Skip to main content
SpringerLink
Log in

Interactive Effects of Prenatal Antidepressant Exposure and Likely Gene Disrupting Mutations on the Severity of Autism Spectrum Disorder

  • Original Paper
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

An Erratum to this article was published on 08 September 2017

This article has been updated

Abstract

To examine the interactive effects of two proposed risk factors which may contribute to symptom severity of Autism Spectrum Disorder (ASD): prenatal antidepressant exposure and likely gene-disrupting (LGD) mutations. Participants included 2748 individuals with ASD from the Simons Simplex Collection. We examined the effects of prenatal antidepressant exposure, maternal depression, presence of an LGD mutation and their interaction on ASD severity. We found a significant interactive effect between antidepressant exposure and the presence of an LGD mutation on ASD severity in the ADOS and ADI-R verbal communication domains. We consider a “two-hit” model in which one variable lays the foundation for an initial risk which is compounded by a second variable.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Change history

  • 08 September 2017

    An erratum to this article has been published.

References

  • American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th edn.). Arlington, VA: American Psychiatric Publishing.

    Book  Google Scholar 

  • Atladóttir HÓ, Henriksen, T. B., Schendel, D. E., et al. (2012). Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study. Pediatrics, 130(6), e1447–e1454.

    Article  PubMed  PubMed Central  Google Scholar 

  • Boukhris, T., Sheehy, O., Mottron, L., et al. (2015). Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatrics, 170(2), 117–124.

    Article  Google Scholar 

  • Chaste, P., & Leboyer, M. (2012). Autism risk factors: Genes, environment, and gene-environment interactions. Dialogues in Clinical Neuroscience, 14(3), 281–292.

    PubMed  PubMed Central  Google Scholar 

  • Cooper, W. O., Willy, M. E., Pont, S. J., & Ray, W. A. (2007). Increasing use of antidepressants in pregnancy. American Journal of Obstetrics and Gynecology, 196(6), 544.e1-5.

    Article  PubMed  Google Scholar 

  • Croen, L. A., Grether, J. K., Yoshida, C. K., et al. (2011). Antidepressant use during pregnancy and childhood autism spectrum disorders. Archives of General Psychiatry, 68(11), 1104–1112.

    Article  PubMed  Google Scholar 

  • Fischbach, G. D., & Lord, C. (2010). The Simons Simplex Collection: A resource for identification of autism genetic risk factors. Neuron, 68(2), 192–195.

    Article  PubMed  Google Scholar 

  • Gardener, H., Spiegelman, D., & Buka, S. L. (2009). Prenatal risk factors for autism: Comprehensive meta-analysis. The British Journal of Psychiatry, 195(1), 7–14.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gentile, S. (2015). Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? Journal of Affective Disorders, 182, 132–137.

    Article  PubMed  Google Scholar 

  • Gidaya, N. B., Lee, B. K., Burstyn, I., et al. (2014). In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. Journal of Autism and Developmental Disorders, 44(10), 2558–2567.

    Article  PubMed  Google Scholar 

  • Girirajan, S., Dennis, M. Y., Baker, C., et al. (2013). Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. American Journal of Human Genetics, 92(2), 221–237.

    Article  PubMed  PubMed Central  Google Scholar 

  • Girirajan, S., & Eichler, E. E. (2010). Phenotypic variability and genetic susceptibility to genomic disorders. Human Molecular Genetics, 19(R2), R176–R187.

    Article  PubMed  PubMed Central  Google Scholar 

  • Girirajan, S., Rosenfeld, J. A., Coe, B. P., et al. (2012). Phenotypic heterogeneity of genomic disorders and rare copy-number variants. The New England Journal of Medicine, 367(14), 1321–1331.

    Article  PubMed  PubMed Central  Google Scholar 

  • Girirajan, S., Rosenfeld, J. A., Cooper, G. M., Antonacci, F., et al. (2010). A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics, 42, 203–209.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gotham, K., Pickles, A., & Lord, C. (2009). Standardizing ADOS scores for a measure of severity in autism spectrum disorders. Journal of Autism and Developmental Disorders, 39(5), 693–705.

    Article  PubMed  Google Scholar 

  • Hanson, E., Bernier, R., Porche, K., et al. (2015). Simons Variation in Individuals Project Consortium. The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population. Biological Psychiatry, 77(9), 785–793.

    Article  PubMed  Google Scholar 

  • Harrington, R. A., Lee, L. C., Crum, R. M., et al. (2014). Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay. Pediatrics 133(5), 1241–1248.

    Article  Google Scholar 

  • Hus, V., Gotham, K., & Lord, C. (2014). Standardizing ADOS domain scores: Separating severity of social affect and restricted and repetitive behaviors. Journal of Autism and Developmental Disorders, 44(10), 2400–2412.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hviid, A., Melbye, M., & Pasternak, B. (2013). Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. The New England Journal of Medicine, 369(25), 2406–2415.

    Article  PubMed  Google Scholar 

  • Iossifov I, O’Roak BJ, Sanders SJ, et al. (2014). The contribution of de novo coding mutations to autism spectrum disorder. Nature 515(7526):216–221.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kalkbrenner, A. E., Windham, G. C., Serre, M. L., et al. (2015). Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders. Epidemiology 26(1), 30–42.

    Article  PubMed  Google Scholar 

  • Krumm, N., O’Roak, B. J., Shendure, J., et al. (2014). A de novo convergence of autism genetics and molecular neuroscience. Trends in Neurosciences, 37(2), 95–105.

    Article  PubMed  Google Scholar 

  • Landrigan, P. J. (2010). What causes autism? Exploring the environmental contribution. Current Opinion in Pediatrics 22(2), 219–225.

    Article  PubMed  Google Scholar 

  • Leblond, C. S., Heinrich, J., Delorme, R., et al. (2012). Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genetics, 8(2), e1002521.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lord, C., Risi, S., Lambrecht, L., et al. (2000). The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223.

    Article  PubMed  Google Scholar 

  • Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24(5), 659–685.

    Article  PubMed  Google Scholar 

  • Man, K. K., Tong, H. H., Wong, L. Y., et al. (2015). Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies. Neuroscience and Biobehavioral Reviews, 49, 82–89.

    Article  PubMed  Google Scholar 

  • Mazina, V., et al. (2015a). Interactive effects of copy number variation and maternal infection on autism impairment. Journal of Developmental and Behavioral Pediatrics: JDBP, 36(2), 61–67.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mazina, V., Gerdts, J., Trinh, S., et al. (2015b). Epigenetics of autism-related impairment: Copy number variation and maternal infection. Journal of Developmental and Behavioral Pediatrics: JDBP, 36(2), 61–67.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitchell, A. A., Gilboa, S. M., Werler, M. M., et al. (2011). Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. American Journal of Obstetrics and Gynecology, 205(51), e1.

    Google Scholar 

  • O’Roak, B. J., Vives, L., Girirajan, S., et al. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485(7397), 246–250.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rai D, Lee BK, Dalman C, et al. (2013). Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: Population based case-control study. BMJ 346, f2059.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., et al. (2011). Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron, 70(5), 863–885.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sanders, S. J., He, X., Willsey, A. J., Ercan-Sencicek, A. G., et al. (2015). Insights into autism spectrum disorder genomic architecture and biology from 71 Risk Loci. Neuron, 87(6), 1215–1233.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shelton, J. F., Geraghty, E. M., Tancredi, D. J., et al. (2014). Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study. Environmental Health Perspectives, 122(10), 1103–1109.

    PubMed  PubMed Central  Google Scholar 

  • Shishido, E., Aleksic, B., & Ozaki, N. (2014). Copy-number variation in the pathogenesis of autism spectrum disorder. Psychiatry and Clinical Neurosciences, 68(2), 85–95.

    Article  PubMed  Google Scholar 

  • Sorensen, M. J., Gronborg, T. K., Christensen, J., et al. (2013). Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clinical Epidemiology 15(5), 449–459.

    Article  Google Scholar 

  • Stefansson, H., Meyer-Lindenberg, A., Steinberg, S., et al. (2014). CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature, 505(7483):361.

    Article  PubMed  Google Scholar 

  • Stessman, H. A., Xiong, B., Coe, B. P., et al. (2017). Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nature Genetics, 49(4), 515–526.

    Article  PubMed  PubMed Central  Google Scholar 

  • Viktorin, A., Uher, R., Reichenberg, A., et al. (2017). Autism risk following antidepressant medication during pregnancy. Psychological Medicine, 22, 1–10.

    Article  Google Scholar 

  • Weiss, L. A., Shen, Y., Korn, J. M., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. The New England Journal of Medicine, 358(7), 667–675.

    Article  PubMed  Google Scholar 

  • Zimmerberg, B., & Germeyan, S. C. (2015). Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait. Developmental Psychobiology, 57(2), 141–152.

    Article  PubMed  Google Scholar 

  • Zufferey, F., Sherr, E. H., Beckmann, N. D., et al. (2012). A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 49(10), 660–668.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base.

Author contributions

SA participated in study design and coordination, and drafted the manuscript; SS participated in the interpretation of the data and the early manuscript drafts; CH performed the statistical analysis; RB conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.

Funding

This work was supported by a grant from the Simons Foundation (SFARI #89368) and from the National Institute of Mental Health (#01MH100047 to R.B.). This study was funded by the Medical Student Research Training Program (MSRTP), University of Washington School of Medicine, Seattle, WA. The funding source did not participate in any part of the performance of the study.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Child & Adolescent Psychiatry, SSM Dean Medical Group, 1313 Fish Hatchery Rd, Madison, WI, 53715, USA

    Sean Ackerman

  2. School of Medicine, University of Washington, Seattle, WA, USA

    Sarah Schoenbrun

  3. Department of Psychiatry, University of Washington, Seattle, WA, USA

    Caitlin Hudac

  4. Department of Psychiatry and Center on Human Development and Disability, University of Washington, Seattle, WA, USA

    Raphael Bernier

Authors
  1. Sean Ackerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Schoenbrun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caitlin Hudac
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raphael Bernier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sean Ackerman.

Ethics declarations

Conflict of interest

All authors report no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Additional information

The original version of this article was revised: The spelling of the co-author Sarah Schoenbrun was misspelled. This has been corrected in this version.

Approved researchers can obtain the SSC population dataset described in this study by applying at https://base.sfari.org.

An erratum to this article is available at https://doi.org/10.1007/s10803-017-3301-3.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ackerman, S., Schoenbrun, S., Hudac, C. et al. Interactive Effects of Prenatal Antidepressant Exposure and Likely Gene Disrupting Mutations on the Severity of Autism Spectrum Disorder. J Autism Dev Disord 47, 3489–3496 (2017). https://doi.org/10.1007/s10803-017-3246-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-017-3246-6

Keywords

Search

Navigation