBLISHER]

This cohort study of primiparae was conducted to answer the following questions: Do older (≧ 35 years) and younger (20-29 years) Japanese primiparous mothers differ when comparing biomarkers of stress and measures of fatigue and depression? Are there changes in fatigue, depression and stress biomarkers when comparing older and younger mothers during the postpartum period? The Postnatal Accumulated Fatigue Scale and the Edinburgh Postnatal Depression Scale were administered in a time-series method four times: shortly after birth and monthly afterwards. Assays to measure biomarkers of stress, urinary 17-ketosteroids, urinary 17-hydroxycorticosteroids and salivary chromogranin-A, were collected shortly after delivery and at 1 month postpartum in both groups and a third time in older mothers at the 4th month. Statistical testing showed very little difference in fatigue, depression or stress biomarkers between older and younger mothers shortly after birth or 1 month later. Accumulated fatigue and depression scores of older mothers were highest 1 month after delivery. Additional cohort studies are required to characterize physical/psychological well-being of older Japanese primiparae. [ABSTRACT FROM AUTHOR]

Paternal age has been associated with offspring congenital heart defects (CHDs), which might be caused by increased mutations in the germ cell line because of cumulated cell replications. Empirical evidences, however, remain inconclusive. Furthermore, it is unknown whether all subtypes of CHDs are affected by paternal age. We aimed to explore the relationship between paternal age and the risk of offspring CHDs and its five common subtypes using national register data in Denmark. A total of 1 893 899 singletons born in Denmark from 1977 to 2008 were included in this national-based cohort study. Cox’s proportion hazards model with robust sandwich estimate option was used to estimate the hazards ratio (95% confidence interval) for the associations between paternal age and all CHDs, as well as subtypes of CHDs (patent ductus arteriosus (PDA), ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of fallot (TOF) and coarctation of the aorta (CoA)). We did not observe an overall association between paternal age and offspring CHDs. However, compared to the paternal age of 25–29 years, paternal age of older than 45 years was associated with a 69% increased risk of PDA (HR45+ = 1.69, 95%CI:1.17–2.43). We observed similar results when subanalyses were restricted to children born to mothers of 27–30 years old. After taking into consideration of maternal age, our data suggested that advanced paternal age was associated with an increased prevalence of one subtype of offspring congenital heart defects (CHDs), namely patent ductus arteriosus (PDA). [ABSTRACT FROM AUTHOR]

In an observational study of 31,257 children we investigated the effects of paternal age at the time of the child's birth, paternal absence and non-biological fathers on children's health. Results are per 5 year change in paternal age. Older fathers were associated with lower rates of unintentional injuries, odds ratio (OR)=0.966, P=0.0027. There was a quadratic association between paternal age and risk of hospital admission, β=0.0121, P=0.0109, with minimum risk at paternal age 37.7. Absent fathers were associated with increased risk of hospital admission, OR=1.19, P<10-3, lower rates of complete immunizations to 9 months, OR=0.562, P<10-3, higher Strength and Difficulties Questionnaire (SDQ) difficulties scores: β=0.304, P=0.0024 (3 year olds), β=0.697, P<10-3 (5 year olds). Non-biological fathers were associated with increased risk of unintentional injury, OR=1.16, P=0.0319 and hospital admission, OR=1.26, P=0.0166; lower rates of complete immunizations to 9 months, OR=0.343, P=0.0309 and higher SDQ difficulties scores: β=0.908, P<10-3. [ABSTRACT FROM AUTHOR]

This study evaluated the prevalence of pre- and perinatal risk factors in a cohort of children with autism spectrum disorders compared with the New Jersey population. Our cohort included 268 individuals with an autism spectrum disorder. Birth histories were obtained by a self-administered questionnaire. The autism spectrum disorders cohort rates of 7 perinatal risk factors were significantly higher than New Jersey state rates: mother’s age 35 years or older, low birth weight, multiple gestation, prematurity, vaginal bleeding, prolonged labor, and hypoxia. Analysis of clustering of risk factors in the cohort showed no significant differences across maternal and paternal age groups. Older mothers in the cohort had a higher risk of infant hypoxia. Multiple risk factors during pregnancy appear to be associated with a higher risk of autism spectrum disorders in offspring, supporting the hypothesis that environmental influences in conjunction with genetics contribute to the causes of autism spectrum disorders. [ABSTRACT FROM PUBLISHER]

A total number of 11,635 screening packs were distributed to 5–10 year-old children in 136 schools in Cambridgeshire to investigate the associations between levels of parental concern (none/minor/strong), socioeconomic status and the risk of having Autism Spectrum Conditions (ASC). The variables for investigating associations and possible confounders were extracted for analysis, including parental concern question score, SES, age of the child, sex, maternal age at birth, paternal age at birth, mother's age of leaving education, father's age of leaving education, birth order and the number of children in the family. The SES, age of the child, sex and mother's age at leaving education were associated with parental concern. Parents with higher SES reported higher levels of concern (Chi-square = 11.8; p = 0.02). However, a higher SES was not associated with the risk of having ASC ( p = 0.50). After adjusting for potential confounders, the odds of children meeting ASC criteria whose parents had reported strong parental concern were 8.5 times (odds ratio: 8.5; 95%CI: 4.5, 16.2; p < 0.001) the odds of children having ASC whose parents reported minor concern. No child met ASC criteria where parents expressed no concerns. Parents with higher social class express more concerns than those from lower social classes. However, the concerns reported by parents in higher SES did not appear to be specific for ASC as there was no relationship between ASC and SES. [ABSTRACT FROM AUTHOR]

Advanced paternal age is associated with an increased risk of fathering children with genetic disorders and other adverse reproductive consequences. However, the mechanisms underlying this phenomenon remain largely unexplored. In this review, we focus on the impact of paternal age on de novo mutations that are an important contributor to genetic disease and can be studied both indirectly through large-scale sequencing studies and directly in the tissue in which they predominantly arise-the aging testis. We discuss the recent data that have helped establish the origins and frequency of de novo mutations, and highlight experimental evidence about the close link between new mutations, parental age, and genetic disease. We then focus on a small group of rare genetic conditions, the so-called "paternal age effect" disorders that show a strong association between paternal age and disease prevalence, and discuss the underlying mechanism ("selfish selection") and implications of this process in more detail. More broadly, understanding the causes and consequences of paternal age on genetic risk has important implications both for individual couples and for public health advice given that the average age of fatherhood is steadily increasing in many developed nations., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The male biological clock as a health risk for the offspringAssociations between maternal pre‐eclampsia and childhood cancers in offspringSudden vigorous fetal movement linked to fetal deathResources for Women's Health [ABSTRACT FROM AUTHOR]

The association between advanced maternal and paternal ages at birth and increased mortality among adult offspring is often attributed to parental reproductive aging, e.g., declining oocyte or sperm quality. Less attention has been paid to alternative mechanisms, including parental socio-demographic characteristics or the timing of parental death. Moreover, it is not known if the parental age-adult mortality association is mediated by socioeconomic attainment of the children, or if it varies over the lifecourse of the adult children. We used register-based data drawn from the Finnish 1950 census (sample size 89,737; mortality follow-up 1971–2008) and discrete-time survival regression with logit link to analyze these alternative mechanisms in the parental age–offspring mortality association when the children were aged 35–49 and 50–72. Consistent with prior literature, we found that adult children of older parents had increased mortality relative to adults whose parents were aged 25–29 at the time of birth. For example, maternal and paternal ages 40–49 were associated with mortality odds ratios (ORs) of 1.31 ( p < .001) and 1.22 ( p < .01), respectively, for offspring mortality at ages 35–49. At ages 50–72 advanced parental age also predicted higher mortality, though not as strongly. Adjustment for parental socio-demographic characteristics (education, occupation, family size, household crowding, language) weakened the associations only slightly. Adjustment for parental survival, measured by whether the parents were alive when the child reached age 35, reduced the advanced parental age coefficients substantially and to statistically insignificant levels. These results indicate that the mechanism behind the advanced parental age–adult offspring mortality association is mainly social, reflecting early parental loss and parental characteristics, rather than physiological mechanisms reflecting reproductive aging. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does paternal age affect semen quality and reproductive outcomes in oocyte donor cycles with ICSI? SUMMARY ANSWER Paternal age is associated with a decrease in sperm quality, however it does not affect either pregnancy or live birth rates in reproductive treatments when the oocytes come from donors <36 years old and ICSI is used. WHAT IS KNOWN ALREADY The weight of evidence suggest that paternal age is associated with decreasing sperm quality, but uncertainty remains as to whether reproductive outcomes are affected. Although developed to treat severe sperm factor infertility, ICSI is gaining popularity and is often used even in the presence of mild male factor infertility. STUDY DESIGN, SIZE, DURATION A retrospective cohort study spanning the period between February 2007 and June 2010. A total of 4887 oocyte donation cycles were included. PARTICIPANTS/MATERIALS, SETTING, METHODS Fertilization was carried out by ICSI in all cycles included, and the semen sample used was from the male partner in all cases. The association of male age with semen parameters (volume, concentration, percentage of motile spermatozoa) was analyzed by multiple analysis of covariance. The association of male age with reproductive outcomes (biochemical pregnancy, miscarriage, ongoing pregnancy and live birth rate) was modeled by logistic regression, where the following covariates were introduced: donor age, recipient age, semen state (fresh versus frozen) and number of transferred embryos (3 and 2 versus 1). MAIN RESULTS AND THE ROLE OF CHANCE We identified a significant relationship between paternal age and all sperm parameters analyzed: for every 5 years of age, sperm volume decreases by 0.22 ml (P < 0.001), concentration increases by 3.1 million sperm/ml (P = 0.003) and percentage motile spermatozoa decreases by 1.2% (P < 0.001). No differences were found in reproductive outcomes (biochemical pregnancy, miscarriage, clinical pregnancy, ongoing pregnancy and live birth) among different male age groups. LIMITATIONS, REASONS FOR CAUTION The use of donor oocytes, while extremely useful in highlighting the role of male age in reproductive outcomes, limits the generalization of our results to a population of young women with older male partners. No data were available on perinatal and obstetrical outcomes of these pregnancies. Most (75%) cycles used frozen/thawed sperm samples which might have introduced a bias owing to loss of viability after thawing. ICSI was performed in all cycles to control for fertilization method; this technique could mask the natural fertilization rate of poorer sperm samples. Furthermore, we did not use stringent ICSI indications; and our data are therefore not generalizable to cases where only severe male factor is considered. However, male patients were of different racial background, thus allowing generalizing our results to a wider patient base. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that paternal age does not affect reproductive outcomes when the oocyte donor is <36 years of age, indicating that ICSI and oocyte quality can jointly overcome the lower reproductive potential of older semen. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by Fundació Privada EUGIN. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

Some previous studies have identified bacteria in semen as being a potential factor in male infertility. However, only few types of bacteria were taken into consideration while using PCR-based or culturing methods. Here we present an analysis approach using next-generation sequencing technology and bioinformatics analysis to investigate the associations between bacterial communities and semen quality. Ninety-six semen samples collected were examined for bacterial communities, measuring seven clinical criteria for semen quality (semen volume, sperm concentration, motility, Kruger's strict morphology, antisperm antibody (IgA), Atypical, and leukocytes). Computer-assisted semen analysis (CASA) was also performed. Results showed that the most abundant genera among all samples were Lactobacillus (19.9%), Pseudomonas (9.85%), Prevotella (8.51%) and Gardnerella (4.21%). The proportion of Lactobacillus and Gardnerella was significantly higher in the normal samples, while that of Prevotella was significantly higher in the low quality samples. Unsupervised clustering analysis demonstrated that the seminal bacterial communities were clustered into three main groups: Lactobacillus, Pseudomonas, and Prevotella predominant group. Remarkably, most normal samples (80.6%) were clustered in Lactobacillus predominant group. The analysis results showed seminal bacteria community types were highly associated with semen health. Lactobacillus might not only be a potential probiotic for semen quality maintenance, but also might be helpful in countering the negative influence of Prevotella and Pseudomonas. In this study, we investigated whole seminal bacterial communities and provided the most comprehensive analysis of the association between bacterial community and semen quality. The study significantly contributes to the current understanding of the etiology of male fertility. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes. [Copyright &y& Elsevier]

Because germline mutations are the source of all evolutionary adaptations and heritable diseases, characterizing their properties and the rate at which they arise across individuals is of fundamental importance for human genetics. After decades during which estimates were based on indirect approaches, notably on inferences from evolutionary patterns, it is now feasible to count de novo mutations in transmissions from parents to offspring. Surprisingly, this direct approach yields a mutation rate that is twofold lower than previous estimates, calling into question our understanding of the chronology of human evolution and raising the possibility that mutation rates have evolved relatively rapidly. Here, we bring together insights from studies of human genetics and molecular evolution, focusing on where they conflict and what the discrepancies tell us about important open questions. We begin by out-lining various methods for studying the properties of mutations in humans. We review what we have learned from their applications about genomic factors that influence mutation rates and the effects of sex, age, and other sources of interindividual variation. We then consider die mutation rate as a product of evolution and discuss how and why it may have changed over time in primates. [ABSTRACT FROM AUTHOR]

The article discusses the highlights of the American Urological Association (AUA) Annual Meeting and provides summaries of the Take Home Messages delivered on the last day of the meeting. Topics discussed include sessions on "Advanced Paternal Age-What the Real Risks?" a lecture "The Adverse Effects of Common Medications on Male Fertility" and a literature review of 7 articles on varicocele repair outcomes (PD24-01).

Abstract: In view of disease risk, Kong et al. (2012) demonstrated that most of the new mutations are explained by the age of the father at conception. Accordingly, paternal age effects have been found for a variety of offspring traits, from physical and mental health to intelligence. Here, we investigated whether facial attractiveness is significantly associated with paternal age. We used the Wisconsin Longitudinal Study (n=4018 male and 4416 female high school graduates) to analyze the association between an individual's father's age at birth and that individual's facial attractiveness (estimated by rating the high school yearbook photographs from 1957), controlling for sex, age as well as mother's age. We find that subject's facial attractiveness decreased with advancing paternal but not maternal age, suggesting that facial attractiveness might be a cue of an individual's new mutation load. [Copyright &y& Elsevier]

Owing to a recent trend for delayed paternity, the genomic integrity of spermatozoa of older men has become a focus of increased interest. Older fathers are at higher risk for their children to be born with several monogenic conditions collectively termed paternal age effect ( PAE) disorders, which include achondroplasia, Apert syndrome and Costello syndrome. These disorders are caused by specific mutations originating almost exclusively from the male germline, in genes encoding components of the tyrosine kinase receptor/RAS/MAPK signalling pathway. These particular mutations, occurring randomly during mitotic divisions of spermatogonial stem cells ( SSCs), are predicted to confer a selective/growth advantage on the mutant SSC. This selective advantage leads to a clonal expansion of the mutant cells over time, which generates mutant spermatozoa at levels significantly above the background mutation rate. This phenomenon, termed selfish spermatogonial selection, is likely to occur in all men. In rare cases, probably because of additional mutational events, selfish spermatogonial selection may lead to spermatocytic seminoma. The studies that initially predicted the clonal nature of selfish spermatogonial selection were based on DNA analysis, rather than the visualization of mutant clones in intact testes. In a recent study that aimed to identify these clones directly, we stained serial sections of fixed testes for expression of melanoma antigen family A4 (MAGEA4), a marker of spermatogonia. A subset of seminiferous tubules with an appearance and distribution compatible with the predicted mutant clones were identified. In these tubules, termed 'immunopositive tubules', there is an increased density of spermatogonia positive for markers related to selfish selection (FGFR3) and SSC self-renewal (phosphorylated AKT). Here we detail the properties of the immunopositive tubules and how they relate to the predicted mutant clones, as well as discussing the utility of identifying the potential cellular source of PAE mutations. [ABSTRACT FROM AUTHOR]

Background: Sperm DNA damage is common in infertile men and is associated with poor semen parameters but the impact of an isolated sperm abnormality on sperm DNA damage has not been studied. Objective: To evaluate sperm DNA damage in a large cohort of infertile men with isolated sperm defects. Design, setting and participants: Retrospective study of 1084 consecutive, non-azoospermic infertile men with an isolated sperm defect: isolated oligozoospermia (iOligo), isolated asthenozoospermia (iAstheno) or isolated teratozoospermia (iTerato). Outcome measurements and statistical analysis: We examined and compared clinical parameters, conventional semen parameters and %sperm DNA fragmentation (%SDF, assessed by flow cytometry-based Terminal deoxynucleotidyl transferase-mediated dUTP Nick End-Labeling assay) in the three groups of men. Results and limitations: The mean (±SD) %SDF was significantly higher in the iAstheno compared to the iOligo and iTerato groups (25.0 ± 14.0 vs. 19.2 ± 11.6 and 20.7 ± 12.1 %, respectively, P < 0.0001). Similarly, the proportion of men with high %SDF (>30 %) was significantly higher in the iAstheno compared to the iOligo and iTerato groups (31 % vs. 18 % and 19 %, respectively, P < 0.0001). In the group of 713 men with iAstheno, %SDF was positively correlated with paternal age ( r = 0.20, P < 0.0001) and inversely correlated with %progressive motility ( r = −0.18, P < 0.0001). In the subset of 218 men with iTerato, %SDF was also positively correlated with paternal age ( r = 0.15, P = 0.018) and inversely correlated with %progressive motility ( r = −0.26, P = 0.0001). Conclusions: In this large cohort of infertile men with isolated sperm abnormalities, we have found that the sperm DNA fragmentation level is highest in the men with sperm motility defects and that 31 % of these men have high levels of sperm DNA fragmentation. The data indicate that poor motility is the sperm parameter abnormality most closely related to sperm DNA damage. [ABSTRACT FROM AUTHOR]

Abstract: The recent trend toward delayed parenthood raises major safety concerns because of the adverse effects of aging on couple fertility. Studies have demonstrated that aging clearly affects female fertility, but can also affect male fertility. Although several theories have been proposed, the exact mechanisms responsible for the observed age-related decline in male fertility remain to be elucidated. It has been shown that advanced paternal age (PA) is associated with reduced semen volume as well as, reduced sperm count, motility and morphology. Recent studies have also reported that paternal aging is associated with a significant increase in the prevalence of both genomic and epigenomic sperm defects. In the context of natural and intrauterine insemination (IUI) conception, advanced paternal age has been associated with lower pregnancy rates and increased rates of spontaneous abortion (independent of maternal age). In IVF and oocyte donation programs, a significant decrease in late blastocyst development has been seen in those cycles using spermatozoa of men older than 55. However, no significant relationship between paternal age and IVF or ICSI pregnancy rates has been observed. Although there are no treatments that can fully restore the age-related decline in male fertility, various measures have been shown to optimize male fertility potential. Specific therapies (e.g. varicocelectomy) and lifestyle changes (e.g. dietary antioxidant supplements) may help minimize some of the age-related deleterious effects on spermatogenesis, such as, oxidative stress and endocrine abnormalities. [Copyright &y& Elsevier]

IMPORTANCE: Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors. OBJECTIVE: To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity. DESIGN, SETTING, AND PARTICIPANTS: We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2 615 081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins. EXPOSURE: Paternal age at childbearing. MAIN OUTCOMES AND MEASURES: Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity. RESULTS: In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI. 1.35-3.20). bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31). suicide attempts (HR = 2.72; 95% CI, 2.08-3.56). substance use problems (HR = 2.44; 95% CI. 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI. 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings. CONCLUSIONS AND RELEVANCE: Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity. [ABSTRACT FROM AUTHOR]

Background Paternal age at childbirth has been increasing worldwide, and we assessed whether this increase affects growth, body composition and metabolism in their children. Methods We studied 277 children (aged 3-12 years) born to fathers aged 19·8-51·8 years. Clinical assessments were height and weight adjusted for parental measurements, DEXA-derived body composition, fasting lipids, glucose homoeostasis and hormonal profiles. Results Children born to fathers aged 31-35 ( P = 0·009) and >35 years ( P = 0·021) were 2 cm taller than those of fathers aged ≤30 years. Children of fathers aged >35 years at childbirth had a lower body mass index ( BMI) (−0·32 SDS) than offspring of fathers aged 31-35 (−0·01 SDS; P = 0·043) and ≤30 (0·22 SDS; P = 0·019). There were marked effects of paternal age at childbirth on childhood blood lipids. LDL-C concentrations in children born to fathers aged >35 years were 11% and 21% higher than in children of fathers aged 31-35 and ≤30 years, respectively ( P < 0·01). Total cholesterol to HDL-C ratio was also higher among the children of fathers aged 31-35 (12%; P = 0·014) and >35 (16%; P = 0·004) years at childbirth compared with the ≤30 group. In addition, HOMA- IR in girls (but not boys) born of fathers aged 31-35 (0·99) and >35 years (1·11) indicated better insulin sensitivity compared with offspring in the ≤30 group (1·63; P < 0·05). Conclusions Increasing paternal age at childbirth is associated with a more favourable phenotype in their children (taller and slimmer, with better insulin sensitivity in girls) but with a less favourable lipid profile. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do children born to fathers of advanced age have an increased risk of dying before the age of 5 years? SUMMARY ANSWER Children born to fathers aged 40 years or more have an increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. WHAT IS KNOWN ALREADY Advanced paternal age has previously been associated with adverse reproductive outcomes and some long-term health problems in the offspring. This is possibly due to specific point mutations, a condition known to increase in the sperm with increasing paternal age. STUDY DESIGN, SIZE, DURATION A Danish population-based register study, designed as a prospective cohort study, of 1 575 521 live born children born from 1978 to 2004. The age of the child (in days) was used as the underlying time and the children entered the cohort the day they were born and were followed until 31 December 2009. The children were censored on date of turning 5 years, date of death or date of emigration, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS Data from population-covering registers from Statistics Denmark including the Integrated Database for Labour Market Research, the Medical Birth Registry and the Registry of Causes of Death was linked using the unique civil registry number. Hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the risk of under-five mortality. The effect of paternal age was examined using restricted cubic splines and paternal age groups. MAIN RESULTS AND THE ROLE OF CHANCE Compared with children born to fathers aged 30–34 years, a statistically significant excess risk was found for children born to fathers aged 40–44 years [HR: 1.10 (95% CI: 1.00–1.21)] and children born to fathers aged 45+ years [HR: 1.16 (95% CI: 1.02–1.32)]. When only looking at 1–5 year olds, the relative risk (HR) among children born to fathers aged 40–44 years increased to 1.24 (95% CI: 1.00–1.53) and the risk in the oldest paternal age group (45+ years) rose to 1.65 (95% CI: 1.24–2.18). The results suggest that the elevated risk for children of fathers aged 40 years or more was primarily attributed to an elevated risk of dying from congenital malformations, malignancies and external causes. LIMITATIONS, REASONS FOR CAUTION Specific causes of death might be misclassified; however, this is not likely to be dependent on paternal age. In some cases, the biological father may differ from the father registered. This misclassification is most likely non-differential. WIDER IMPLICATIONS OF THE FINDINGS The excess risk of mortality among children born to older fathers is in accordance with the literature. The association needs further attention as it can provide valuable knowledge of the etiology of genetic diseases. Also, the association could become of greater importance in the future if the proportion of fathers aged 40+ years keeps growing. STUDY FUNDING/COMPETING INTEREST (S) None. [ABSTRACT FROM AUTHOR]

Paternal age at conception has been found to predict the number of new genetic mutations. We examined the effect of father’s age at birth on offspring intelligence, head circumference and personality traits. Using the Minnesota Twin Family Study sample we tested paternal age effects while controlling for parents’ trait levels measured with the same precision as offspring’s. From evolutionary genetic considerations we predicted a negative effect of paternal age on offspring intelligence, but not on other traits. Controlling for parental intelligence (IQ) had the effect of turning an initially positive association non-significantly negative. We found paternal age effects on offspring IQ and Multidimensional Personality Questionnaire Absorption, but they were not robustly significant, nor replicable with additional covariates. No other noteworthy effects were found. Parents’ intelligence and personality correlated with their ages at twin birth, which may have obscured a small negative effect of advanced paternal age (<1% of variance explained) on intelligence. We discuss future avenues for studies of paternal age effects and suggest that stronger research designs are needed to rule out confounding factors involving birth order and the Flynn effect. [ABSTRACT FROM AUTHOR]

The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects’ birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age–endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia. [ABSTRACT FROM AUTHOR]

The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline. [ABSTRACT FROM AUTHOR]

Background This nationwide register-based study investigates how often obsessive-compulsive disorders (OCD) with different age at diagnosis occur in affected families compared to control families. Furthermore, the study addresses the impact of certain risk factors, that is, sex, degree of urbanization, year of birth, and maternal and paternal age at birth. Methods A total of N = 2,057 child and adolescent psychiatric subjects born between 1952 and 2000 and registered in the Danish Psychiatric Central Research Register developed OCD before the age of 18. In addition, N = 6,055 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses were also obtained for the first-degree relatives as a part of the Danish Three-Generation Study. A family load component was obtained by using various mixed regression models. Results OCD occurred significantly more often in case than in control families. Having a mother, father, sibling, or an offspring with the disorder was proven to be a risk factor. Maternal age above 35 years, male sex by tendency, and ascending year of birth were associated with having OCD. Furthermore, case relatives did not develop OCD earlier than control relatives. The risk of OCD in the case probands was significantly increased when first-degree family members had either OCD, or tic disorders, or affective disorders, or anxiety disorders. Conclusions These findings based on a very large and representative dataset provide further and very solid evidence for the high family aggregation of OCD. [ABSTRACT FROM AUTHOR]

Parental age can have considerable effects on offspring phenotypes and health. However, intergenerational effects may also have longer term effects on offspring fitness. Few studies have investigated parental age effects on offspring fitness in natural populations while also testing for sex- and environment-specific effects. Further, longitudinal parental age effects may be masked by population-level processes such as the selective disappearance of poor-quality individuals. Here, we used multigenerational data collected on individually marked Seychelles warblers ( Acrocephalus sechellensis ) to investigate the impact of maternal and paternal age on offspring life span and lifetime reproductive success. We found negative effects of maternal age on female offspring life span and lifetime reproductive success, which were driven by within-mother effects. There was no difference in annual reproductive output of females born to older versus younger mothers, suggesting that the differences in offspring lifetime reproductive success were driven by effects on offspring life span. In contrast, there was no association between paternal age and female offspring life span or either maternal or paternal age and male offspring life span. Lifetime reproductive success, but not annual reproductive success, of male offspring increased with maternal age, but this was driven by between-mother effects. No paternal age effects were found on female offspring lifetime reproductive success but there was a positive between-father effect on male offspring lifetime reproductive success. We did not find strong evidence for environment-dependent parental age effects. Our study provides evidence for parental age effects on the lifetime fitness of offspring and shows that such effects can be sex dependent. These results add to the growing literature indicating the importance of intergenerational effects on long-term offspring performance and highlight that these effects can be an important driver of variation in longevity and fitness in the wild., (© 2022 The Authors. Evolution Letters published by Wiley Periodicals LLC on behalf of Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEB).)

Neurofibromatosis type 1 (NF1) belongs to RASopathies, a group of syndromes caused by germline mutations in Ras/MAPK pathway genes. Most NF1 patients exhibit single inactivating pathogenic variants within the NF1 gene. We performed extensive genetic analyses in two NF1 families disclosing the first two cases of double de novo monoallelic NF1 variants. Both index patients described in this study had classical NF1. Probands were born from fathers in their late 30s and presented closely spaced double mutations (<100 bp) in NF1 regions showing an excess of somatic mutations. Closely spaced multiple mutations have been reported in RAS/MAPK signaling genes but never in NF1. Mutagenesis is a quasi-random process in humans, therefore two causative variants in the same gene, moreover in the same allele are exceptional. Here, we discuss possible mechanisms for this ultrarare event. Our findings confirm the possibility of a higher risk of concurrent de novo variants in NF1., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

The Developmental Origins of Health and Disease Science indicate that chronic diseases in adulthood are associated with prenatal and early-life traits. Our study aimed to explore the metabolic phenotype of offspring from advanced paternal age (APA) and the inherited alterations in sperm. 3-month-old (Young father, YF-F0) and 21-month-old male (Old Father, OF-F0) C57BL/6J mice were used to study paternal aging's effect on offspring. Blood glucose testing, lipid analysis, indirect calorimetry and RNA sequencing were performed. The characterized metabolic changes in OF-F1 male mice offspring were glucose intolerance, hepatic lipid accumulation, increased adipocytes and impaired energy balance that lasted until they were elderly. Gene expression in both 8-week-old and 52-week-old offspring livers significantly altered in lipid metabolism- and thermogenesis-related pathways. PPAR signaling pathway was activated in both young and elderly offspring livers as indicated by significant upregulation of Cyp7a1 , Cyp8b1 , Cyp4a10 , Cyp4a31 , Fabp2 , and Scd1. These targeted genes were also confirmed to be increased in offspring adipocytes. Furthermore, when examined the differentially expressed genes in F0 and F1 sperm, upregulated pathways including cholesterol metabolism, type II diabetes mellitus and endocrine resistance were strongly related to the APA offspring phenotype. Importantly, approximately 46.7% of enriched pathways in the sperm of APA offspring were consistent with those of APA fathers. These findings added evidence of the connection between paternal gametes and alterations in progeny genome and raised the possibility that inherited alterations in sperm contribute to the intergenerational effects of paternal aging offspring's chronic metabolic risks. • Advanced paternal age (APA) was associated with increased metabolic risks of offspring. • Glucose intolerance, lipid accumulation and impaired energy balance were identified in old father offspring mice. • Pathways regulating lipid metabolism and energy balance were significantly altered in offspring livers. • In F0 and F1 sperm, cholesterol metabolism, type II diabetes mellitus and endocrine resistance pathways were up regulated. [ABSTRACT FROM AUTHOR]

A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80%) or hypomethylated (<20%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here. [ABSTRACT FROM AUTHOR]