Age at fatherhood: heritability and associations with psychiatric disorders

2016 ◽  
Vol 46 (14) ◽  
pp. 2981-2988 ◽  
Author(s):  
E. M. Frans ◽  
P. Lichtenstein ◽  
C. M. Hultman ◽  
R. Kuja-Halkola
Keyword(s):  
Psychiatric Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Genetic Component ◽  
Paternal Age ◽  
Genetic Liability ◽  
Healthy Men ◽  
Twin Model ◽  
Men 2 ◽  
Affected Sibling

BackgroundAdvancing paternal age has been linked to psychiatric disorders. These associations might be caused by the increased number of de novo mutations transmitted to offspring of older men. It has also been suggested that the associations are confounded by a genetic liability for psychiatric disorders in parents. The aim of this study was to indirectly test the confounding hypotheses by examining if there is a genetic component to advancing paternal age and if men with a genetic liability for psychiatric disorders have children at older ages.MethodWe examined the genetic component to advancing paternal age by utilizing the twin model in a cohort of male twins (N = 14 679). We also studied ages at childbirth in men with or without schizophrenia, bipolar disorder and/or autism spectrum disorder. Ages were examined in: (1) healthy men, (2) affected men, (3) healthy men with an affected sibling, (4) men with healthy spouses, (5) men with affected spouses, and (6) men with healthy spouses with an affected sibling.ResultsThe twin analyses showed that late fatherhood is under genetic influence (heritability = 0.33). However, affected men or men with affected spouses did not have children at older ages. The same was found for healthy individuals with affected siblings. Instead, these men were generally having children at younger ages.ConclusionAlthough there is a genetic component influencing late fatherhood, our data suggest that the associations are not explained by psychiatric disorders or a genetic liability for psychiatric disorders in the parent.

scholarly journals Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Kyleen Luhrs ◽  
Tracey Ward ◽  
Caitlin M. Hudac ◽  
Jennifer Gerdts ◽  
Holly A. F. Stessman ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Copy Number ◽  
Depressive Disorders ◽  
De Novo ◽  
Familial Risk ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Genetic Etiology ◽  
Additive Contribution ◽  
Familial Risk Factors

The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n=62), de novo deletion copy number variations (DEL, n=74), de novo likely gene-disrupting mutations (LGDM, n=267), and children without a known genetic etiology (NON, n=2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.

scholarly journals Association of genetic liability for psychiatric disorders with accelerometer-assessed physical activity in the UK Biobank

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249189
Author(s):  
Charlotte A. Dennison ◽  
Sophie E. Legge ◽  
Matthew Bracher-Smith ◽  
Georgina Menzies ◽  
Valentina Escott-Price ◽  
...  
Keyword(s):  
Physical Activity ◽  
Psychiatric Disorders ◽  
Genetic Correlations ◽  
Autism Spectrum ◽  
Moderate Activity ◽  
Activity Levels ◽  
Accelerometer Data ◽  
Uk Biobank ◽  
Genetic Liability ◽  
Shared Risk

Levels of activity are often affected in psychiatric disorders and can be core symptoms of illness. Advances in technology now allow the accurate assessment of activity levels but it remains unclear whether alterations in activity arise from shared risk factors for developing psychiatric disorders, such as genetics, or are better explained as consequences of the disorders and their associated factors. We aimed to examine objectively-measured physical activity in individuals with psychiatric disorders, and assess the role of genetic liability for psychiatric disorders on physical activity. Accelerometer data were available on 95,529 UK Biobank participants, including measures of overall mean activity and minutes per day of moderate activity, walking, sedentary activity, and sleep. Linear regressions measured associations between psychiatric diagnosis and activity levels, and polygenic risk scores (PRS) for psychiatric disorders and activity levels. Genetic correlations were calculated between psychiatric disorders and different types of activity. Having a diagnosis of schizophrenia, bipolar disorder, depression, or autism spectrum disorders (ASD) was associated with reduced overall activity compared to unaffected controls. In individuals without a psychiatric disorder, reduced overall activity levels were associated with PRS for schizophrenia, depression, and ASD. ADHD PRS was associated with increased overall activity. Genetic correlations were consistent with PRS findings. Variation in physical activity is an important feature across psychiatric disorders. Whilst levels of activity are associated with genetic liability to psychiatric disorders to a very limited extent, the substantial differences in activity levels in those with psychiatric disorders most likely arise as a consequences of disorder-related factors.

scholarly journals Impact of Paternal Age at Conception on Human Health

2019 ◽  
Vol 65 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Mathieu Simard ◽  
Catherine Laprise ◽  
Simon L Girard
Keyword(s):  
Maternal Age ◽  
De Novo ◽  
Autism Spectrum ◽  
Age Effect ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Brain Functions ◽  
Offspring Health ◽  
Paternal Age Effect

Abstract BACKGROUND The effect of maternal age at conception on various aspects of offspring health is well documented and often discussed. We seldom hear about the paternal age effect on offspring health, although the link is now almost as solid as with maternal age. The causes behind this, however, are drastically different between males and females. CONTENT In this review article, we will first examine documented physiological changes linked to paternal age effect. We will start with all morphological aspects of the testis that have been shown to be altered with aging. We will then move on to all the parameters of spermatogenesis that are linked with paternal age at conception. The biggest part of this review will focus on genetic changes associated with paternal age effects. Several studies that have established a strong link between paternal age at conception and the rate of de novo mutations will be reviewed. We will next discuss paternal age effects associated with telomere length and try to better understand the seemingly contradictory results. Finally, severe diseases that affect brain functions and normal development have been associated with older paternal age at conception. In this context, we will discuss the cases of autism spectrum disorder and schizophrenia, as well as several childhood cancers. SUMMARY In many Western civilizations, the age at which parents have their first child has increased substantially in recent decades. It is important to summarize major health issues associated with an increased paternal age at conception to better model public health systems.

Advancing paternal age and simplex autism

Autism ◽  
2011 ◽  
Vol 16 (4) ◽  
pp. 367-380 ◽  
Author(s):  
Connor Morrow Puleo ◽  
James Schmeidler ◽  
Abraham Reichenberg ◽  
Alexander Kolevzon ◽  
Latha V Soorya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Autism Spectrum Disorder ◽  
Significant Interaction ◽  
Maternal Age ◽  
De Novo ◽  
Autism Spectrum ◽  
Paternal Age ◽  
Family Type ◽  
Simplex Family ◽  
Age And Sex

De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers’ offspring. This study examined whether advancing paternal age predicts an increase in simplex ( n = 90) versus multiplex ASD cases ( n = 587) in 677 participants (340 families). Whether or not controlling for maternal age, results support a significant interaction of linear paternal age and sex of the child on simplex family type. Female ASD cases were significantly more likely to be simplex as paternal age increased, but the increase for males was not significant. Findings suggest that ASD arising from non-familial, de novo events may be far less prominent in males than in females, even if more prevalent in males, due to the substantially larger number of male cases attributable to other, more strongly male-biased risk factors.

scholarly journals Neurodevelopmental Plasticity in Pre- and Postnatal Environmental Interactions: Implications for Psychiatric Disorders from an Evolutionary Perspective

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Young-A Lee ◽  
Yoshie Yamaguchi ◽  
Yukiori Goto
Keyword(s):  
Psychiatric Disorders ◽  
De Novo ◽  
Gene Mutations ◽  
Normal Subjects ◽  
Autism Spectrum ◽  
Biological Mechanisms ◽  
Behavioral Phenotypes ◽  
Environmental Interactions ◽  
De Novo Gene ◽  
Adverse Environmental Conditions

Psychiatric disorders are disadvantageous behavioral phenotypes in humans. Accordingly, a recent epidemiological study has reported decreased fecundity in patients with psychiatric disorders, such as schizophrenia and autism spectrum disorders. Moreover, the fecundity of the relatives of these patients is not exceedingly higher compared to the fecundity of the relatives of normal subjects. Collectively, the prevalence of psychiatric disorders among humans is expected to decrease over generations. Nevertheless, in reality, the prevalence rates of psychiatric disorders in humans either have been constant over a long period of time or have even increased more recently. Several attempts to explain this fact have been made using biological mechanisms, such as de novo gene mutations or variants, although none of these explanations is fully comprehensive. Here, we propose a hypothesis towards understanding the biological mechanisms of psychiatric disorders from evolutionary perspectives. This hypothesis considers that behavioral phenotypes associated with psychiatric disorders might have emerged in the evolution of organisms as a neurodevelopmental adaptation against adverse environmental conditions associated with stress.

scholarly journals Paternal-age-related de novo mutations and risk for five disorders

2017 ◽  
Author(s):  
Jacob L. Taylor ◽  
Jean-Christophe P.G. Debost ◽  
Sarah U. Morton ◽  
Emilie M. Wigdor ◽  
Henrike O. Heyne ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
National Registry ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Advanced Paternal Age ◽  
Age Related ◽  
Rate Ratios

AbstractBackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.MethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.ResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01–1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).ConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

scholarly journals Elevated DNA Methylation Gestational Age is associated with the Risk of Later Bipolar Disorder and Anorexia Nervosa in Twins

2020 ◽  
Author(s):  
Christine Soeholm Hansen ◽  
Anna Starnawska ◽  
Alexander Werner Drong ◽  
Shantel Marie Weinsheimer ◽  
Marie Baekvad-Hansen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bipolar Disorder ◽  
Molecular Marker ◽  
Psychiatric Disorders ◽  
Gestational Age ◽  
Autism Spectrum ◽  
Foetal Development ◽  
Genetic Liability ◽  
Mz Twins ◽  
Psychiatric Outcome

Background: Foetal development indicates the risk of later disease, but has only been associated with few psychiatric disorders. An aggregated molecular marker of development - DNA methylation based estimates of gestational age (DNAmGA) adjusted for GA, can be indicative of foetal health and development. Twins have the same chronological GA and monozygotic (MZ) twins share genetic liability. We leveraged this to examine whether DNAmGA in neonates associate with later psychiatric disorder, independent of chronological GA, maternal characteristics, genetic influences, and shared environmental factors. Method: We estimated DNAmGA in 260 MZ and 396 dizygotic (DZ) twin pairs, later diagnosed with schizophrenia, bipolar disorder, affective/depressive mood disorder, autism spectrum disorder, attention deficit hyperactivity disorder or anorexia. DNAmGA was tested for association with psychiatric outcome by mean discordant twin differences and by linear mixed model (LMM), adjusting for relatedness and potential confounders. Results: We found elevated DNAmGA to associate with anorexia between discordant DZ and MZ twins (0.74 weeks, 95%CI[0.34:1.14] and 0.28 weeks, 95%CI[0.04:0.53], respectively), and with bipolar disorder between discordant MZ twins (0.85 weeks, 95%CI[0.16:1.53]). Elevated DNAmGA associated significantly with both in the LMM analysis (0.56 weeks, 95%CI[0.32:0.83] and 0.89 weeks, 95%CI[0.32:1.51], respectively). Conclusions: Elevated DNAmGA is associated with two later onset psychiatric disorders in twins, and thus supports a developmental origin of disease. This association was not confounded by variation in conventional measures of foetal development nor genetic liability. We therefore propose that a novel molecular marker of development, can differentiate between later psychiatric outcome in newborn twins.

scholarly journals Limited contribution of rare, noncoding variation to autism spectrum disorder from sequencing of 2,076 genomes in quartet families

2017 ◽  
Author(s):  
Donna M. Werling ◽  
Harrison Brand ◽  
Joon-Yong An ◽  
Matthew R. Stone ◽  
Joseph T. Glessner ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Multiple Testing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Paternal Age ◽  
Loss Of Function ◽  
Protein Coding ◽  
Missense Variation ◽  
Genomic Studies

SummaryGenomic studies to date in autism spectrum disorder (ASD) have largely focused on newly arising mutations that disrupt protein coding sequence and strongly influence risk. We evaluate the contribution of noncoding regulatory variation across the size and frequency spectrum through whole genome sequencing of 519 ASD cases, their unaffected sibling controls, and parents. Cases carry a small excess of de novo (1.02-fold) noncoding variants, which is not significant after correcting for paternal age. Assessing 51,801 regulatory classes, no category is significantly associated with ASD after correction for multiple testing. The strongest signals are observed in coding regions, including structural variation not detected by previous technologies and missense variation. While rare noncoding variation likely contributes to risk in neurodevelopmental disorders, no category of variation has impact equivalent to loss-of-function mutations. Average effect sizes are likely to be smaller than that for coding variation, requiring substantially larger samples to quantify this risk.

Developmental milestones in early childhood and genetic liability to neurodevelopmental disorders

2020 ◽  
Author(s):  
Laurie John Hannigan ◽  
Ragna Bugge Askeland ◽  
Helga Ask ◽  
Martin Tesli ◽  
Elizabeth Corfield ◽  
...  
Keyword(s):  
Language Development ◽  
Motor Development ◽  
Neurodevelopmental Disorders ◽  
Autism Spectrum ◽  
Probit Regression ◽  
Developmental Milestones ◽  
Genetic Liability ◽  
Polygenic Scores ◽  
Walking Age ◽  
Children First

BackgroundEarly developmental milestones, such as the age at first walking or talking, are associated with later diagnoses of neurodevelopmental disorders, but the relationship to genetic risk for neurodevelopmental disorders are unknown. Here, we investigate associations between genetic liability to autism spectrum disorder (autism), attention deficit hyperactivity disorder (ADHD), and schizophrenia and attainment of early-life language and motor development milestones.MethodsWe use data from a genotyped sub-set (N = 15 205) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). In this sample, we calculate polygenic scores for autism; ADHD and schizophrenia and predict maternal reports of children’s age at first walking and talking, motor delays at 18 months, language delays at 3 years, and a generalized measure of concerns about development. We use linear and probit regression models in a multi-group framework to test for sex differences.ResultsADHD polygenic scores predicted earlier walking age in both males and females (β=-0.037, pFDR=0.001), and earlier first use of sentences (β=-0.087, pFDR=0.032) but delayed language development at 3 years in females only (β=0.194, pFDR=0.001). Additionally, we found evidence that autism polygenic scores were associated with later walking (β=0.027, pFDR=0.024) and motor delays at 18 months (β = 0.065, pFDR=0.028). Schizophrenia polygenic scores were associated with a measure of general concerns about development at 3 years in females only (β=0.132, pFDR=0.024).ConclusionsGenetic liabilities for neurodevelopmental disorders show some specific associations with measures of early motor and language development in the general population, including the age at which children first walk and talk. Associations are generally small and occasionally in unexpected directions. Sex differences are evident in some instances, but clear patterns across different polygenic scores and outcomes are hard to discern. These findings suggest that genetic susceptibility for neurodevelopmental disorders is manifested in the timing of developmental milestones in infancy.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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