Genetic associations between ADHD and dopaminergic genes (DAT1 and DRD4) VNTRs in Korean children
- 193 Downloads
It is well known that dopaminergic genes affect the development of attention deficit hyperactivity disorder (ADHD) in various populations. Many studies have shown that variable number tandem repeats (VNTRs) located within the 3′-untranslated region of DAT1 and in exon 3 of DRD4 are associated with ADHD development; however, these results were inconsistent. Therefore, we investigated the genetic association between two VNTRs and ADHD in Korean children. We determined the VNTRs using PCR. We examined genotype and allele frequency differences between the experimental and control groups, along with the odds ratios, using Chi square and exact tests. We observed a significant association between the children with ADHD and the control group in the 10R/10R genotype of DAT1 VNTRs (p = 0.025). In addition, the 11R allele of DAT1 VNTRs showed a higher frequency in the control group than in the ADHD group (p = 0.023). Also, the short repeat (without 11R) and long repeat alleles (including 11R) were associated with ADHD (p < 0.05). The analysis of DRD4 VNTRs revealed that the 2R allele is associated with ADHD (p = 0.025). A significant result was also observed in long and short repeats (p < 0.05). Additionally, ADHD subtypes showed that the DRD4 VNTRs are associated with combined and hyperactive-impulsive subtype groups (p < 0.05). Therefore, our results suggest that DAT1 VNTRs and DRD4 VNTRs play a role in the genetic etiology of ADHD in Korean children.
KeywordsADHD DAT1 DRD4 VNTRs Korean children Genetic association
This work was supported by the National Research Foundation of Korea Grant funded by the Korea Government (NRF-2016R1D1A3B03933507).
Compliance with ethical standards
Conflict of interest
Jun Ho Hong, In Wook Hwang, Myung Ho Lim, Ho Jang Kwon, Han Jun Jin declare that they have no conflict of interest.
The study was approved by the Ethics Committee of the Dankook University Hospital.
Informed consent was obtained from all individual participants included in the study.
- American Psychiatric Association Committee on Nomenclature and Statistics (1994) Diagnostic and statistical manual of mental disorders (DSM-IV), 4th edn. American Psychiatric Assocaition Press, Washington, DCGoogle Scholar
- Barkley RA, Murphy K (1998) Attention-deficit hyperactivity disorder: a clinical workbook, 2nd edn. Guilford Press, New YorkGoogle Scholar
- Cornish KM, Manly T, Savage R, Swanson J, Morisano D, Butler N, Grant C, Cross G, Bentley L, Hollis CP (2005) Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Mol Psychiatry 10:686–698CrossRefGoogle Scholar
- Gornick MC, Addington A, Shaw P, Bobb AJ, Sharp W, Greenstein D, Arepalli S, Castellanos FX, Rapoport JL (2007) Association of the dopamine receptor d4 (DRD4) gene 7-repeat allele with children with attention deficit/hyperactivity disorder (adhd) an update. Am J Med Genet B 144B:379–382CrossRefGoogle Scholar
- Holmes J, Payton A, Barrett JH, Hever T, Fitzpatrick H, Trumper AL, Harrington R, McGuffin P, Owen M, Ollier W et al (2000) A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder. Mol Psychiatry 5:523–530CrossRefGoogle Scholar
- Kim YS, So YK, Noh JS, Ko SG, Koh YJ (2002) The reliability and validity of Korean parent and teacher ADHD rating scale. J Korean Neuropsychiatr Assoc 41:283–289Google Scholar
- Lahey BB, Pelham WE, Stein MA, Loney J, Trapani C, Nugent K, Kipp H, Schmidt E, Lee S, Cale M et al (1998) Validity of DSM-IV attention-deficit/hyperactivity disorder for younger children. J Am Acad Child Adolesc Psychiatry 37:95–702Google Scholar
- Leung PW, Lee CC, Hung SF, Ho TP, Tang CP, Kwong SL, Leung SY, Yuen ST, Lieh-Mak F, Oosterlaan J et al (2005) Dopamine receptor D4 (DRD4) gene in han chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele. Am J Med Genet B 133B:54–56CrossRefGoogle Scholar
- Levitan RD, Masellis M, Lam RW, Muglia P, Basile VS, Jain U, Kaplan AS, Tharmalingam S, Kennedy SH, Kennedy JL (2004) Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder. Neuropsychopharmacology 29:179–186CrossRefGoogle Scholar
- Ludolph AG, Kassubek J, Schmeck K, Glaser C, Wunderlich A, Buck AK, Reske SN, Fegert JM, Mottaghy FM (2008) Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults; a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study. Neuroimage 41:718–727CrossRefGoogle Scholar
- Moharrari F, Barabadian S (2015) Is dopamine transporter gene effective on therapeutic response of methylphenidate in ADHD patients? Rev Clin Med 2:65–71Google Scholar
- Onnink AM, Franke B, van Hulzen K, Zwiers MP, Mostert JC, Schene AH, Heslenfeld DJ, Oosterlaan J, Hoekstra PJ, Hartman CA et al (2016) Enlarged striatal volume in adults with ADHD carrying the 9–6 haplotype of the dopamine transporter gene DAT1. J Neural Transm (Vienna) 123:905–915CrossRefGoogle Scholar
- Qian Q, Wang Y, Zhou R, Yang L, Faraone SV (2004) Family-based and case-control association studies of DRD4 and DAT1 polymorphisms in chinese attention deficit hyperactivity disorder patients suggest long repeats contribute to genetic risk for the disorder. Am J Med Genet B 128B:84–89CrossRefGoogle Scholar
- Spencer TJ, Biederman J, Faraone SV, Madras BK, Bonab AA, Dougherty DD, Batchelder H, Clarke A, Fischman AJ (2013) Functional genomics of attention-deficit/hyperactivity disorder (ADHD) risk alleles on dopamine transporter binding in ADHD and healthy control subjects. Biol Psychiatry 74:84–89CrossRefGoogle Scholar
- van Hulzen KJE, Scholz CJ, Franke B, Ripke S, Klein M, McQuillin A, Sonuga-Barke EJ, PGC ADHD Working Group, Kelsoe JR, Landen M et al (2017) Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder: evidence from genome-wide association study meta-analysis. Biol Psychiatry 82:634–641CrossRefGoogle Scholar
- Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL, Cleveland HH, Sanders ML, Gard JM, Stever C (1998) Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 63:1767–1776CrossRefGoogle Scholar
- Yoo SW, Kim SJ, Kim CH (2006) Association between obsessive-compulsive disorder and dopamine transporter gene polymorphism. Psychiatry Invest 3:72–77Google Scholar