Âge parental et estimations différentielles du risque de troubles neuropsychiatriques: résultats de la cohorte de naissance danoise

Aperçu: G.M.

Il a été démontré que l'âge parental à la naissance avait une incidence sur les taux d'une série de troubles neurodéveloppementaux, mais il reste encore à comprendre les mécanismes par lesquels elle induit différents résultats. Nous avons utilisé une cohorte basée sur la population pour évaluer les effets différentiels de l'âge des parents sur les estimations du risque de troubles neuropsychiatriques apparents: troubles du spectre de l'autisme (TSA), trouble de déficit de l'attention avec hyperactivité  (TDAH), trouble obsessionnel-compulsif (TOC) et syndrome de Tourette / trouble tic chronique (TS / CT).
MÉTHODE:

Notre cohorte d’étude comprenait toutes les naissances uniques au Danemark entre 1980 et 2007 avec des informations complètes sur l’âge des parents (N = 1 490 745), suivies jusqu’au 31 décembre 2013. Des cas de TSA, de TDAH, de TOC et de TS/CT ont été identifiés dans le Centre psychiatrique danois.

Les associations avec l'âge parental ont été modélisées à l'aide d'une régression stratifiée de Cox, permettant des modifications des taux de diagnostic de base au fil du temps.
RÉSULTATS:
L'âge parental plus jeune était associé de manière significative à une augmentation des estimations du risque de TDAH et de TS/CT, tandis que l'âge parental plus âgé était associé à un TSA et à un TOC. À l'exception des TOC, nous n'avons observé aucune preuve d'effets différentiels de l'âge des parents sur la progéniture des garçons et des filles.
CONCLUSION:
Nous apportons une nouvelle preuve du lien existant entre l'âge de la parentalité et le TS / CT et le TOC, et montrons pour la première fois dans un échantillon de population que l'âge des parents confère des taux de risque différents pour les troubles psychiatriques apparus en pédiatrie. Nos résultats sont cohérents avec un modèle d'architecture de risque partagé et non partagé pour les affections neuropsychiatriques apparaissant en pédiatrie, mettant en évidence les contributions uniques des âges maternel et paternel.

J Am Acad Child Adolesc Psychiatry. 2019 Feb 27. pii: S0890-8567(19)30126-1. doi: 10.1016/j.jaac.2018.09.447.

Parental Age and Differential Estimates of Risk for Neuropsychiatric Disorders: Findings From the Danish Birth Cohort

Janecka M¹, Hansen SN², Modabbernia A³, Browne HA⁴, Buxbaum JD⁵, Schendel DE⁶, Reichenberg A⁷, Parner ET², Grice DE⁸.

Author information

1

Icahn School of Medicine at Mount Sinai, New York, NY; Seaver Autism Center for Research and Treatment.

2

Aarhus University, Denmark.

3

Icahn School of Medicine at Mount Sinai, New York, NY.

4

Icahn School of Medicine at Mount Sinai, New York, NY; Division of Tics, OCD, and Related Disorders.

5

Icahn School of Medicine at Mount Sinai, New York, NY; Seaver Autism Center for Research and Treatment; Friedman Brain Institute and Mindich Child Health and Development Institute.

6

Section for Epidemiology, the National Centre for Register-Based Research, Aarhus University, Denmark, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

7

Icahn School of Medicine at Mount Sinai, New York, NY; Seaver Autism Center for Research and Treatment; Friedman Brain Institute and Mindich Child Health and Development Institute; Institute for Translational Epidemiology.

8

Icahn School of Medicine at Mount Sinai, New York, NY; Division of Tics, OCD, and Related Disorders; Friedman Brain Institute and Mindich Child Health and Development Institute. Electronic address: Dorothy.Grice@mssm.edu.

Abstract

OBJECTIVE:

Parental age at birth has been shown to affect the rates of a range of neurodevelopmental disorders, but the understanding of the mechanisms through which it mediates different outcomes is still lacking. We used a population-based cohort to assess differential effects of parental age on estimates of risk across pediatric-onset neuropsychiatric disorders: autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) and Tourette syndrome/chronic tic disorder (TS/CT).

METHOD:

Our study cohort included all singleton births in Denmark between 1980 and 2007 with full information on parental ages (N=1,490,745), followed through December 31, 2013. Cases of ASD, ADHD, OCD and TS/CT were identified in the Danish Psychiatric Central Register and the National Patient Register. Associations with parental age were modeled using a stratified Cox regression, allowing for changes in baseline diagnostic rates across time.

RESULTS:

Younger parental age was significantly associated with increased estimates of risk for ADHD and TS/CT, while older parental age was associated with ASD and OCD. Except for OCD, we did not observe any evidence for differential effects of parental ages on male vs. female offspring.

CONCLUSION:

We provide novel evidence for the association between age at parenthood and TS/CT and OCD, and show for the first time in a population-based sample that parental age confers differential risk rates for pediatric-onset psychiatric disorders. Our results are consistent with a model of both shared and unshared risk architecture for pediatric-onset neuropsychiatric conditions, highlighting unique contributions of maternal and paternal ages.

Copyright © 2019. Published by Elsevier Inc.

PMID:30825496

DOI:10.1016/j.jaac.2018.09.447

L'âge paternel altère le développement social chez les descendants

Aperçu: G.M.

L'âge paternel avancé (APA) à la conception a été lié à l'autisme et à la schizophrénie dans les progénitures.

Dans la population générale, les âges paternels très jeunes et avancés ont été tous deux associés à une trajectoire modifiée du développement social. 

J Am Acad Child Adolesc Psychiatry. 2017 May;56(5):383-390. doi: 10.1016/j.jaac.2017.02.006. Epub 2017 Mar 6.

Paternal Age Alters Social Development in Offspring

Janecka M¹, Haworth CMA², Ronald A³, Krapohl E⁴, Happé F⁴, Mill J⁵, Schalkwyk LC⁶, Fernandes C⁴, Reichenberg A⁷, Rijsdijk F⁴.

Author information

1

Social, Genetic and Developmental Psychiatry (SGDP) Centre, King's College London, UK; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York. Electronic address: magdalena.janecka@mssm.edu.

2

MRC Integrative Epidemiology Unit, School of Experimental Psychology and School of Social and Community Medicine, University of Bristol, UK.

3

Birkbeck University of London, UK.

4

Social, Genetic and Developmental Psychiatry (SGDP) Centre, King's College London, UK.

5

Social, Genetic and Developmental Psychiatry (SGDP) Centre, King's College London, UK; University of Exeter Medical School, University of Exeter, Exeter, UK.

6

School of Biological Sciences, University of Essex, Colchester, UK.

7

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York.

Abstract

OBJECTIVE:

Advanced paternal age (APA) at conception has been linked with autism and schizophrenia in offspring, neurodevelopmental disorders that affect social functioning. The current study explored the effects of paternal age on social development in the general population.

METHOD:

We used multilevel growth modeling to investigate APA effects on socioemotional development from early childhood until adolescence, as measured by the Strengths and Difficulties Questionnaire (SDQ) in the Twins Early Development Study (TEDS) sample. We also investigated genetic and environmental underpinnings of the paternal age effects on development, using the Additive genetics, Common environment, unique Environment (ACE) and gene-environment (GxE) models.

RESULTS:

In the general population, both very young and advanced paternal ages were associated with altered trajectory of social development (intercept: p = .01; slope: p = .03). No other behavioral domain was affected by either young or advanced age at fatherhood, suggesting specificity of paternal age effects. Increased importance of genetic factors in social development was recorded in the offspring of older but not very young fathers, suggesting distinct underpinnings of the paternal age effects at these two extremes.

CONCLUSION:

Our findings highlight that the APA-related deficits that lead to autism and schizophrenia are likely continuously distributed in the population.

Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 28433087

DOI: 10.1016/j.jaac.2017.02.006

Âge parental et psychopathologie des descendants dans la cohorte neurodéveloppementale de Philadelphie

Aperçu: G.M.

Les âges parentaux plus jeunes étaient généralement associés à des taux accrus de psychopathologie des descendants. Après avoir contrôlé les caractéristiques socio-démographiques et la comorbidité, les âges maternels et paternels plus jeunes ont été associés à des syndromes de comportement et à une psychose chez les jeunes, alors que l'âge paternel avancé était associé à des troubles du développement / troubles du spectre de l'autisme.

Ces résultats suggèrent que l'âge des parents plus jeune et plus âgé à la naissance est associé à des formes spécifiques de psychopathologie chez les descendants. La persistance de l'influence de l'âge parental après le contrôle des facteurs démographiques et un indice de l'environnement social suggère nt que des explications supplémentaires pour ces résultats devraient être examinées dans les études futures.

J Am Acad Child Adolesc Psychiatry. 2017 May;56(5):391-400. doi: 10.1016/j.jaac.2017.02.004. Epub 2017 Mar 6.

Parental Age and Offspring Psychopathology in the Philadelphia Neurodevelopmental Cohort

Merikangas AK¹, Calkins ME², Bilker WB³, Moore TM², Gur RC², Gur RE².

Author information

1

Lifespan Brain Institute, Children's Hospital of Philadelphia and Neuropsychiatry Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Electronic address: ameri@upenn.edu

2

Lifespan Brain Institute, Children's Hospital of Philadelphia and Neuropsychiatry Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

3

Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Abstract

OBJECTIVE:

Increasing evidence implicates advanced paternal age at offspring birth in neuropsychiatric disorders. Advanced maternal age has also been associated with schizophrenia and other neurodevelopmental disorders, whereas younger maternal age has been linked with behavioral disorders. Few studies have considered the specificity of the associations with respect to comorbidity. In addition, most prior studies have been conducted in clinical samples or registries that may reflect more severe forms of psychopathology. The aim of this research is to examine the independent and joint associations of maternal and paternal age with specific subtypes of psychopathology in offspring in a pediatric sample of adolescents with emergent psychiatric syndromes.

METHOD:

A total of 8,725 youths (aged 8-21 years) from the Philadelphia Neurodevelopmental Cohort were included in the analyses. Logistic regression models with parental age predicting offspring psychopathology were adjusted for sociodemographic factors and comorbid disorders.

RESULTS:

We found that younger parental ages were generally associated with increased rates of offspring psychopathology. After controlling for sociodemographic characteristics and comorbidity, both younger maternal and paternal ages were associated with behavior syndromes and psychosis in youth, whereas advanced paternal age was associated with pervasive developmental disorders/autism spectrum disorder (PDD/ASD).

CONCLUSION:

These findings suggest that both younger and older parental age at birth are associated with specific forms of psychopathology in offspring. The persistence of the influence of parental age after control for demographic factors and an index of social environment suggests that additional explanations for these findings should be examined in future studies.

Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 28433088

DOI: 10.1016/j.jaac.2017.02.004

L'âge paternel et les troubles psychiatriques: revue

Aperçu: G.M.

L'âge paternel avancé par rapport aux troubles du spectre de l'autisme et à la schizophrénie a fourni les preuves épidémiologiques les plus robustes d'une association.

Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):202-213. doi: 10.1002/ajmg.b.32508. Epub 2016 Oct 22.

Paternal age and psychiatric disorders: A review

de Kluiver H^1,2, Buizer-Voskamp JE³, Dolan CV^1,2, Boomsma DI^1,2,4.

Author information

1

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

2

EMGO+ Institute for Health and Care Research, Amsterdam, The Netherlands.

3

Department of Social and Behavioral Sciences, Utrecht University, Utrecht, The Netherlands.

4

Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.

Abstract

We review the hypotheses concerning the association between the paternal age at childbearing and childhood psychiatric disorders (autism spectrum- and attention deficit/hyperactive disorder) and adult disorders (schizophrenia, bipolar-, obsessive-compulsive-, and major depressive disorder) based on epidemiological studies. Several hypotheses have been proposed to explain the paternal age effect. We discuss the four main-not mutually exclusive-hypotheses. These are the de novo mutation hypothesis, the hypothesis concerning epigenetic alterations, the selection into late fatherhood hypothesis, and the environmental resource hypothesis. Advanced paternal age in relation to autism spectrum disorders and schizophrenia provided the most robust epidemiological evidence for an association, with some studies reporting a monotonic risk increase over age, and others reporting a marked increase at a given age threshold. Although there is evidence for the de novo mutation hypothesis and the selection into late fatherhood hypothesis, the mechanism(s) underlying the association between advanced paternal age and psychiatric illness in offspring remains to be further clarified. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

© 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

PMID: 27770494

DOI: 10.1002/ajmg.b.32508

Age gestationnel et trouble du spectre de l'autisme: Tendances du risque dans le temps

Traduction: G.M.

Autism Res. 2015 Sep 12. doi: 10.1002/aur.1525.

Gestational Age and Autism Spectrum Disorder: Trends in Risk Over Time

Atladóttir HÓ¹, Schendel DE^1,2,3, Henriksen TB⁴, Hjort L^1,5, Parner ET⁶.

Author information

• ¹Department of Public Health, Section of Epidemiology, Aarhus University, Denmark.
• ²Department of Economics and Business, National Centre for Register-based Research, Aarhus University, Denmark.
• ³Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
• ⁴Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Denmark.
• ⁵Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Denmark.
• ⁶Department of Public Health, Section of Biostatistics, University of Aarhus, Denmark.

Abstract

Autism Spectrum Disorder (ASD) is a serious neurodevelopmental disorder. Several previous studies have identified preterm birth as a risk factor for ASD but none has studied whether the association between gestational age and ASD has changed over time. This is a Danish population-based follow-up study including live-born singletons born in Denmark between 1980 and 2009, identified in the Danish Medical Birth Registry, a study population of 1,775,397 children. We used a Cox regression model combined with spline to study the risk for ASD by gestational age across three decades of birth cohorts. We included 19,020 children diagnosed with ASD. 
Across all birth year cohorts, we found that the risk of being diagnosed with ASD increased with lower gestational age (P-value: <0.01). 
Across all gestational weeks, we found a statistically significant higher risk estimates in birth cohort 1980 to 1989, compared to birth cohorts 1990 to 1999 and 2000 to 2009, respectively. No statistically significant difference in risk estimates was observed between birth cohort 1990 to 1999 and 2000 to 2009. The observed time trend in risk of ASD after preterm birth may reflect: (1) a change in the risk profile of persons with ASD due to the broadening of ASD diagnostic criteria over time; or (2) improved neonatal care for low GA infants, which has reduced risk of adverse outcomes like ASD in preterm children. Autism Res 2015. 
Le troubles du spectre de l'autisme (TSA) est un trouble neurologique grave. Plusieurs études précédentes ont identifié des naissances prématurées comme un facteur de risque de TSA mais aucune n'a étudié si l'association entre l'âge gestationnel et le TSA  changeait au fil du temps. Ceci est une étude de suivi basée sur la population danoise, y compris des singletons nés vivants nés au Danemark entre 1980 et 2009, identifiés dans le registre médical des naissances danois, une population d'étude de 1,775,397 enfants. Nous avons utilisé un modèle de régression de Cox combiné avec spline pour étudier le risque de TSA par âge gestationnel à travers trois décennies de cohortes de naissance. Nous avons inclus 19,020 enfants diagnostiqués avec TSA.  
A travers toutes les cohortes de l'année de naissance, nous avons constaté que le risque d'être diagnostiqué avec TSA augmente avec l'âge gestationnel inférieur (P-valeur: <0,01).
A travers toutes les semaines de gestation, nous avons constaté un risque statistiquement significatif plus élevé dans la cohorte de naissance de 1980 à 1989, par rapport respectivement à des cohortes de naissance de 1990 à 1999 et de 2000 à 2009, . Aucune différence statistiquement significative dans les estimations du risque n'a été observée entre la cohorte de naissance 1990 à 1999 et de 2000 à 2009. 
La tendance observée de temps dans le risque de TSA après la naissance de prématurés peut refléter: 

1. un changement dans le profil de risque des personnes avec TSA en raison de l'élargissement des critères de diagnostic de TSA au fil du temps; ou 
2. l'amélioration des soins néonataux pour les nourrissons avec un faible âge gestationnel, qui a réduit le risque d'effets indésirables comme les TSA chez les enfants prématurés.

© 2015 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 26363410

Association of NCAM1 Polymorphisms with Autism and Parental Age at Conception in Chinese Han Population

Traduction: G.M.

Genet Test Mol Biomarkers. 2014 Aug 19. [Epub ahead of print]

Association des polymorphismes NCAM1 avec l'autisme et l'âge parental à la conception dans la population Han chinoise

Zhang J¹, Wang A, Li Y, Lu X, Wang F, Fang F.

Author information

• ¹Department of Neurology, Beijing Children's Hospital Affiliated to Capital Medical University , Beijing, People's Republic of China .

Abstract

Aims

The neural cell adhesion molecule (NCAM) has been reported to be involved in the development of the central nervous system and its mRNA level might decrease in the serum of autistic patients. However, there was no evidence of the association of the NCAM1 gene polymorphisms with autism. In the present study, we enrolled 237 children with autism and 451 healthy control subjects. Then, we used the direct DNA sequencing for genotyping five tag single-nucleotide polymorphisms (SNPs) in the NCAM1 gene. 

La molécule d'adhérence cellulaire neurale (NCAM) a été signalée comme étant impliquée dans le développement du système nerveux central et son niveau d'ARNm peut diminuer dans le sérum de patients autistes. Cependant, il n'y avait aucune preuve de l'association des polymorphismes du gène NCAM1 avec l'autisme.
Dans la présente étude, nous avons enrôlè 237 enfants avec autisme et 451 sujets témoins sans autisme. Ensuite, nous avons utilisé le séquençage direct de l'ADN pour le génotypage des polymorphismes de cinq étiquettes d'un nucléotide simple (SNP) dans le gène NCAM1.

Results

By using case-control association analyses, we found that three SNPs at the NCAM1 gene were associated with autism (rs4937786, p=0.015; rs12418058, p=0.0076; rs1436109, p=0.0023). Two of them remained significant after the Bonferroni multiple testing correction (rs12418058, pcorrcted=0.038; rs1436109, pcorrcted=0.012). Moreover, two of the SNPs were associated with the parental age at conception in autism (rs12418058, p=0.037; rs1436109, p=0.01).
En utilisant l'analyse de l'association de cas-témoins, nous avons constaté que trois SNP au niveau du gène NCAM1 ont été associés à l'autisme (rs4937786, p = 0,015; rs12418058, p = 0,0076; rs1436109, p = 0,0023). Deux d'entre eux sont restés significatifs après la correction de tests multiples de Bonferroni (de rs12418058, pcorrcted = 0,038; rs1436109, pcorrcted = 0,012). En outre, deux des SNPs ont été associés à l'âge des parents lors de la conception dans l'autisme (rs12418058, p = 0,037; rs1436109, p = 0,01).

Conclusion

These results showed that NCAM1 might play an important role in the pathogenesis of autism.
Ces résultats ont montré que NCAM1 pourrait jouer un rôle important dans la pathogenèse de l'autisme.  

PMID: 25137309