Skip to main content
Log in

Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood

  • Original Article
  • Published:
ADHD Attention Deficit and Hyperactivity Disorders

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common behavioural disorder that affects not only children and adolescents but also adults; however, diagnosis of adult ADHD is difficult because patients seem to have reduced externalized behaviour. ADHD is a multifactorial disorder in which many genes, all with small effects, are thought to cause the disorder in the presence of unfavourable environmental conditions. Therefore, in this pilot study, we explored the expression profile of a list of previously established candidate genes in peripheral blood samples from adult ADHD subjects (n = 108) and compared these results with those of healthy controls (n = 35). We demonstrate that combining the gene expression levels of dopamine transporter (SLC6A3), dopamine D5 receptor, tryptophan hydroxylase-1, and SNAP25 as predictors in a regression model resulted in sensitivity and specificity of over 80 % (ROC: max R 2 = 0.587, AUC = 0.917, P < 0.001, 95 % CI: 0.900–0.985). In conclusion, the combination of these four genes could represent a potential method for estimating risk and could be of diagnostic value for ADHD. Nevertheless, further investigation in a larger independent population including different subtypes of ADHD (inattentive, hyperactive, or combined type) patients is required to obtain more specific sets of biomarkers for each subtype as well as to differentiate between child, adolescent, and adulthood forms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  • American Psychiatric Association (2000) American Psychiatric Association: diagnostic and statistical manual of mental disorders—DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Banaschewski T, Becker K, Scherag S, Franke B, Coghill D (2010) Molecular genetics of attention-deficit/hyperactivity disorder: an overview. Eur Child Adolesc Psychiatry 19(3):237–257. doi:10.1007/s00787-010-0090-z

    Article  PubMed  Google Scholar 

  • Biederman J (2005) Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 57(11):1215–1220. doi:10.1016/j.biopsych.2004.10.020

    Article  PubMed  Google Scholar 

  • Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95. doi:10.1067/mcp.2001.113989

    Article  Google Scholar 

  • Burczynski ME, Dorner AJ (2006) Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics 7(2):187–202

    Article  PubMed  CAS  Google Scholar 

  • Cai C, Langfelder P, Fuller TF, Oldham MC, Luo R, van den Berg LH, Ophoff RA, Horvath S (2010) Is human blood a good surrogate for brain tissue in transcriptional studies? BMC Genomics 11:589. doi:10.1186/1471-2164-11-589

    Article  PubMed  Google Scholar 

  • Faraone SV, Mick E (2010) Molecular genetics of attention deficit hyperactivity disorder. Psychiatr Clin N Am 33(1):159–180. doi:10.1016/j.psc.2009.12.004

    Article  PubMed  Google Scholar 

  • Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2(2):104–113

    PubMed  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Williams JBW (eds) (1997) Structured clinical interview for DSM-IV axis I disorders (SCID-I), clinician version. American Psychiatric Publishing Inc., Arlington, VA

    Google Scholar 

  • Forero DA, Arboleda GH, Vasquez R, Arboleda H (2009) Candidate genes involved in neural plasticity and the risk for attention-deficit hyperactivity disorder: a meta-analysis of 8 common variants. J Psychiatry Neurosci 34(5):361–366

    PubMed  Google Scholar 

  • Franke B, Neale BM, Faraone SV (2009) Genome-wide association studies in ADHD. Hum Genet 126(1):13–50. doi:10.1007/s00439-009-0663-4

    Article  PubMed  CAS  Google Scholar 

  • Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Casas M, Ribases M, Bosch R, Sanchez-Mora C, Gomez-Barros N, Fernandez-Castillo N, Bayes M, Halmoy A, Halleland H, Landaas ET, Fasmer OB, Knappskog PM, Heister AJ, Kiemeney LA, Kooij JJ, Boonstra AM, Kan CC, Asherson P, Faraone SV, Buitelaar JK, Haavik J, Cormand B, Ramos-Quiroga JA, Reif A (2010) Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology 35(3):656–664. doi:10.1038/npp.2009.170

    Article  PubMed  CAS  Google Scholar 

  • Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126(1):51–90. doi:10.1007/s00439-009-0694-x

    Article  PubMed  CAS  Google Scholar 

  • Gladkevich A, Kauffman HF, Korf J (2004) Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 28(3):559–576

    Article  PubMed  Google Scholar 

  • Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Khanlou N, Han M, Liew CC, Tsuang MT (2005) Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. Proc Natl Acad Sci USA 102(43):15533–15538. doi:10.1073/pnas.0507666102

    Article  PubMed  CAS  Google Scholar 

  • Grünblatt E, Schlößer R, Fischer P, Fischer MO, Li J, Koutsilieri E, Wichart I, Sterba N, Rujescu D, Moller HJ, Adamcyk W, Dittrich B, Muller F, Oberegger K, Gatterer G, Jellinger KJ, Mostafaie N, Jungwirth S, Huber K, Tragl KH, Danielczyk W, Riederer P (2005) Oxidative stress related markers in the “VITA” and the centenarian projects. Neurobiol Aging 26(4):429–438

    Article  PubMed  Google Scholar 

  • Grünblatt E, Bartl J, Zehetmayer S, Ringel TM, Bauer P, Riederer P, Jacob CP (2009) Gene expression as peripheral biomarkers for sporadic Alzheimer’s disease. J Alzheimers Dis 16(3):627–634. doi:10.3233/JAD-2009-0996

    PubMed  Google Scholar 

  • Grünblatt E, Zehetmayer S, Jacob CP, Muller T, Jost WH, Riederer P (2010) Pilot study: peripheral biomarkers for diagnosing sporadic Parkinson’s disease. J Neural Transm. doi:10.1007/s00702-010-0509-1

    Google Scholar 

  • Haavik J, Halmoy A, Lundervold AJ, Fasmer OB (2010) Clinical assessment and diagnosis of adults with attention-deficit/hyperactivity disorder. Expert Rev Neurother 10(10):1569–1580. doi:10.1586/ern.10.149

    Article  PubMed  Google Scholar 

  • Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29(1):8–16

    Article  PubMed  CAS  Google Scholar 

  • Jacob CP, Romanos J, Dempfle A, Heine M, Windemuth-Kieselbach C, Kruse A, Reif A, Walitza S, Romanos M, Strobel A, Brocke B, Schafer H, Schmidtke A, Boning J, Lesch KP (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257(6):309–317. doi:10.1007/s00406-007-0722-6

    Article  PubMed  Google Scholar 

  • Johansson S, Halmoy A, Mavroconstanti T, Jacobsen KK, Landaas ET, Reif A, Jacob C, Boreatti-Hummer A, Kreiker S, Lesch KP, Kan CC, Kooij JJ, Kiemeney LA, Buitelaar JK, Franke B, Ribases M, Bosch R, Bayes M, Casas M, Ramos-Quiroga JA, Cormand B, Knappskog P, Haavik J (2010) Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations. Am J Med Genet B Neuropsychiatr Genet 153B(5):1008–1015. doi:10.1002/ajmg.b.31067

    PubMed  CAS  Google Scholar 

  • Kim JW, Biederman J, Arbeitman L, Fagerness J, Doyle AE, Petty C, Perlis RH, Purcell S, Smoller JW, Faraone SV, Sklar P (2007) Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 144B(6):781–790. doi:10.1002/ajmg.b.30522

    Article  PubMed  CAS  Google Scholar 

  • Klassen LJ, Katzman MA, Chokka P (2010) Adult ADHD and its comorbidities, with a focus on bipolar disorder. J Affect Disord 124(1–2):1–8. doi:10.1016/j.jad.2009.06.036

    Article  PubMed  Google Scholar 

  • Lara C, Fayyad J, de Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, Demytteneare K, de Girolamo G, Haro JM, Jin R, Karam EG, Lepine JP, Mora ME, Ormel J, Posada-Villa J, Sampson N (2009) Childhood predictors of adult attention-deficit/hyperactivity disorder: results from the World Health Organization World Mental Health Survey Initiative. Biol Psychiatry 65(1):46–54. doi:10.1016/j.biopsych.2008.10.005

    Article  PubMed  Google Scholar 

  • Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274(5292):1527–1531

    Article  PubMed  CAS  Google Scholar 

  • Mehler-Wex C, Duvigneau JC, Hartl RT, Ben-Shachar D, Warnke A, Gerlach M (2006) Increased mRNA levels of the mitochondrial complex I 75-kDa subunit. A potential peripheral marker of early onset schizophrenia? Eur Child Adolesc Psychiatry 15(8):504–507. doi:10.1007/s00787-006-0560-5

    Article  PubMed  Google Scholar 

  • Nigg J, Nikolas M, Burt SA (2010) Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49(9):863–873. doi:10.1016/j.jaac.2010.01.025

    Article  PubMed  Google Scholar 

  • Noori-Daloii MR, Kheirollahi M, Mahbod P, Mohammadi F, Astaneh AN, Zarindast MR, Azimi C, Mohammadi MR (2010) Alpha- and beta-synucleins mRNA expression in lymphocytes of schizophrenia patients. Genet Test Mol Biomarkers 14(5):725–729. doi:10.1089/gtmb.2010.0050

    Article  PubMed  CAS  Google Scholar 

  • Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164(6):942–948. doi:10.1176/appi.ajp.164.6.942

    Article  PubMed  Google Scholar 

  • Renner TJ, Walitza S, Dempfle A, Eckert L, Romanos M, Gerlach M, Schafer H, Warnke A, Lesch KP, Jacob C (2008) Allelic variants of SNAP25 in a family-based sample of ADHD. J Neural Transm 115(2):317–321. doi:10.1007/s00702-007-0840-3

    Article  PubMed  CAS  Google Scholar 

  • Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci USA 104(3):955–960

    Article  PubMed  CAS  Google Scholar 

  • Simon V, Czobor P, Balint S, Meszaros A, Bitter I (2009) Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 194(3):204–211. doi:10.1192/bjp.bp.107.048827

    Article  PubMed  Google Scholar 

  • Squassina A, Lanktree M, De Luca V, Jain U, Krinsky M, Kennedy JL, Muglia P (2008) Investigation of the dopamine D5 receptor gene (DRD5) in adult attention deficit hyperactivity disorder. Neurosci Lett 432(1):50–53. doi:10.1016/j.neulet.2007.12.003

    Article  PubMed  CAS  Google Scholar 

  • Stergiakouli E, Thapar A (2010) Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatr Dis Treat 6:551–560. doi:10.2147/NDT.S11322

    Article  PubMed  CAS  Google Scholar 

  • Sullivan PF, Fan C, Perou CM (2006) Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 141(3):261–268

    Google Scholar 

  • Taurines R, Thome J, Duvigneau JC, Forbes-Robertson S, Yang L, Klampfl K, Romanos J, Muller S, Gerlach M, Mehler-Wex C (2010) Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia. Eur Child Adolesc Psychiatry 19(5):441–448. doi:10.1007/s00787-009-0074-z

    Article  PubMed  Google Scholar 

  • Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschlager L, Walitza S, Renner T, Gerlach M, Thome J, Romanos M (2011) Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatry 12(Suppl 1):104–108. doi:10.3109/15622975.2011.600297

    PubMed  Google Scholar 

  • Tsuang MT, Nossova N, Yager T, Tsuang MM, Guo SC, Shyu KG, Glatt SJ, Liew CC (2005) Assessing the validity of blood-based gene expression profiles for the classification of schizophrenia and bipolar disorder: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 133B(1):1–5. doi:10.1002/ajmg.b.30161

    Article  PubMed  Google Scholar 

  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034

    Article  PubMed  Google Scholar 

  • Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knolker U, Friedel S, Schafer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10(12):1126–1132. doi:10.1038/sj.mp.4001734

    Article  PubMed  CAS  Google Scholar 

  • Walitza S, Scherag A, Renner TJ, Hinney A, Remschmidt H, Herpertz-Dahlmann B, Schulz E, Schafer H, Lange KW, Wewetzer C, Gerlach M (2008) Transmission disequilibrium studies in early onset of obsessive-compulsive disorder for polymorphisms in genes of the dopaminergic system. J Neural Transm 115(7):1071–1078. doi:10.1007/s00702-008-0051-6

    Article  PubMed  CAS  Google Scholar 

  • Wallis D (2010) The search for biomarkers for attention deficit/hyperactivity disorder. Drug News Perspect 23(7):438–449. doi:10.1358/dnp.2010.23.7.1472296

    PubMed  Google Scholar 

  • Wood AC, Neale MC (2010) Twin studies and their implications for molecular genetic studies: endophenotypes integrate quantitative and molecular genetics in ADHD research. J Am Acad Child Adolesc Psychiatry 49(9):874–883. doi:10.1016/j.jaac.2010.06.006

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to express our gratitude to all the participants. In addition, we would also like to thank Dr. S. Kreiker for her assistance in recruitment and M. Hofmann and N. Döring for their excellent technical assistance. The study was supported by the Deutsche Forschungsgemeinschaft KFO 125.

Conflict of interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Edna Grünblatt.

Additional information

Edna Grünblatt and Julia Geißler have contributed equally.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grünblatt, E., Geißler, J., Jacob, C.P. et al. Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood. ADHD Atten Def Hyp Disord 4, 77–84 (2012). https://doi.org/10.1007/s12402-012-0074-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12402-012-0074-6

Keywords

Navigation