Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

Abstract

Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p = 0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p = 0.002), and Restrictive/Repetitive Behavior score (p = 0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p = 0.01 and SNAP ADHD p = 0.03), replicating a previous finding. We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD.

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Acknowledgements

The authors are grateful to Gloria Smith for assistance with sample preparation and to the participating families for volunteering for this research.

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Correspondence to Michael G. Aman.

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Funding

This work was supported by grants from: the National Institute of General Medical Sciences (U01GM092655), Center for Clinical and Translational Science at The Ohio State University (ARRA Pilot Project UL1 RR025755 project 60023888), National Institute of Mental Health to Ohio State University (5R01MH079080), University of Pittsburgh (5R01MH079082–05), and University of Rochester (5R01 MH083247), by Eli Lilly and Co., who provided atomoxetine and placebo, the National Center for Research Resources [University of Rochester CTSA (UL1 RR024160), Ohio State University CTSA (UL1TR001070)] and the National Center for Advancing Translational Sciences of the National Institutes of Health and the United States Air Force Department of Defense (FA7014–09–2-0004 and FA8650–12–2-6359). We are grateful to all the families participating in the CORA registry. The views and opinions expressed in this article are those of the author(s) and do not reflect official policy or position of the National Institutes of Health (NIH), United State Air Force, Department of Defense, or US Government. The use of product(s) and/or manufacturer name(s) is added for clarification only; in no way implies endorsement by the authors, USAF, or DoD of the product(s) or manufacturer(s). The funders have not imposed any restrictions on free access to or publication of the research data.

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

This study was approved by the institutional review boards at all sites; parents/legal guardians of all participants signed informed consent documents, and children assented if able to do so.

Conflicts of Interest

Dr. Elizabeth Barrie declares that she has no conflict of interest.

Dr. Julia K. Pinsonneault received research funding from the Center for Clinical and Translational Science at The Ohio State University.

Dr. Wolfgang Sadee received research funding from the National Institute of General Medical Sciences.

Dr. Jill Hollway has received research contracts from Forest Research Institute, Supernus Pharmaceuticals, Sunovion Pharmaceuticals, Young Living Essential Oils, and Hoffman-La-Roche.

Dr. Tristram Smith has received research funding from the National Center for Research Resources and the National Institute of Mental Health.

Dr. Benjamin Handen has received research funding from Curemark, Autism Speaks, Eli Lilly and Co., Roche and the National Institute of Mental Health.

Dr. L. Eugene Arnold has received research funding from Curemark, Forest, Lilly, Neuropharm, Novartis, Noven, Shire, Supernus, and YoungLiving (as well as NIH and Autism Speaks), has consulted with Gowlings, Neuropharm, Organon, Pfizer, Sigma Tau, Shire, Tris Pharma, and Waypoint, been on advisory boards for Arbor, Ironshore, Novartis, Noven, Otsuka, Pfizer, Roche, Seaside Therapeutics, Sigma Tau, Shire, and received travel support from Noven.

Dr. Eric Butter has received research funding from CogState, Bracket, Autism Speaks, the Simons Foundation, and Roche.

Ms. Emily Hansen-Kiss, LGC declares that she has no conflict of interest.

Dr. Gail E. Herman has received research funding from the National Center for Advancing Translational Sciences of the National Institutes of Health and the United States Air Force Department of Defense.

Dr. Michael Aman has received research contracts, consulted with, served on advisory boards, or done investigator training for Aevi Genomic Medicine, AMO Pharma, CogState, Inc.; CogState Clinical Trials, Ltd.; Coronado Biosciences; Forest Research; Hoffman-La Roche; Johnson and Johnson; Lumos Pharma, MedAvante, Inc.; Ovid Therapeutics, ProPhase LLC; and Supernus Pharmaceuticals. He also received research funding from the National Institute of Mental Health, and the Ohio State University CTSA.

Glossary of Genetic Terms

Allele

a version of the gene, each inherited from a different parent.

Heterozygous

a genotype of two different alleles at a given SNP, also referred to as carrier.

Homozygous

a genotype where both alleles are the same at a given SNP.

Major allele

the allele that is most frequent in the general population.

Minor allele

the allele that is less frequently observed in the population.

SNP

single nucleotide polymorphism, also referred to as genetic variant.

Wild-type

homozygous for the major allele.

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Barrie, E.S., Pinsonneault, J.K., Sadee, W. et al. Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD. J Dev Phys Disabil 30, 355–371 (2018). https://doi.org/10.1007/s10882-018-9590-4

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Keywords

  • Autism spectrum disorder (ASD)
  • Genetics
  • Restrictive and repetitive behavior
  • Atomoxetine (Strattera)
  • Tryptophan hydroxylase 2 (TPH2)
  • Dopamine transporter (DAT
  • SLC6A3)
  • Attention deficit/hyperactivity disorder (ADHD)