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01-03-2013 | Original Paper

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

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

Published in: NeuroMolecular Medicine | Issue 1/2013

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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Achenbach, T. M. (1991). Manual for the child behavioral checklist/4-18 and 1991 profile. Burlington, Vermont: University of Vermont Department of Psychiatry.

Arnsten, A. F., & Rubia, K. (2012). Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 51, 356–367.PubMedCrossRef

Bachmann, A. W., Sedgley, T. L., Jackson, R. V., Gibson, J. N., Young, R. M., & Torpy, D. J. (2005). Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology, 30, 297–306.PubMedCrossRef

Barkley, R. A. (1990). Attention deficit hyperactivity disorder: A handbook for diagnosis and treatment. New York: The Guilford Press.

Biederman, J., & Faraone, S. V. (2005). Attention-deficit hyperactivity disorder. Lancet, 366, 237–248.PubMedCrossRef

Chrousos, G. P., Charmandari, E., & Kino, T. (2004). Glucocorticoid action networks–an introduction to systems biology. The Journal of clinical endocrinology and metabolism, 89, 563–564.PubMedCrossRef

Claes, S. (2009). Glucocorticoid receptor polymorphisms in major depression. Annals of the New York Academy of Sciences, 1179, 216–228.PubMedCrossRef

Conners, C. K. (1985). The computerized continuous performance test. Psychopharmacology Bulletin, 21, 891–892.PubMed

Conners, C. K., Sitarenios, G., Parker, J. D., & Epstein, J. N. (1998a). Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): factor structure, reliability, and criterion validity. Journal of Abnormal Child Psychology, 26, 279–291.PubMedCrossRef

Conners, C. K., Sitarenios, G., Parker, J. D., & Epstein, J. N. (1998b). The revised Conners’ Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. Journal of Abnormal Child Psychology, 26, 257–268.PubMedCrossRef

Corominas, M., Ramos-Quiroga, J. A., Ferrer, M., Saez-Francas, N., Palomar, G., Bosch, R., et al. (2012). Cortisol responses in children and adults with attention deficit hyperactivity disorder (ADHD): A possible marker of inhibition deficits. Attention Deficit and Hyperactivity Disorders, 4, 63–75.PubMedCrossRef

de Kloet, E. R., Oitzl, M. S., & Joels, M. (1999). Stress and cognition: are corticosteroids good or bad guys? Trends in Neurosciences, 22, 422–426.PubMedCrossRef

de Kloet, E. R., Joels, M., & Holsboer, F. (2005). Stress and the brain: from adaptation to disease. Nature Reviews Neuroscience, 6, 463–475.PubMedCrossRef

DeRijk, R. H., & de Kloet, E. R. (2008). Corticosteroid receptor polymorphisms: Determinants of vulnerability and resilience. European Journal of Pharmacology, 583, 303–311.PubMedCrossRef

DeRijk, R. H., Wust, S., Meijer, O. C., Zennaro, M. C., Federenko, I. S., Hellhammer, D. H., et al. (2006). A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. Journal of Clinical Endocrinology and Metabolism, 91, 5083–5089.PubMedCrossRef

Ehrich, M., Bocker, S., & van den Boom, D. (2005). Multiplexed discovery of sequence polymorphisms using base-specific cleavage and MALDI-TOF MS. Nucleic Acids Research, 33, e38.PubMedCrossRef

Faraone, S. V., Perlis, R. H., Doyle, A. E., Smoller, J. W., Goralnick, J. J., Holmgren, M. A., et al. (2005). Molecular genetics of attention-deficit/hyperactivity disorder. Biological Psychiatry, 57, 1313–1323.PubMedCrossRef

Fischer, M., & Newby, R. F. (1998). Use of the restricted academic task in ADHD dose-response relationships. Journal of Learning Disabilities, 31, 608–612.PubMedCrossRef

Freitag, C. M., Hanig, S., Palmason, H., Meyer, J., Wust, S., & Seitz, C. (2009). Cortisol awakening response in healthy children and children with ADHD: Impact of comorbid disorders and psychosocial risk factors. Psychoneuroendocrinology, 34, 1019–1028.PubMedCrossRef

Grizenko, N., Bhat, M., Schwartz, G., Ter-Stepanian, M., & Joober, R. (2006). Efficacy of methylphenidate in children with attention-deficit hyperactivity disorder and learning disabilities: A randomized crossover trial. Journal of Psychiatry and Neuroscience, 31, 46–51.PubMed

Gruber, R., Grizenko, N., Schwartz, G., Bellingham, J., Guzman, R., & Joober, R. (2007). Performance on the continuous performance test in children with ADHD is associated with sleep efficiency. Sleep, 30, 1003–1009.PubMed

Hastings, P. D., Fortier, I., Utendale, W. T., Simard, L. R., & Robaey, P. (2009). Adrenocortical functioning in boys with attention-deficit/hyperactivity disorder: examining subtypes of ADHD and associated comorbid conditions. Journal of Abnormal Child Psychology, 37, 565–578.PubMedCrossRef

Heaton, R. K., Chelune, G. J., Talley, J. L., Kay, G. G., & Curtiss, G. (1993). The Wisconsin card sorting test manual-revised and expanded. Odessa, Florida: Psychological Assessment Resources.

Huizenga, N. A., Koper, J. W., de Lange, P., Pols, H. A., Stolk, R. P., Grobbee, D. E., et al. (1998). Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. Journal of Clinical Endocrinology and Metabolism, 83, 47–54.PubMedCrossRef

Karama, S., Ben, A. L., Grizenko, N., Ciampi, A., Mbekou, V., Ter-Stepanian, M., et al. (2009). Factor structure of the restricted academic situation scale: implications for ADHD. Journal of Attention Disorders, 12, 442–448.PubMedCrossRef

King, J. A., Barkley, R. A., & Barrett, S. (1998). Attention-deficit hyperactivity disorder and the stress response. Biological Psychiatry, 44, 72–74.PubMedCrossRef

Kirschbaum, C., Pirke, K. M., & Hellhammer, D. H. (1993). The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology, 28, 76–81.PubMedCrossRef

Koper, J. W., Stolk, R. P., de Lange, P., Huizenga, N. A., Molijn, G. J., Pols, H. A., et al. (1997). Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Human Genetics, 99, 663–668.PubMedCrossRef

Kortmann, G. L., Contini, V., Bertuzzi, G. P., Mota, N. R., Rovaris, D. L., Paixao-Cortes, V. R., de Lima, L. L., Grevet, E. H., Salgado, C. A., Vitola, E. S., Rohde, L. A., Belmonte-de-Abreu P., & Bau, C. H. (2012) The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD. European Archives of Psychiatry and Clinical Neuroscience. Epub ahead of print.

Kudielka, B. M., Hellhammer, D. H., & Wust, S. (2009). Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge. Psychoneuroendocrinology, 34, 2–18.PubMedCrossRef

Kumsta, R., Entringer, S., Koper, J. W., van Rossum, E. F., Hellhammer, D. H., & Wust, S. (2007). Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress. Biological Psychiatry, 62, 863–869.PubMedCrossRef

Laird, N. M., Horvath, S., & Xu, X. (2000). Implementing a unified approach to family-based tests of association. Genetic Epidemiology, 19(Suppl 1), S36–S42.PubMedCrossRef

Lu, N. Z., & Cidlowski, J. A. (2004). The origin and functions of multiple human glucocorticoid receptor isoforms. Annals of the New York Academy of Science, 1024, 102–123.CrossRef

Lupien, S. J., Maheu, F., Tu, M., Fiocco, A., & Schramek, T. E. (2007). The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition. Brain and Cognition, 65, 209–237.PubMedCrossRef

Ma, L., Chen, Y. H., Chen, H., Liu, Y. Y., & Wang, Y. X. (2011). The function of hypothalamus-pituitary-adrenal axis in children with ADHD. Brain Research, 1368, 159–162.PubMedCrossRef

Manenschijn, L., van den Akker, E. L., Lamberts, S. W., & van Rossum, E. F. (2009). Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Annals of the New York Academy of Sciences, 1179, 179–198.PubMedCrossRef

Oosterlaan, J., Geurts, H. M., Knol, D. L., & Sergeant, J. A. (2005). Low basal salivary cortisol is associated with teacher-reported symptoms of conduct disorder. Psychiatry Research, 134, 1–10.PubMedCrossRef

Petrides, M., & Milner, B. (1982). Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia, 20, 249–262.PubMedCrossRef

Rabinowitz, D., & Laird, N. (2000). A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Human Heredity, 50, 211–223.PubMedCrossRef

Randazzo, W. T., Dockray, S., & Susman, E. J. (2008). The stress response in adolescents with inattentive type ADHD symptoms. Child Psychiatry and Human Development, 39, 27–38.PubMedCrossRef

Rohleder, N., Wolf, J. M., & Kirschbaum, C. (2003). Glucocorticoid sensitivity in humans-interindividual differences and acute stress effects. Stress, 6, 207–222.PubMedCrossRef

Russcher, H., Smit, P., van den Akker, E. L., van Rossum, E. F., Brinkmann, A. O., de Jong, F. H., et al. (2005). Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression. The Journal of Clinical Endocrinology and Metabolism, 90, 5804–5810.PubMedCrossRef

Scerbo, A. S., & Kolko, D. J. (1994). Salivary testosterone and cortisol in disruptive children: relationship to aggressive, hyperactive, and internalizing behaviors. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 1174–1184.PubMedCrossRef

Sengupta, S., Grizenko, N., Schmitz, N., Schwartz, G., Bellingham, J., Polotskaia, A., et al. (2008). COMT Val108/158Met polymorphism and the modulation of task-oriented behavior in children with ADHD. Neuropsychopharmacology, 33, 3069–3077.PubMedCrossRef

Sengupta, S. M., Grizenko, N., Thakur, G. A., Bellingham, J., Deguzman, R., Robinson, S., et al. (2012). Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype. Journal of Psychiatry and Neuroscience, 37, 129–137.PubMedCrossRef

Shallice, T. (1982). Specific impairments of planning. Philosophical Transactions of the Royal Society of London. Series B, 298, 199–209.PubMedCrossRef

Sheslow, D., & Adams, W. (1990). Wide range assessment of memory and learning: Administration manual. Wilmington, DE: Jastak.

Shin, D. W., & Lee, S. H. (2007). Blunted hypothalamo-pituitary-adrenal axis reactivity is associated with the poor intelligence performance in children with attention-deficit/hyperactivity disorder. Neuropediatrics, 38, 298–303.PubMedCrossRef

Snoek, H., Van Goozen, S. H., Matthys, W., Buitelaar, J. K., & van Engeland, H. (2004). Stress responsivity in children with externalizing behavior disorders. Development and Psychopathology, 16, 389–406.PubMedCrossRef

Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993). Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). American Journal of Human Genetics, 52, 506–516.PubMed

Stephens, M., Smith, N. J., & Donnelly, P. (2001). A new statistical method for haplotype reconstruction from population data. American Journal of Human Genetics, 68, 978–989.PubMedCrossRef

Stergiakouli, E., & Thapar, A. (2010). Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatric Disease and Treatment, 6, 551–560.PubMedCrossRef

Taerk, E., Grizenko, N., Ben Amor, L., Lageix, P., Mbekou, V., Deguzman, R., et al. (2004). Catechol-O-methyltransferase (COMT) Val108/158 Met polymorphism does not modulate executive function in children with ADHD. BMC Medical Genetics, 5, 30.PubMedCrossRef

Thapar, A., Langley, K., O’Donovan, M., & Owen, M. (2006). Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies. Molecular Psychiatry, 11, 714–720.PubMedCrossRef

van den Akker, E. L., Nouwen, J. L., Melles, D. C., van Rossum, E. F., Koper, J. W., Uitterlinden, A. G., et al. (2006). Staphylococcus aureus nasal carriage is associated with glucocorticoid receptor gene polymorphisms. Journal of Infectious and Diseases, 194, 814–818.CrossRef

van Leeuwen, N., Kumsta, R., Entringer, S., de Kloet, E. R., Zitman, F. G., DeRijk, R. H., et al. (2010). Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone. Psychoneuroendocrinology, 35, 339–349.PubMedCrossRef

van Leeuwen, N., Bellingrath, S., de Kloet, E. R., Zitman, F. G., DeRijk, R. H., Kudielka, B. M., et al. (2011). Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response. Psychoneuroendocrinology, 36, 699–709.PubMedCrossRef

van Rossum, E. F., Koper, J. W., Huizenga, N. A., Uitterlinden, A. G., Janssen, J. A., Brinkmann, A. O., et al. (2002). A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels 920. Diabetes, 51, 3128–3134.PubMedCrossRef

van Rossum, E. F., Binder, E. B., Majer, M., Koper, J. W., Ising, M., Modell, S., et al. (2006). Polymorphisms of the glucocorticoid receptor gene and major depression. Biological Psychiatry, 59, 681–688.PubMedCrossRef

van West, D., Claes, S., & Deboutte, D. (2009). Differences in hypothalamic-pituitary-adrenal axis functioning among children with ADHD predominantly inattentive and combined types. European Child and Adolescent Psychiatry, 18, 543–553.PubMedCrossRef

Wechsler, D. (1991). Manual for the wechsler intelligence scale for children (3rd ed.). Oxford (UK): The Psychological Corporation.

Willcutt, E. G., Doyle, A. E., Nigg, J. T., Faraone, S. V., & Pennington, B. F. (2005). Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review. Biological Psychiatry, 57, 1336–1346.PubMedCrossRef

Wust, S., van Rossum, E. F., Federenko, I. S., Koper, J. W., Kumsta, R., & Hellhammer, D. H. (2004). Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. Journal of Clinical Endocrinology and Metabolism, 89, 565–573.PubMedCrossRef

Title: Genetic Evidence for the Association of the Hypothalamic–Pituitary–Adrenal (HPA) Axis with ADHD and Methylphenidate Treatment Response
Authors: Marie-Ève Fortier
Sarojini M. Sengupta
Natalie Grizenko
Zia Choudhry
Geeta Thakur
Ridha Joober
Publication date: 01-03-2013
Publisher: Humana Press Inc
Published in: NeuroMolecular Medicine / Issue 1/2013
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-012-8202-1

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

Abstract

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Abstract

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