Paternal-Age-Related de Novo Mutations and Risk for Five Disorders

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.

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Meta-regression analysis using latitude as moderator of paternal age related schizophrenia risk: High ambient temperature induced de novo mutations or is it related to the cold?

Schizophrenia Research ◽

10.1016/j.schres.2007.10.016 ◽

2008 ◽

Vol 99 (1-3) ◽

pp. 71-76 ◽

Cited By ~ 8

Author(s):

Jackie Y.W. Cheng ◽

John S.N. Ko ◽

Ronald Y.L. Chen ◽

Emil M.L. Ng

Keyword(s):

Regression Analysis ◽

Ambient Temperature ◽

De Novo ◽

High Ambient Temperature ◽

Paternal Age ◽

De Novo Mutations ◽

Age Related ◽

Meta Regression ◽

Meta Regression Analysis

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A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

10.20944/preprints202007.0583.v1 ◽

2020 ◽

Author(s):

Sana Amanat ◽

Teresa Requena ◽

Jose Antonio Lopez-Escamez

Keyword(s):

Systematic Review ◽

Candidate Genes ◽

Rare Variants ◽

De Novo ◽

Complex Diseases ◽

De Novo Mutations ◽

Genetic Studies ◽

Complex Disorders ◽

Extreme Phenotype ◽

Age Related

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

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Schizophrenia Risk and Paternal Age: A Potential Role for De Novo Mutations in Schizophrenia Vulnerability Genes

CNS Spectrums ◽

10.1017/s1092852900022239 ◽

2002 ◽

Vol 7 (1) ◽

pp. 26-29 ◽

Cited By ~ 27

Author(s):

Dolores Malaspina ◽

Alan Brown ◽

Deborah Goetz ◽

Nelly Alia-Klein ◽

Jill Harkavy-Friedman ◽

...

Keyword(s):

Human Population ◽

Potential Role ◽

De Novo ◽

Paternal Age ◽

Current Evidence ◽

Parental Age ◽

De Novo Mutations ◽

New Mutations

ABSTRACTHow schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.

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Advancing paternal age and offspring violent offending: A sibling-comparison study

Development and Psychopathology ◽

10.1017/s095457941200034x ◽

2012 ◽

Vol 24 (3) ◽

pp. 739-753 ◽

Cited By ~ 12

Author(s):

Ralf Kuja-Halkola ◽

Yudi Pawitan ◽

Brian M. D'Onofrio ◽

Niklas Långström ◽

Paul Lichtenstein

Keyword(s):

Violent Crime ◽

De Novo ◽

Causal Effect ◽

Paternal Age ◽

De Novo Mutations ◽

Criminal Convictions ◽

Violent Offending ◽

Genes And Environment ◽

Life Course Persistent ◽

Severe Psychopathology

AbstractChildren born to older fathers are at higher risk to develop severe psychopathology (e.g., schizophrenia and bipolar disorder), possibly because of increased de novo mutations during spermatogenesis with older paternal age. Because severe psychopathology is correlated with antisocial behavior, we examined possible associations between advancing paternal age and offspring violent offending. Interlinked Swedish national registers provided information on fathers' age at childbirth and violent criminal convictions in all offspring born from 1958 to 1979 (N= 2,359,921). We used ever committing a violent crime and number of violent crimes as indices of violent offending. The data included information on multiple levels; we compared differentially exposed siblings in within-family analyses to rigorously test causal influences. In the entire population, advancing paternal age predicted offspring violent crime according to both indices. Congruent with a causal effect, this association remained for rates of violent crime in within-family analyses. However, in within-family analyses, we found no association with ever committing a violent crime, suggesting that factors shared by siblings (genes and environment) confounded this association. Life-course persistent criminality has been proposed to have a partly biological etiology; our results agree with a stronger biological effect (i.e., de novo mutations) on persistent violent offending.

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Risk of Psychiatric Illness From Advanced Paternal Age Is Not Predominantly From De Novo Mutations

Obstetrical & Gynecological Survey ◽

10.1097/01.ogx.0000512485.13448.c7 ◽

2017 ◽

Vol 72 (2) ◽

pp. 96

Author(s):

Jacob Gratten ◽

Naomi R. Wray ◽

Wouter J. Peyrot ◽

John J. McGrath ◽

Peter M. Visscher ◽

...

Keyword(s):

Psychiatric Illness ◽

De Novo ◽

Paternal Age ◽

De Novo Mutations ◽

Advanced Paternal Age

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Impact of Paternal Age at Conception on Human Health

Clinical Chemistry ◽

10.1373/clinchem.2018.294421 ◽

2019 ◽

Vol 65 (1) ◽

pp. 146-152 ◽

Cited By ~ 8

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.

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