The Relationship between Gene SLC6A3 Variable Number of Tandem Repeat (VNTR) and Attention-Deficit / Hyperactivity Disorder
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Abstract
Objective: This research investigates the alleles of Variable Number of Tandem Repeats (VNTR) intron 8 of the gene SLC6A3 with attention-deficit / hyperactivity disorder (ADHD) in children and adolescents.
Method: The study’s target population consisted of children and adolescents referred to the specialized clinic, as well as students attending school in Rasht city during 2021-2022. A sample of 95 children between the ages of 6 and 10 with ADHD was selected as the ADHD group, and 95 healthy children were selected as the control group using purposive sampling. The subjects completed the Child Symptom Inventory-4 (CSI-4) checklist after a clinical interview, and demographic information was collected. Genetic sampling was carried out through hair follicles. The sequence of interest was proliferated using the Polymerase Chain Reaction technique )PCR(; afterward, the samples were used for genotype identification on polyacrylamide gel electrophoresis.
Results: The chi-square test results indicated that the 5R / 5R genotype (P = 0.026, χ2 = 7.26) and the 5R allele (P = 0.002, χ2 = 9.35) had a higher frequency compared to the control group. Additionally, the odds ratio test indicated that, compared to other genotypes and alleles, the 5R / 5R genotype (OR = 2.75, 95% CI = 1.29-5.82, P = 0.01) and the 5R allele (OR = 2.02, 95% CI = 1.28-3.19, P = 0.002) increase the odds of developing ADHD by 2.7 and 2 times higher, respectively.
Conclusion: The present study successfully showed the association between intron 8 gene polymorphism, which is responsible for encoding the dopamine transporter as well as ADHD in children and adolescents in Iran.
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7. Huang X, Zhang Q, Gu X, Hou Y, Wang M, Chen X, et al. LPHN3 gene variations and susceptibility to ADHD in Chinese Han population: a two-stage case–control association study and gene–environment interactions. Eur Child Adolesc Psychiatry. 2019;28:861-73.
8. Yasumura A, Omori M, Fukuda A, Takahashi J, Yasumura Y, Nakagawa E, et al. Age-related differences in frontal lobe function in children with ADHD. Brain and Development. 2019;41(7):577-86.
9. Wu W, McAnulty G, Hamoda HM, Sarill K, Karmacharya S, Gagoski B, et al. Detecting microstructural white matter abnormalities of frontal pathways in children with ADHD using advanced diffusion models. Brain Imaging Behav. 2020;14(4):981-97.
10. Tajima-Pozo K, Yus M, Ruiz-Manrique G, Lewczuk A, Arrazola J, Montañes-Rada F. Amygdala Abnormalities in Adults With ADHD. J Atten Disord. 2018;22(7):671-8.
11. Wang Y, Xu Q, Li S, Li G, Zuo C, Liao S, et al. Gender differences in anomalous subcortical morphology for children with ADHD. Neurosci Let. 2018;665:176-81.
12. Rosch KS, Crocetti D, Hirabayashi K, Denckla MB, Mostofsky SH, Mahone EM. Reduced subcortical volumes among preschool-age girls and boys with ADHD. Psychiatry Res Neuroimaging. 2018;271:67-74.
13. Hoogman M, Bralten J, Hibar DP, Mennes M, Zwiers MP, Schweren LS, et al. Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. LANCET PSYCHIAT. 2017;4(4):310-9.
14. Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. LANCET PSYCHIAT. 2018;5(9):727-38.
15. Wilens TE. Pharmacotherapy of ADHD in adults. CNS spectr. 2008;13(S8):11-3.
16. Laasonen-Balk T, Kuikka J, Viinamäki H, Husso-Saastamoinen M, Lehtonen J, Tiihonen J. Striatal dopamine transporter density in major depression. Psychopharmacology. 1999;144:282-5.
17. Sibley MH, Graziano PA, Ortiz M, Rodriguez L, Coxe S. Academic impairment among high school students with ADHD: The role of motivation and goal-directed executive functions. J. Sch. Psychol. 2019;77:67-76.
18. Yang DY, Chi MH, Chu CL, Lin CY, Hsu SE, Chen KC, et al. Orbitofrontal dysfunction during the reward process in adults with ADHD: An fMRI study. Clin Neurophysiol. 2019;130(5):627-33.
19. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24(4):562-75.
20. Shumay E, Fowler JS, Volkow ND. Genomic features of the human dopamine transporter gene and its potential epigenetic States: implications for phenotypic diversity. PLoS One. 2010;5(6):e11067.
21. Grünblatt E, Werling AM, Roth A, Romanos M, Walitza S. Association study and a systematic meta-analysis of the VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention-deficit hyperactivity disorder. J NEURAL TRANSM. 2019;126:517-29.
22. Soleimani R, Salehi Z, Soltanipour S, Hasandokht T, Jalali MM. SLC6A3 polymorphism and response to methylphenidate in children with ADHD: A systematic review and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2018;177(3):287-300.
23. Bonvicini C, Faraone S, Scassellati C. Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry. 2016;21(7):872-84.
24. Maitra S, Sarkar K, Ghosh P, Karmakar A, Bhattacharjee A, Sinha S, et al. Potential contribution of dopaminergic gene variants in ADHD core traits and co-morbidity: a study on eastern Indian probands. Cell Mol Neurobiol. 2014;34(4):549-64.
25. Hoogman M, Onnink M, Cools R, Aarts E, Kan C, Arias Vasquez A, et al. The dopamine transporter haplotype and reward-related striatal responses in adult ADHD. Eur Neuropsychopharmacol. 2013;23(6):469-78.
26. Saha S, Chatterjee M, Shom S, Sinha S, Mukhopadhyay K. Functional SLC6A3 polymorphisms differentially affect autism spectrum disorder severity: a study on Indian subjects. Metab Brain Dis. 2022;37(2):397-410.
27. Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, et al. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacol. 2011;36(8):1644-55.
28. Stolf AR, Müller D, Schuch JB, Akutagava-Martins GC, Guimaraes LSP, Szobot CM, et al. Association between the Intron 8 VNTR Polymorphism of the DAT1 Gene and Crack Cocaine Addiction. Neuropsychobiology. 2017;75(3):141-4.
29. Koijam AS, Hijam AC, Singh AS, Jaiswal P, Mukhopadhyay K, Rajamma U, et al. Association of Dopamine Transporter Gene with Heroin Dependence in an Indian Subpopulation from Manipur. J Mol Neurosci. 2021;71(1):122-36.
30. Tiili EM, Mitiushkina NV, Sukhovskaya OA, Imyanitov EN, Hirvonen AP. The effect of SLC6A3 variable number of tandem repeats and methylation levels on individual susceptibility to start tobacco smoking and on the ability of smokers to quit smoking. Pharmacogenet Genomics. 2020;30(6):117-23.
31. Guindalini C, Howard M, Haddley K, Laranjeira R, Collier D, Ammar N, et al. A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample. Proc Natl Acad Sci U S A. 2006;103(12):4552-7.
32. Hill M, Anney RJ, Gill M, Hawi Z. Functional analysis of intron 8 and 3' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants. Pharmacogenomics J. 2010;10(5):442-7.
33. Moreau C, Meguig S, Corvol JC, Labreuche J, Vasseur F, Duhamel A, et al. Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease. Brain. 2015;138(Pt 5):1271-83.
34. Silva MA, Cordeiro Q, Louzã M, Vallada H. Association between a SLC6A3 intron 8 VNTR functional polymorphism and ADHD in a Brazilian sample of adult patients. Braz J Psychiatry. 2009;31(4):390-95.
35. Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hümmer A, et al. Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology. 2010;35(3):656-64.
36. Brüggemann D, Sobanski E, Alm B, Schubert T, Schmalzried H, Philipsen A, et al. No association between a common haplotype of the 6 and 10-repeat alleles in intron 8 and the 3'UTR of the DAT1 gene and adult attention deficit hyperactivity disorder. Psychiatr Genet. 2007;17(2):121.
37. Spencer TJ, Biederman J, Faraone SV, Madras BK, Bonab AA, Dougherty DD, et al. Functional genomics of attention-deficit/hyperactivity disorder (ADHD) risk alleles on dopamine transporter binding in ADHD and healthy control subjects. Biol Psychiatry. 2013;74(2):84-9.
38. de Azeredo LA, Rovaris DL, Mota NR, Polina ER, Marques FZ, Contini V, et al. Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults. Eur Arch Psychiatry Clin Neurosci. 2014;264(5):401-8.
39. Stanley A, Chavda K, Subramanian A, Prabhu SV, Ashavaid TF. DRD4 and DAT1 VNTR Genotyping in Children with Attention Deficit Hyperactivity Disorder. Indian J Clin Biochem. 2017;32(2):239-42.
40. Liu Y, Chang X, Qu H, Glessner J, Tian L, Li D, et al. Non-coding structural variation differentially impacts attention-deficit hyperactivity disorder (ADHD) gene networks in African American vs Caucasian children. Sci Rep. 2020;10(1):15252.
41. Spencer TJ, Biederman J, Madras BK, Faraone SV, Dougherty DD, Bonab AA, et al. In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter. Biol Psychiatry. 2005;57(11):1293-300.
2. de la Côte-Sainte-Catherine C. ADHD and comorbid disorders in childhood psychiatric problems, medical problems, learning disorders and developmental coordination. J Clin Psychiatry. 2015;1(1):1-9.
3. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4):e994-e1001.
4. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24(4):562-75.
5. Larsson H, Sariaslan A, Långström N, D'Onofrio B, Lichtenstein P. Family income in early childhood and subsequent attention deficit/hyperactivity disorder: a quasi-experimental study. J Child Psychol Psychiatry. 2014;55(5):428-35.
6. Guney E, Cetin FH, Iseri E. The role of environmental factors in etiology of attention-deficit hyperactivity disorder. ADHD—new directions in diagnosis and treatment. 2015:15-34.
7. Huang X, Zhang Q, Gu X, Hou Y, Wang M, Chen X, et al. LPHN3 gene variations and susceptibility to ADHD in Chinese Han population: a two-stage case–control association study and gene–environment interactions. Eur Child Adolesc Psychiatry. 2019;28:861-73.
8. Yasumura A, Omori M, Fukuda A, Takahashi J, Yasumura Y, Nakagawa E, et al. Age-related differences in frontal lobe function in children with ADHD. Brain and Development. 2019;41(7):577-86.
9. Wu W, McAnulty G, Hamoda HM, Sarill K, Karmacharya S, Gagoski B, et al. Detecting microstructural white matter abnormalities of frontal pathways in children with ADHD using advanced diffusion models. Brain Imaging Behav. 2020;14(4):981-97.
10. Tajima-Pozo K, Yus M, Ruiz-Manrique G, Lewczuk A, Arrazola J, Montañes-Rada F. Amygdala Abnormalities in Adults With ADHD. J Atten Disord. 2018;22(7):671-8.
11. Wang Y, Xu Q, Li S, Li G, Zuo C, Liao S, et al. Gender differences in anomalous subcortical morphology for children with ADHD. Neurosci Let. 2018;665:176-81.
12. Rosch KS, Crocetti D, Hirabayashi K, Denckla MB, Mostofsky SH, Mahone EM. Reduced subcortical volumes among preschool-age girls and boys with ADHD. Psychiatry Res Neuroimaging. 2018;271:67-74.
13. Hoogman M, Bralten J, Hibar DP, Mennes M, Zwiers MP, Schweren LS, et al. Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. LANCET PSYCHIAT. 2017;4(4):310-9.
14. Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. LANCET PSYCHIAT. 2018;5(9):727-38.
15. Wilens TE. Pharmacotherapy of ADHD in adults. CNS spectr. 2008;13(S8):11-3.
16. Laasonen-Balk T, Kuikka J, Viinamäki H, Husso-Saastamoinen M, Lehtonen J, Tiihonen J. Striatal dopamine transporter density in major depression. Psychopharmacology. 1999;144:282-5.
17. Sibley MH, Graziano PA, Ortiz M, Rodriguez L, Coxe S. Academic impairment among high school students with ADHD: The role of motivation and goal-directed executive functions. J. Sch. Psychol. 2019;77:67-76.
18. Yang DY, Chi MH, Chu CL, Lin CY, Hsu SE, Chen KC, et al. Orbitofrontal dysfunction during the reward process in adults with ADHD: An fMRI study. Clin Neurophysiol. 2019;130(5):627-33.
19. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019;24(4):562-75.
20. Shumay E, Fowler JS, Volkow ND. Genomic features of the human dopamine transporter gene and its potential epigenetic States: implications for phenotypic diversity. PLoS One. 2010;5(6):e11067.
21. Grünblatt E, Werling AM, Roth A, Romanos M, Walitza S. Association study and a systematic meta-analysis of the VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention-deficit hyperactivity disorder. J NEURAL TRANSM. 2019;126:517-29.
22. Soleimani R, Salehi Z, Soltanipour S, Hasandokht T, Jalali MM. SLC6A3 polymorphism and response to methylphenidate in children with ADHD: A systematic review and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2018;177(3):287-300.
23. Bonvicini C, Faraone S, Scassellati C. Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry. 2016;21(7):872-84.
24. Maitra S, Sarkar K, Ghosh P, Karmakar A, Bhattacharjee A, Sinha S, et al. Potential contribution of dopaminergic gene variants in ADHD core traits and co-morbidity: a study on eastern Indian probands. Cell Mol Neurobiol. 2014;34(4):549-64.
25. Hoogman M, Onnink M, Cools R, Aarts E, Kan C, Arias Vasquez A, et al. The dopamine transporter haplotype and reward-related striatal responses in adult ADHD. Eur Neuropsychopharmacol. 2013;23(6):469-78.
26. Saha S, Chatterjee M, Shom S, Sinha S, Mukhopadhyay K. Functional SLC6A3 polymorphisms differentially affect autism spectrum disorder severity: a study on Indian subjects. Metab Brain Dis. 2022;37(2):397-410.
27. Pinsonneault JK, Han DD, Burdick KE, Kataki M, Bertolino A, Malhotra AK, et al. Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacol. 2011;36(8):1644-55.
28. Stolf AR, Müller D, Schuch JB, Akutagava-Martins GC, Guimaraes LSP, Szobot CM, et al. Association between the Intron 8 VNTR Polymorphism of the DAT1 Gene and Crack Cocaine Addiction. Neuropsychobiology. 2017;75(3):141-4.
29. Koijam AS, Hijam AC, Singh AS, Jaiswal P, Mukhopadhyay K, Rajamma U, et al. Association of Dopamine Transporter Gene with Heroin Dependence in an Indian Subpopulation from Manipur. J Mol Neurosci. 2021;71(1):122-36.
30. Tiili EM, Mitiushkina NV, Sukhovskaya OA, Imyanitov EN, Hirvonen AP. The effect of SLC6A3 variable number of tandem repeats and methylation levels on individual susceptibility to start tobacco smoking and on the ability of smokers to quit smoking. Pharmacogenet Genomics. 2020;30(6):117-23.
31. Guindalini C, Howard M, Haddley K, Laranjeira R, Collier D, Ammar N, et al. A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample. Proc Natl Acad Sci U S A. 2006;103(12):4552-7.
32. Hill M, Anney RJ, Gill M, Hawi Z. Functional analysis of intron 8 and 3' UTR variable number of tandem repeats of SLC6A3: differential activity of intron 8 variants. Pharmacogenomics J. 2010;10(5):442-7.
33. Moreau C, Meguig S, Corvol JC, Labreuche J, Vasseur F, Duhamel A, et al. Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease. Brain. 2015;138(Pt 5):1271-83.
34. Silva MA, Cordeiro Q, Louzã M, Vallada H. Association between a SLC6A3 intron 8 VNTR functional polymorphism and ADHD in a Brazilian sample of adult patients. Braz J Psychiatry. 2009;31(4):390-95.
35. Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hümmer A, et al. Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology. 2010;35(3):656-64.
36. Brüggemann D, Sobanski E, Alm B, Schubert T, Schmalzried H, Philipsen A, et al. No association between a common haplotype of the 6 and 10-repeat alleles in intron 8 and the 3'UTR of the DAT1 gene and adult attention deficit hyperactivity disorder. Psychiatr Genet. 2007;17(2):121.
37. Spencer TJ, Biederman J, Faraone SV, Madras BK, Bonab AA, Dougherty DD, et al. Functional genomics of attention-deficit/hyperactivity disorder (ADHD) risk alleles on dopamine transporter binding in ADHD and healthy control subjects. Biol Psychiatry. 2013;74(2):84-9.
38. de Azeredo LA, Rovaris DL, Mota NR, Polina ER, Marques FZ, Contini V, et al. Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults. Eur Arch Psychiatry Clin Neurosci. 2014;264(5):401-8.
39. Stanley A, Chavda K, Subramanian A, Prabhu SV, Ashavaid TF. DRD4 and DAT1 VNTR Genotyping in Children with Attention Deficit Hyperactivity Disorder. Indian J Clin Biochem. 2017;32(2):239-42.
40. Liu Y, Chang X, Qu H, Glessner J, Tian L, Li D, et al. Non-coding structural variation differentially impacts attention-deficit hyperactivity disorder (ADHD) gene networks in African American vs Caucasian children. Sci Rep. 2020;10(1):15252.
41. Spencer TJ, Biederman J, Madras BK, Faraone SV, Dougherty DD, Bonab AA, et al. In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter. Biol Psychiatry. 2005;57(11):1293-300.
| Files | ||
| Issue | Vol 19 No 1 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijps.v19i1.14345 | |
| Keywords | ||
| Attention Deficit / Hyperactivity Disorder DAT1 Protein Gene Polymorphisms Human Variable Number of Tandem Repeat | ||
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How to Cite
1.
Seymari A, Naseh A, Rezaei S, Salehi Z, Kousha M. The Relationship between Gene SLC6A3 Variable Number of Tandem Repeat (VNTR) and Attention-Deficit / Hyperactivity Disorder. Iran J Psychiatry. 2023;19(1):99-106.
