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European Child & Adolescent Psychiatry

, Volume 19, Issue 1, pp 67–74 | Cite as

Adenosine A2A receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder

  • Christine M. Freitag
  • Konstantin Agelopoulos
  • Ellen Huy
  • Matthias Rothermundt
  • Petra Krakowitzky
  • Jobst Meyer
  • Jürgen Deckert
  • Alexander von Gontard
  • Christa Hohoff
Original Contribution

Abstract

Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A2A receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A2A receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.

Keywords

Autism spectrum disorder ADORA2A Anxiety Basal ganglia Caudate nucleus Glutamate 

Notes

Acknowledgments

We thank the participating individuals for taking part in the study. The study was supported by grant T6 03 10 00-45 of the Saarland University to Christine M. Freitag.

Conflict of interest statement

None of the authors has any conflicts of interest.

References

  1. 1.
    Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 28:1694–1702CrossRefPubMedGoogle Scholar
  2. 2.
    American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (DSM-IV), 4th edn. American Psychiatric Association, Washington, DCGoogle Scholar
  3. 3.
    Baird G, Simonoff E, Pickles A, Chandler S, Loucas T, Meldrum D, Charman T (2006) Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the special needs and autism project (SNAP). Lancet 368:210–215CrossRefPubMedGoogle Scholar
  4. 4.
    Bolte S, Poustka F (2004) The German form of the autism diagnostic observation schedule (ADOS): first results on reliability and validity. Zeitschrift fur Kinder-und Jugendpsychiatrie und Psychotherapie 32:45–50CrossRefPubMedGoogle Scholar
  5. 5.
    Chen JF, Moratalla R, Impagnatiello F, Grandy DK, Cuellar B, Rubinstein M, Beilstein MA, Hackett E, Fink JS, Low MJ, Ongini E, Schwarzschild MA (2001) The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice. Proc Natl Acad Sci USA 98:1970–1975CrossRefPubMedGoogle Scholar
  6. 6.
    Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 33:2791–2800CrossRefPubMedGoogle Scholar
  7. 7.
    Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, Knapp M, Maier W, Beckmann H, Propping P (1998) Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 3:81–85CrossRefPubMedGoogle Scholar
  8. 8.
    Freitag CM (2007) The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 12:2–22CrossRefPubMedGoogle Scholar
  9. 9.
    Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA (2004) Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology 29:558–565CrossRefPubMedGoogle Scholar
  10. 10.
    Hohoff C, Marziniak M, Lesch KP, Deckert J, Sommer C, Mossner R (2007) An adenosine A2A receptor gene haplotype is associated with migraine with aura. Cephalalgia 27:177–181CrossRefPubMedGoogle Scholar
  11. 11.
    Hohoff C, McDonald JM, Baune BT, Cook EH, Deckert J, de Wit H (2005) Interindividual variation in anxiety response to amphetamine: possible role for adenosine A2A receptor gene variants. Am J Med Genet B Neuropsychiatr Genet 139:42–44Google Scholar
  12. 12.
    Koles L, Wirkner K, Illes P (2001) Modulation of ionotropic glutamate receptor channels. Neurochem Res 26:925–932CrossRefPubMedGoogle Scholar
  13. 13.
    Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Morgan J, Tager-Flusberg H, Lainhart JE (2006) Comorbid psychiatric disorders in children with autism: interview development and rates of disorders. J Autism Dev Disord 36:849–861CrossRefPubMedGoogle Scholar
  14. 14.
    Lord C, Risi S, Lambrecht L, Cook E H Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30:205–223CrossRefPubMedGoogle Scholar
  15. 15.
    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. J Autism Dev Disord 24:659–685CrossRefPubMedGoogle Scholar
  16. 16.
    Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488CrossRefPubMedGoogle Scholar
  17. 17.
    Melchers, P., Preuß, U. (2001) Kaufman assessment battery for children, German version, 6th edn. Hogrefe, GöttingenGoogle Scholar
  18. 18.
    Moreau JL, Huber G (1999) Central adenosine A(2A) receptors: an overview. Brain Res Brain Res Rev 31:65–82CrossRefPubMedGoogle Scholar
  19. 19.
    Pardo CA, Eberhart CG (2007) The neurobiology of autism. Brain Pathol 17:434–447CrossRefPubMedGoogle Scholar
  20. 20.
    Poustka F, Lisch S, Ruhl D, Sacher A, Schmotzer G, Werner K (1996) The standardized diagnosis of autism, autism diagnostic interview-revised: interrater reliability of the German form of the interview. Psychopathology 29:145–153PubMedCrossRefGoogle Scholar
  21. 21.
    Retey JV, Adam M, Honegger E, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP (2005) A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci USA 102:15676–15681CrossRefPubMedGoogle Scholar
  22. 22.
    Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferre S (2007) Adenosine A(2A) receptors and basal ganglia physiology. Prog Neurobiol 83:277–292CrossRefPubMedGoogle Scholar
  23. 23.
    Schneider T, Ziolkowska B, Gieryk A, Tyminska A, Przewlocki R (2007) Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology (Berl) 193:547–555CrossRefGoogle Scholar
  24. 24.
    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449CrossRefPubMedGoogle Scholar
  25. 25.
    Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM (2008) Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur Psychiatry 23:289–299CrossRefPubMedGoogle Scholar
  26. 26.
    Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169CrossRefPubMedGoogle Scholar
  27. 27.
    Tellegen PJ, Winkel M, Laros JA (1998) SON-R 2 1/2-7. Non-verbaler IntelligenztestGoogle Scholar
  28. 28.
    Tewes U, Neubauer A, von Aster M (2006) WIE. Wechsler Intelligenztest für ErwachseneGoogle Scholar
  29. 29.
    Tewes U, Rossmann P, Schallberger U (2000) HAWIK-III. Hamburg-Wechsler-Intelligenztest für Kinder IIIGoogle Scholar
  30. 30.
    Vorstman JA, Morcus ME, van Engeland H (2007) Autism in children with 22q11.2 deletion syndrome. J Am Acad Child Adolesc Psychiatry 46:434–435CrossRefGoogle Scholar
  31. 31.
    Yu L, Frith MC, Suzuki Y, Peterfreund RA, Gearan T, Sugano S, Schwarzschild MA, Weng Z, Fink JS, Chen JF (2004) Characterization of genomic organization of the adenosine A2A receptor gene by molecular and bioinformatics analyses. Brain Res 1000:156–173CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Christine M. Freitag
    • 1
    • 2
  • Konstantin Agelopoulos
    • 4
  • Ellen Huy
    • 2
  • Matthias Rothermundt
    • 3
  • Petra Krakowitzky
    • 6
  • Jobst Meyer
    • 5
  • Jürgen Deckert
    • 3
    • 7
  • Alexander von Gontard
    • 2
  • Christa Hohoff
    • 3
  1. 1.Department of Child and Adolescent PsychiatryJohann Wolfgang Goethe-UniversitätFrankfurt am MainGermany
  2. 2.Department of Child and Adolescent PsychiatrySaarland University HospitalHomburgGermany
  3. 3.Department of PsychiatryUniversity of MünsterMünsterGermany
  4. 4.Institute of PathologyUniversity of MünsterMünsterGermany
  5. 5.Department of Neurobehavioral GeneticsUniversity of TrierTrierGermany
  6. 6.Institute of Transfusion MedicineUniversity of MünsterMünsterGermany
  7. 7.Department of PsychiatryUniversity of WürzburgWürzburgGermany

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