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

Taylor, Jacob; Debost, Jean-Christophe; Morton, Sarah U.; Wigdor, Emilie M.; Heyne, Henrike O.; Lal, Dennis; Howrigan, Daniel P.; Bloemendal, Alex; Larsen, Janne Tidselbak; Kosmicki, Jack A.; Weiner, Daniel J.; Homsy, Jason; Seidman, Jonathan G.; Seidman, Christine E.; Agerbo, Esben; McGrath, John J.; Mortensen, Preben Bo; Petersen, Liselotte; Daly, Mark J.; Robinson, Elise

doi:10.1038/s41467-019-11039-6

Cited by 73 publications

(48 citation statements)

References 45 publications

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“…Using spontaneous labor as a reference (no exposure to sOT), cases categorized as “fetal indication” for delivery ( Table 1 ) as a group had significantly higher odds of ASD (OR = 2.00, 95% CI = 1.01–3.94, p = 0.044). To control for the possibility that fetal indications could confound the results in Tables 3 to 6 , this variable was included as a covariate in subsequent analysis as was the presence of maternal hypertension ( Curran et al, 2018 ), maternal diabetes ( Li et al, 2016 ; OR = 2.04, p = 0.077), maternal education (as a substitute for the lack of socioeconomic status data), birth weight ( Burstyn et al, 2010 ), maternal smoking ( Caramaschi et al, 2018 ) or alcohol use during pregnancy ( Bölte et al, 2019 ), the child’s race ( Baio et al, 2018 ), and paternal age ( Taylor et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

Soltys

Scherbel

Kurian

et al. 2020

Autism

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A case-control study was performed to determine whether an association exists between exposure to synthetic oxytocin and a subsequent autism spectrum disorder diagnosis; 171 children under age 18 meeting Diagnostic and Statistical Manual of Mental Disorders (5th ed.) autism spectrum disorder criteria were compared to 171 children without autism spectrum disorder diagnosis matched by gender, birth year, gestational age, and maternal age at birth. A conditional logistic regression model was used to examine the association of clinical variables and autism spectrum disorder. Significantly elevated odds ratios for autism spectrum disorder were associated with first-time Cesarean section (odds ratio = 2.56), but not a repeat Cesarean section. Odds ratios were also significantly elevated for subjects whose mother’s body mass index was 35 or higher at birth (odds ratio = 2.34) and subjects in which the reason for delivery was categorized as “fetal indication” (odds ratio = 2.00). When controlling for these and other variables, the odds of developing autism spectrum disorder were significantly elevated in males with long duration of exposure (odds ratio = 3.48) and high cumulative dose of synthetic oxytocin (odds ratio = 2.79). No significant associations of synthetic oxytocin dosing and autism spectrum disorder were noted in female subjects. The association of elevated autism spectrum disorder odds found with high duration and high cumulative dose synthetic oxytocin in male subjects suggests the need for further investigation to fully elucidate any cause and effect relationship. Lay abstract Oxytocin is a hormone naturally produced in the human body that can make the womb (uterus) contract during labor. Manufactured oxytocin is frequently given to mothers in labor to strengthen the contractions or in some cases to start labor. This study compared children with a diagnosis of autism and children without autism to see whether children with autism received more oxytocin during labor. The odds of a child having an autism diagnosis were significantly higher if the delivery was a first-time Cesarean section, if the mother had a body mass index of 35 or higher, or if the reason for delivery were a range of fetal problems that made delivery necessary. It was found that boys who were exposed to oxytocin for longer periods of time during labor and received higher total doses of oxytocin had significantly higher odds of developing autism. There were no significant associations of oxytocin dosing and autism noted in female children. As this is the first study to look at any relationship between the dose of oxytocin received during labor and the odds of developing autism, further study needs to be done to determine whether there is any cause and effect relationship. Thus, at this time, there is no recommended change in clinical practice.

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Section: Resultsmentioning

confidence: 99%

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

Soltys

Scherbel

Kurian

et al. 2020

Autism

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“…Regarding an underlying mechanism of neurodevelopmental disorders induced by paternal aging, de novo mutation in sperm of aged fathers has previously been proposed [46, 47], although more recent studies report that contribution of de novo mutations has less impact on the risk of ASD in offspring [48, 49]. In our unpublished data, abnormal behaviors were observed in F1 generation but abolished in F2 generation when F1 male mice were mated at the young stage, suggesting epigenetic mechanisms underlying.…”

Section: Discussionmentioning

confidence: 99%

Advanced paternal age diversifies individual trajectories of vocalization patterns in neonatal mice

Mai

Kimura

Hori

et al. 2019

Preprint

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25Autism Spectrum Disorder (ASD) is one of the neurodevelopmental disorders and 26 characterized with persistent impairments in social communication (including verbal 27 and nonverbal communication) and repetitive behavior together with various 28 comorbid symptoms. Epidemiological studies suggest a significant association 29 between advanced paternal age and incidence of ASD in offspring, which has been 30 modeled in rodents. However, how paternal aging makes an impact on the offspring's 31 early communicative behavior, especially at the individual level, has not been 32 addressed. Here we systematically analyzed postnatal development of vocal 33 communication of pups by measuring ultrasonic vocalization (USV) induced by 34 maternal separation that is considered to correspond to baby's cry, an earliest verbal 35 communication in human. Maternal separation-induced USV of each offspring 36 derived from young (3 months) or aged (>12 months) father was individually 37 measured for 5 minutes at postnatal day 3 (P3), P6, P9, and P12. We classified USV 38 syllables into twelve types according to Scattoni's classification with minor 39 modifications, and analyzed duration, maximum frequency, maximum amplitude and 40 interval of each syllable. Compared between the two groups, the offspring derived 41 from aged fathers emitted the syllables with less number, shorter duration, different 42 syllable components and less diversity. From an individual perspective, offspring 43 derived from young father showed a developmental convergence in vocal 44 communication, while those from aged fathers exhibited atypical developmental 45 patterns. Taken together, we showed for the first time a significant influence of 46 paternal aging on early vocal development with qualitative and quantitative aspects in 47 50 Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by 51 two core symptoms; i.e., social interaction impairment (including verbal and 52 nonverbal communication deficits) and repetitive behavior [1][2][3] . In most cases, the 53 exact etiology of ASD remains unclear, although researchers believe that genetic, 54 environmental and epigenetic factors are involved in the neuropathology of ASD [4][5][6] . 55In recent years, epidemiological studies repeatedly suggest a significant association 56 between paternal aging and a risk of ASD in offspring. Compared with the children of 57 young fathers, the children were more likely to be diagnosed ASD if their fathers 58 were older [7][8][9][10] . Thus, paternal aging can be worth to be focused as one of the 59 non-genetic mechanisms leading to ASD. 60 61In the new criteria of DSM-5, the communication and social interaction parts are 62 combined into one, i.e., "Social/Communication Deficits". This modification 63 emphasizes the importance of the social communication domain in ASD in early 64 infancy. Human infant crying is an innate social communication [11, 12] , which has a 65 natural peak in frequency of approximately 2.5 hours of crying per day at aroun...

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“…One of the most replicated associations for ASD is advanced paternal age, with increased risk in the offspring of fathers in their mid-to-late 30s, further increasing with more advanced paternal ages [ 52 , 53 , 54 , 55 ]. The rate of de novo mutations in sperm increases with paternal age [ 43 , 44 , 56 , 57 , 58 , 59 ], and most de novo mutations found in ASD studies are of paternal origin [ 26 , 27 ]. However, studies based on simulated [ 60 ] and empirical [ 59 ] data indicate that de novo variation is likely not the major driver for the association between advanced paternal age and ASD risk.…”

Section: Asd Risk Architecturementioning

confidence: 99%

“…The rate of de novo mutations in sperm increases with paternal age [ 43 , 44 , 56 , 57 , 58 , 59 ], and most de novo mutations found in ASD studies are of paternal origin [ 26 , 27 ]. However, studies based on simulated [ 60 ] and empirical [ 59 ] data indicate that de novo variation is likely not the major driver for the association between advanced paternal age and ASD risk. Rather, the common polygenic risk for adverse psychiatric outcomes might contribute to later age of childbearing [ 60 , 61 ].…”

Section: Asd Risk Architecturementioning

confidence: 99%

Linking Autism Risk Genes to Disruption of Cortical Development

Garcia‐Forn

Boitnott

Akpinar

et al. 2020

Cells

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Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

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

Cited by 73 publications

References 45 publications

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

Advanced paternal age diversifies individual trajectories of vocalization patterns in neonatal mice

Linking Autism Risk Genes to Disruption of Cortical Development

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