Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder


Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, pnom = 1 padj = 1) and rs356219 (OR 1.28; pnom = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, pnom = 0.020), which survived Bonferroni correction (padj = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, padj = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.

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  1. Albayrak Ö, Friedel S, Schimmelmann BG, Hinney A, Hebebrand J (2008) Genetic aspects in attention-deficit/hyperactivity disorder. J Neural Transm 115:305–315

    Article  CAS  PubMed  Google Scholar 

  2. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn, Text Revision. American Psychiatric Association, Washington

  3. Ascherio A, Schwarzschild MA (2016) The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15:1257–1272

    Article  PubMed  Google Scholar 

  4. Banaschewski T, Becker K, Döpfner M, Holtmann M, Rösler M, Romanos M (2017) Attention-deficit/hyperactivity disorder: a current review. Dtsch Arztebl Int 114:149–159

    PubMed  PubMed Central  Google Scholar 

  5. Barkley RA, Shelton TL, Crosswait C, Moorehouse M, Fletcher K, Barrett S, Jenkins L, Metevia L (2002) Preschool children with disruptive behavior: three-year outcome as a function of adaptive disability. Dev Psychopathol 14:45–67

    Article  PubMed  Google Scholar 

  6. Butler B, Sambo D, Khoshbouei H (2017) Alpha-synuclein moduldates dopamine neurotransmission. J Chem Anat 83:41–49

    Google Scholar 

  7. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, Baldursson G, Belliveau R, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, Chambert K, Churchhouse C, Dumont A, Eriksson N, Gandal M, Goldstein JI, Grasby KL, Grove J, Gudmundsson OO, Hansen CS, Hauberg ME, Hollegaard MV, Howrigan DP, Huang H, Maller JB, Martin AR, Martin NG, Moran J, Pallesen J, Palmer DS, Pedersen CB, Pedersen MG, Poterba T, Poulsen JB, Ripke S, Robinson EB, Satterstrom FK, Stefansson H, Stevens C, Turley P, Walters GB, Won H, Wright MJ ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; 23andMe Research Team, Andreassen OA, Asherson P, Burton CL, Boomsma DI, Cormand B, Dalsgaard S, Franke B, Gelernter J, Geschwind D, Hakonarson H, Haavik J, Kranzler HR, Kuntsi J, Langley K, Lesch KP, Middeldorp C, Reif A, Rohde LA, Roussos P, Schachar R, Sklar P, Sonuga-Barke EJS, Sullivan PF, Thapar A, Tung JY, Waldman ID, Medland SE, Stefansson K, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Daly MJ, Faraone SV, Børglum AD, Neale BM (2018) Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet.

  8. Faraone SV, Asherson P, Banaschewski T, Biederman J, Buitelaar JK, Ramos-Quiroga JA, Rohde LA, Sonuga-Barke EJS, Tannock R, Franke B (2015) Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 1:15020

    Article  PubMed  Google Scholar 

  9. Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U (2012) Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. Am J Psychiatry 169:264–272

    Article  PubMed  Google Scholar 

  10. Geissler JM, International Parkinson Disease Genomics Consortium members, Romanos M, Gerlach M, Berg D, Schulte C (2017) No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs. Atten Defic Hyperact Disord 9:121–127

  11. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612

    Article  CAS  PubMed  Google Scholar 

  12. Jarick I, Volckmar AL, Pütter C, Pechlivanis S, Nguyen TT, Dauvermann MR, Beck S, Albayrak Ö, Scherag S, Gilsbach S, Cichon S, Hoffmann P, Degenhardt F, Nöthen MM, Schreiber S, Wichmann HE, Jöckel KH, Heinrich J, Tiesler CM, Faraone SV, Walitza S, Sinzig J, Freitag C, Meyer J, Herpertz-Dahlmann B, Lehmkuhl G, Renner TJ, Warnke A, Romanos M, Lesch KP, Reif A, Schimmelmann BG, Hebebrand J, Scherag A, Hinney A (2014) Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Mol Psychiatry 19:115–121

    Article  CAS  PubMed  Google Scholar 

  13. Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912

    Article  CAS  Google Scholar 

  14. Kehagia AA, Housden CR, Regenthal R, Barker RA, Müller U, Rowe J, Sahakian BJ, Robbins TW (2014) Targeting impulsivity in Parkinson’s disease using atomoxetine. Brain 137:1986–1997

    Article  PubMed  PubMed Central  Google Scholar 

  15. Krauel K, Feldhaus HC, Simon A, Rehe C, Glaser M, Flechtner HH, Heinze HJ, Niehaus L (2010) Increased echogenicity of the substantia nigra in children and adolescents with attention-deficit/hyperactivity disorder. Biol Psychiat 68:352–358

    Article  PubMed  Google Scholar 

  16. Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Krüger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C; Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:661–670

  17. Mehler-Wex C, Riederer P, Gerlach M (2006) Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder. Neurotox Res 10:167–179

    Article  CAS  PubMed  Google Scholar 

  18. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Renner TJ, Walitza S, Dempfle A, Eckert L, Romanos M, Gerlach M, Schäfer H, Warnke A, Lesch KP, Jacob C (2008) Allelic variants of SNAP25 in a family-based sample of ADHD. J Neural Transm 115:317–321

    Article  CAS  PubMed  Google Scholar 

  20. Romanos M, Weise D, Schliesser M, Schecklmann M, Löffler J, Warnke A, Gerlach M, Classen J, Mehler-Wex C (2010) Abnormality of substantia nigra in attention-defi-cit/hyperactivity disorder. J Psychiatry Neurosci 35:55–58

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shelton TL, Barkley RA, Crosswait C, Moorehouse M, Fletcher K, Barrett S, Jenkins L, Metevia L (2000) Multimethod psychoeducational intervention for preschool children with disruptive behavior: two-year post-treatment follow-up. J Abnorm Child Psychol 28:253–266

    Article  CAS  PubMed  Google Scholar 

  22. Sian J, Gerlach M, Youdim MB, Riederer P (1999) Parkinson’s disease: a major hypokinetic basal ganglia disorder. J Neural Transm 106:443–476

    Article  CAS  PubMed  Google Scholar 

  23. Sidhu A, Wersinger C, Vernier P (2004) α-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson’s disease. FEBS Lett 565:1–5

    Article  CAS  PubMed  Google Scholar 

  24. Thapar A, Cooper M (2016) Attention deficit hyperactivity disorder. Lancet 387:1240–1250

    Article  PubMed  Google Scholar 

  25. The Brainstorm Consortium (2018) Science 360, eaap8757.

  26. Venda LL, Cragg SJ, Buchman VL, Wade-Martins R (2010) α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci 33:559–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Walitza S, Romanos M, Warnke A, Greenhill L, Gerlach M (2014) Psychostimulants and other drugs used in the treatment of attention-deficit/hyperactivity disorder (ADHD). In: Gerlach M, Warnke A, Greenhill L (eds) Psychiatric drugs in childhood and adolescents. Springer, Vienna

    Google Scholar 

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Correspondence to Manfred Gerlach.

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Gerlach, M., Sharma, M., Romanos, M. et al. Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder. ADHD Atten Def Hyp Disord 11, 107–111 (2019).

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  • ADHD
  • Dopamine transporter
  • Alpha-synuclein
  • Pathogenesis
  • Parkinson’s disease