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Genetic Evidence for the Association of the Hypothalamic–Pituitary–Adrenal (HPA) Axis with ADHD and Methylphenidate Treatment Response

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Abstract

Exposure to stressors results in a spectrum of autonomic, endocrine, and behavioral responses. A key pathway in this response to stress is the hypothalamic–pituitary–adrenal (HPA) axis, which results in a transient increase in circulating cortisol, which exerts its effects through the two related ligand-activated transcription factors: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Genetic polymorphisms in these receptors have been shown to influence HPA axis reactivity, and chronic dysregulation of the HPA axis has been associated with the development of several psychiatric disorders. The objective of the study was to test the association between four functional polymorphisms in NR3C1 (encoding GR: ER22/23EK-rs6189, N363S-rs6195, BclI-rs41423247, A3669G-rs6198) and two in NR3C2 (encoding MR: 215G/C-rs2070951, I180 V-rs5522) with childhood ADHD. Family-based association tests (FBAT) were conducted with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, as well as with treatment response assessed in a 2-week, double-blind, placebo-controlled trial with methylphenidate. A specific haplotype (G:A:G:G; ER22/23EK- N363S- BclI- A3669G) of NR3C1 showed a significant association with behaviors related to ADHD (particularly thought and attention problems, aggressive behavior), comorbidity with oppositional defiant disorder, and executive function domains. An association was also observed with treatment response (assessed by the Conners’-Teachers and Restricted Academic Situation Scale). In contrast, MR gene polymorphisms were not associated with any of the variables tested. To the best of our knowledge, this is the first report showing an association between functional polymorphisms in NR3C1 and ADHD, providing genetic evidence for involvement of the HPA axis in the disorder and treatment response.

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Acknowledgments

This work was supported in part by grants from the Fonds de la recherche en santé du Québec and the Canadian Institutes of Health Research to RJ and NG. MEF is a recipient of the 2011 Claude-Laberge scholarship from the Réseau de medicine génétique appliquée. SMS is a recipient of the 2008 NARSAD Young Investigator and 2009 Dr. Mortimer D. Sackler Developmental Psychology Investigator Awards. We thank Johanne Bellingham, Sandra Robinson, Jacqueline Richard, Phuong-Thao Nguyen, Matthew Lebaron, Nicole Pawliuk, and Sharon Hill for technical and clinical assistance and a special word of thanks to the families who participated in the research.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Douglas Mental Health University Institute, 6875 LaSalle Blvd, Verdun, QC, H4H 1R3, Canada

    Marie-Ève Fortier, Sarojini M. Sengupta, Natalie Grizenko, Zia Choudhry, Geeta Thakur & Ridha Joober

  2. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Marie-Ève Fortier, Sarojini M. Sengupta, Natalie Grizenko & Ridha Joober

  3. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Zia Choudhry & Ridha Joober

  4. Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada

    Geeta Thakur & Ridha Joober

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  1. Marie-Ève Fortier
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  2. Sarojini M. Sengupta
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Correspondence to Sarojini M. Sengupta.

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Marie-Ève Fortier and Sarojini M. Sengupta have contributed equally to the manuscript.

Natalie Grizenko and Ridha Joober have contributed equally to the research design and collection of data.

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Fortier, MÈ., Sengupta, S.M., Grizenko, N. et al. Genetic Evidence for the Association of the Hypothalamic–Pituitary–Adrenal (HPA) Axis with ADHD and Methylphenidate Treatment Response. Neuromol Med 15, 122–132 (2013). https://doi.org/10.1007/s12017-012-8202-1

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