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Impact of autism-associated genetic variants in interaction with environmental factors on ADHD comorbidities: an exploratory pilot study

  • Regina Waltes
  • Christine M. Freitag
  • Timo Herlt
  • Thomas Lempp
  • Christiane Seitz
  • Haukur Palmason
  • Jobst Meyer
  • Andreas G. ChiocchettiEmail author
Psychiatry and Preclinical Psychiatric Studies - Original Article

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is determined by genetic and environmental factors, and shares genetic risk with ASD. Functional single-nucleotide polymorphisms of the metabotropic glutamatergic signaling pathway are reported to increase the risk for ASD. The aim of this pilot study was to explore the main effects of respective ASD variants as well as their interaction effects with well-replicated ADHD environmental risk factors on the risk for ADHD, ADHD symptom severities, and comorbidities. We included 318 children with ADHD, aged 5–13 years, and their parents (N = 164 trios, N = 113 duos, N = 41 singletons). Interaction of ASD risk variants CYFIP1-rs7170637, CYFIP1-rs3693, CAMK4-rs25925, and GRM1-rs6923492 with prenatal biological and lifetime psychosocial risk factors was explored in a subsample with complete environmental risk factors (N = 139 trios, N = 83 duos, two singletons) by transmission disequilibrium test and stepwise regression analyses. We identified nominally significant (alpha < 0.05) GxE interactions of acute life events with CYFIP1-rs3693 on ADHD diagnosis (p = 0.004; fdr = 0.096) but no significant association of any single marker. Further results suggest that the risk for comorbid disruptive disorders was significantly modulated by GxE interactions between familial risk factors and CAMK4-rs25925 (p = 0.001; fdr = 0.018) and prenatal alcohol exposure with CYFIP1-rs3693 (p = 0.003; fdr = 0.027); both findings survived correction for multiple testing (fdr value < 0.05). Nominal significant GxE interactions moderating the risk for anxiety disorders have also been identified, but did not pass multiple testing corrections. This pilot study suggests that common ASD variants of the glutamatergic system interact with prenatal and lifetime psychosocial risk factors influencing the risk for ADHD common comorbidities and thus warrants replication in larger samples.

Keywords

ADHD subtypes Comorbidities Environment Glutamatergic variants ODD/CD Anxiety 

Notes

Acknowledgements

We thank all patients and their families for taking part in this study. In addition, we thoroughly thank Silvia Lindlar and Hiacynta Jelen for excellent technical assistance and Heiko Zerlaut for database management.

Funding

This work was supported by the EC Seventh Framework funded Grant No. 602407-FemNAT-CD to CMF, the EC H2020 funded Grant No. 667302-CoCA to CMF, the EC funded ITN 643051-MIND to CMF, and the German Research Foundation (Deutsche Forschungsgemeinschaft DFG) funded Grants ME 1923/5-1, ME 1923/5-3 to JM and CMF, and GRK 1389/1 to JM.

Compliance with ethical standards

Conflicts of interest

CMF has served as consultant for Desitin and Roche, and receives royalties for books on ADHD, ASD, and MDD. TL receives royalties for a textbook on child and adolescent psychiatry. The other authors do not report any possible conflicts of interest.

Supplementary material

702_2019_2101_MOESM1_ESM.docx (112 kb)
Supplementary material 1 (DOCX 112 kb)

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© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital FrankfurtJW Goethe UniversityFrankfurt am MainGermany
  2. 2.Department of Child and Adolescent Psychiatry and PsychotherapySaarland University HospitalHomburgGermany
  3. 3.Department of Neurobehavioral Genetics, Institute of PsychobiologyUniversity of TrierTrierGermany

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