Advertisement

Neurochemical Research

, Volume 39, Issue 11, pp 2058–2067 | Cite as

A Pilot Study on the Contribution of Folate Gene Variants in the Cognitive Function of ADHD Probands

  • T. Saha
  • S. Dutta
  • U. Rajamma
  • S. Sinha
  • K. MukhopadhyayEmail author
Original Paper

Abstract

Genetic abnormalities in components important for the folate cycle confer risk for various disorders since adequate folate turnover is necessary for normal methylation, gene expression and chromosome structure. However, the system has rarely been studied in children diagnosed with attention deficit hyperactivity disorder (ADHD). We hypothesized that ADHD related cognitive deficit could be attributed to abnormalities in the folate cycle and explored functional single nucleotide polymorphisms in methylenetetrahydrofolate dehydrogenase (rs2236225), reduced folate carrier (rs1051266), and methylenetetrahydrofolate reductase (rs1801131 and rs1801133) in families with ADHD probands (N = 185) and ethnically matched controls (N = 216) recruited following the DSM-IV. After obtaining informed written consent for participation, peripheral blood was collected for genomic DNA isolation and PCR-based analysis of target sites. Data obtained was analyzed by UNPHASED. Interaction between sites was analyzed by the multi dimensionality reduction (MDR) program. Genotypic frequencies of the Indian population were strikingly different from other ethnic groups. rs1801133 “T” allele showed biased transmission in female probands (p < 0.05). Significant difference in genotypic frequencies for female probands was also noticed. rs1801131 and rs1801133 showed an association with low intelligence quotient (IQ). MDR analysis exhibited independent effects and contribution of these sites to IQ, thus indicating a role of these genes in ADHD related cognitive deficit.

Keywords

ADHD Folate genes MTHFR IQ 

Notes

Acknowledgments

Active participation of the volunteers for the study is gratefully acknowledged. Part of this work was presented at the 4th World ADHD Congress held in Milan, Italy during 6th–9th June, 2013, PP# 15-5.

Conflict of interests

The authors declare that there is no conflict of interests regarding the research, authorship and publication of this article.

Supplementary material

11064_2014_1393_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOCX 21 kb)

References

  1. 1.
    American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DCGoogle Scholar
  2. 2.
    Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatr 2:104–113Google Scholar
  3. 3.
    Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366:237–248PubMedCrossRefGoogle Scholar
  4. 4.
    Stergiakouli E, Thapar A (2010) Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatr Dis Treat 6:551–560PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatr 57:1313–1323CrossRefGoogle Scholar
  6. 6.
    Dickstein SG, Bannon K, Castellanos FX, Milham MP (2006) The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatr 47:1051–1062CrossRefGoogle Scholar
  7. 7.
    Zukier Z, Solomon JA, Hamadeh MJ (2010) The role of nutrition in mental health: Attention Deficit Hyperactivity Disorder (ADHD). Canadian Mental Health Association, Toronto, Ontario, CanadaGoogle Scholar
  8. 8.
    Gokcen C, Kocak N, Pekgor A (2011) Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder. Int J Med Sci 8:523–528PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Lozoff B, Georgieff MK (2006) Iron deficiency and brain development. Semin Pediatr Neurol 13:158–165PubMedCrossRefGoogle Scholar
  10. 10.
    Zeisel SH (2009) Importance of methyl donors during reproduction. Am J Clin Nutr 89:673S–677SPubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    de Souza AS, Fernandes FS, do Carmo MD (2011) Effects of maternal malnutrition and postnatal nutritional rehabilitation on brain fatty acids, learning, and memory. Nutr Rev 69:132–144PubMedCrossRefGoogle Scholar
  12. 12.
    Blencowe H, Cousens S, Modell B, Lawn J (2010) Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol 39:i110–i121PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Ng KH, Meyer BJ, Reece L, Sinn N (2009) Dietary PUFA intakes in children with attention-deficit/hyperactivity disorder symptoms. Br J Nutr 102:1635–1641PubMedCrossRefGoogle Scholar
  14. 14.
    Arnold LE, Bozzolo H, Hollway J, Cook A, DiSilvestro RA, Bozzolo DR, Crowl L, Ramadan Y, Williams C (2005) Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 15:628–636PubMedCrossRefGoogle Scholar
  15. 15.
    Lakhan SE, Vieira KF (2008) Nutritional therapies for mental disorders. Nutr J 7:2Google Scholar
  16. 16.
    Schlotz W, Jones A, Phillips DI, Gale CR, Robinson SM, Godfrey KM (2010) Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring. J Child Psychol Psychiatr 51:594–602CrossRefGoogle Scholar
  17. 17.
    Zhang XM, Huang GW, Tian ZH, Ren DL, Wilson JX (2009) Folate stimulates ERK1/2 phosphorylation and cell proliferation in fetal neural stem cells. Nutr Neurosci 12:226–232PubMedCrossRefGoogle Scholar
  18. 18.
    Pavarino ÉC, Zampieri BL, Biselli JM, Bertollo EMG (2011) Abnormal folate metabolism and maternal risk for Down Syndrome. In: Gen Etiol Downs Syndrome, S. Dey (ed), Chapter 5, 97–120Google Scholar
  19. 19.
    Mattson MP, Shea TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26:137–146PubMedCrossRefGoogle Scholar
  20. 20.
    Dutta S, Das Bhowmik A, Sinha S, Chattopadhyay A, Mukhopadhyay K (2008) Screening for methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Indian patients with idiopathic mental retardation. Nutr Neurosci 11:18–24PubMedCrossRefGoogle Scholar
  21. 21.
    Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T et al (2008) Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. J Autism Dev Disord 38:1170–1177PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    De Lau MLL, Refsum H, Smith AD, Johnston C, Breteler MMB (2007) Plasma folate concentration and cognitive performance: Rotterdam scans study. Am J Clin Nutr 86:728–734PubMedGoogle Scholar
  23. 23.
    Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N et al (2006) The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 11:934–953PubMedCrossRefGoogle Scholar
  24. 24.
    Zhao R, Chen Y, Tan W, Waly M, Sharma A, Stover P, Rosowsky A, Malewicz B, Deth RC (2001) Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway. J Neurochem 78:788–796PubMedCrossRefGoogle Scholar
  25. 25.
    Kuznetsova AY, Deth RC (2008) A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation. J Comput Neurosci 24:314–329PubMedCrossRefGoogle Scholar
  26. 26.
    Neagos D, Cretu R, Tutulan-Cunita A, Stoian V, Bohiltea LC (2010) Methylenetetrahydrofolate dehydrogenase (MTHFD) enzyme polymorphism as a maternal risk factor for trisomy 21: a clinical study. J Med Life 3:454–457PubMedPubMedCentralGoogle Scholar
  27. 27.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113PubMedCrossRefGoogle Scholar
  28. 28.
    Fernstrom JD (2000) Can nutrient supplements modify brain function? Am J Clin Nutr 71:1669S–1675SPubMedGoogle Scholar
  29. 29.
    Miller AL (2008) The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev 13:216–226PubMedGoogle Scholar
  30. 30.
    Hamon CG, Blair JA, Barford PA (1986) The effect of tetrahydrofolate on tetrahydrobiopterin metabolism. J Ment Defic Res 30:179–183PubMedGoogle Scholar
  31. 31.
    Hyland K (2007) Inherited disorders affecting dopamine and serotonin: critical neurotransmitters derived from aromatic amino acids. J Nutr 137:1568S–1572SPubMedGoogle Scholar
  32. 32.
    Meiser J, Weindl D, Hiller K (2013) Complexity of dopamine metabolism. Cell Commun Signal 11:34PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Pu D, Shen Y, Wu J (2013) Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res 6:384–392PubMedCrossRefGoogle Scholar
  34. 34.
    Spellicy CJ, Northrup H, Fletcher JM, Cirino PT, Dennis M, Morrison AC, Martinez CA, Au KS (2012) Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in Myelomeningocele patients. PLoS One 7:e51330Google Scholar
  35. 35.
    Conners CK, Sitarenios G, Parker JD, Epstein JN (1998) Revision and re-standardization of the Conners teacher rating scale (CTRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol 26:279–291PubMedCrossRefGoogle Scholar
  36. 36.
    Wechsler D (1991) Wechsler intelligence scale for children, 3rd edn. Manual Psychological Corporation, San Antonio, TexasGoogle Scholar
  37. 37.
    Bharat Raj J (1971) AIISH norms on SFB with Indian children. J All India Inst Speech Hearing 2:34–39Google Scholar
  38. 38.
    Lee PH, Shatkay H (2008) F-SNP: computationally predicted functional SNPs for disease association studies. Nucl Acids Res, 36 (Database issue), D820–D824Google Scholar
  39. 39.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–221PubMedCrossRefGoogle Scholar
  41. 41.
    Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516PubMedPubMedCentralGoogle Scholar
  42. 42.
    Moore JH, Gilbert JC, Tsai CT, Chiang F, Holden T, Barney N, White BC (2006) A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol 241:252–261PubMedCrossRefGoogle Scholar
  43. 43.
    Das M, Das Bhowmik A, Bhaduri N, Sarkar K, Ghosh P, Sinha S, Ray A, Chatterjee A, Mukhopadhyay K (2011) Role of gene–gene/gene-environment interaction in the etiology of eastern Indian ADHD probands. Prog Neuropsychopharmacol Biol Psychiatr 35:577–587CrossRefGoogle Scholar
  44. 44.
    Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene–gene and gene: environment interactions. Bioinformatics 19:376–382PubMedCrossRefGoogle Scholar
  45. 45.
    Lenth RV (2007) Statistical power calculations. J Anim Sci 85:E24–E29PubMedCrossRefGoogle Scholar
  46. 46.
    Brown TE (2013) A new understanding of ADHD in children and adults: executive function impairments. Taylor and Francis, New YorkGoogle Scholar
  47. 47.
    Frazier TW, Youngstrom EA, Glutting JJ, Watkins MW (2007) ADHD and achievement: meta-analysis of the child, adolescent, and adult literatures and a concomitant study with college students. J Learn Disabil 40:49–65PubMedCrossRefGoogle Scholar
  48. 48.
    Shaw GM, Lu W, Zhu H, Yang W, Briggs FB, Carmichael SL, Barcellos LF, Lammer EJ, Finnell RH (2009) 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet 10:49PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Pangilinan F, Molloy AM, Mills JL, Troendle JF, Parle-McDermott A et al (2012) Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects. BMC Med Genet 13:62PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Etheredge AJ, Finnell RH, Carmichael SL, Lammer EJ, Zhu H, Mitchell LE, Shaw GM (2012) Maternal and infant gene-folate interactions and the risk of neural tube defects. Am J Med Genet A 158A:2439–2446PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    James SJ, Melnyk S, Jernigan S, Pavliv O, Trusty T, Lehman S, Seidel L, Gaylor DW, Cleves MA (2010) A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism. Am J Med Genet B Neuropsychiatr Genet 153B:1209–1220PubMedPubMedCentralGoogle Scholar
  52. 52.
    Neagos D, Cretu R, Tutulan-Cunita A, Stoian V, Bohiltea LC (2010) RFC - 1 gene polymorphism and the risk of down syndrome in Romanian population. Maedica (Buchar) 5:280–285Google Scholar
  53. 53.
    Guo T, Chen H, Liu B, Ji W, Yang C (2012) Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genet Test Mol Biomarkers 16:968–973PubMedCrossRefGoogle Scholar
  54. 54.
    Ergul E, Sazci A, Kara I (2012) Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder. Genet Test Mol Biomarkers 16:67–69PubMedCrossRefGoogle Scholar
  55. 55.
    Guéant JL, Anello G, Bosco P, Guéant-Rodríguez RM, Romano A, Barone C, Gérard P, Romano C (2005) Homocysteine and related genetic polymorphisms in Down’s syndrome IQ. J Neurol Neurosurg Psychiatry 76:706–709PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Faraone SV, Biederman J, Mick E, Williamson S, Wilens T, Spencer T, Weber W, Jetton J, Kraus I, Pert J, Zallen B (2000) Family study of girls with attention deficit hyperactivity disorder. Am J Psychiatry 157:1077–1083PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • T. Saha
    • 1
  • S. Dutta
    • 1
    • 2
  • U. Rajamma
    • 1
  • S. Sinha
    • 1
  • K. Mukhopadhyay
    • 1
    Email author
  1. 1.Manovikas Biomedical Research and Diagnostic CentreKolkataIndia
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations