Association of dopamine D4 receptor gene variants with autism


  • Maha Moustafa Kamal Faculty of Science, Biochemistry Department, Department of Genetics, Ain Shams University, Cairo
  • Ghada H. El Nady Center for Genetic Engineering and Biotechnology and Medical Research Center, Department of Genetics, Ain Shams University, Cairo
  • Asmaa M. Abushady Faculty of Agriculture, Department of Genetics, Ain Shams University, Cairo
  • Mohamed Farouk Mohamed Khalil Center for Genetic Engineering and Biotechnology and Medical Research Center, Department of Genetics, Ain Shams University, Cairo



Autism, Dopamine D4 receptor, Gene polymorphism, Egyptian children


Background: Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system have been linked to ASD. This study aimed to estimate the distribution frequency of dopamine D4 receptor-exon III repeat region polymorphic genotypes among Egyptian children with autism.

Methods: This case-control study included 178 children with autism (mean age 4.46±1.72 years) (118 males and 60 females) and a normal control group (n=128) of matching age and gender. Assessments by DSMIV- TR criteria, Stanford-Binet intelligence scale and childhood autism rating scale (CARS) were done. Assay for DRD4 48 bp VNTR genotypes was performed on amplified DNA by RFLP-PCR.

Results: The 4/4 allele had the highest frequency among both autistic (39.32%) and control children (62.5%), with no significant difference between them. The 7/7 allele had also a high frequency (33.7%) among autistic patients, which was significantly different (p˂0.05) from the control group (12.5%) Furthermore, 70% of the patients carrying the 7/7 allele had the lowest IQ scores (58.5±6.5).

Conclusions: There is a strong evidence that the DRD4 7/7 allele might be a risk factor for autism.



Geschwind DH. Autism: many genes, common pathways? Cell. 2008;135:391–5.

Matson JL, Kozlowski A.M., Matson M.M. Speech deficits in persons with autism: etiology and symptom presentation. Res. Autism Spectrum Dis. 2012;6:573–7.

Kesli R, Gokcen C, Bulug U, Terzi Y. Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children. J. Immunoassay Immunochem. 2014;35:101–9

Mayes SD, Calhoun SL, Murray MJ, Ahuja M, Smith LA. Anxiety, depression, and irritability in children with autism relative to other neuropsychiatric disorders and typical development. Res. Autism Spectrum Dis 2011;5:474–85.

Evans B. How autism became autism: the radical transformation of a central concept of child development in Britain. Hist Hum. 2013;26:3–31.

Lina J. Genetic Studies of Autism and Autistic-Like Traits. © Lina Jonsson. Printed by Ineko AB, Gothenburg, Sweden ISBN: 978-91-628-9269-2 2015. ISBN: 978-91-628-9270-8 (electronic version).

Edvardson S, Ashikov A, Jalas C, Sturiale L, Shaag A, Fedick A, Treff NR, Garozzo D, Gerardy-Schahn R, Elpeleg O. Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis. J. Med. Genet. 2013;50(11):733–9.

Lake CR, Ziegler MG, Murphy DL. Increased norepinephrine levels and decreased dopamine-beta-hydroxylase activity in primary autism. Arch. Gen. Psychiatr. 1977;34:553–6.

Garnier C, Comoy E, Barthelemy C, Leddet I, Garreau B, Muh JP, Lelord G. Dopamine-beta-hydroxylase (DBH) and homovanillic acid (HVA) in autistic children. J. Autism Dev Disord. 1986;16:23–9.

Hamilton PJ, Campbell NG, Sharma S, Erreger K, Herborg HF, Saunders C. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Mol. Psychiatr. 2013;18(12):1315–23.

Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature. 1979;277:93–6.

Van Tol, Wu CM, Guan HC. Multiple dopamine D4 receptor variants in the human population. Nature 1992;358(6382):149–52.

Radek P, Hana K and George BS. Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Med Sci Monit. 2011;17(9): RA215-220.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Fourth ed., text revision (DSM-IV Text Revision). 2000, ISBN10 0890420254 and ISBN13: 9780890420256. American Psychiatric Publishing, Inc., Arlington, Virginia, U.S.A. pdf.

Stanford-Binet intelligence scales (SB-5), two years to adult 2003; fifth ed. Available online at: < clinical/sbis5/home.html>.

Schopler E, Reichler RJ, Renner BR. The childhood autism rating scale (CARS) for diagnostic screening and classification of autism. 1986. New York: Irvington.

Keun-Ah Cheon1, Boong-Nyun Kim, Soo-Churl Cho. Association of the 4 repeat allele of the dopamine D4 receptor gene exon III polymorphism and response to methyl-phenidate treatment in Korean ADHD children. Neuropsechopharmacology. 2007;32:1377-83.

Main AE, Angley MT, Thomas P, Fenech M. Folate and methionine metabolism in autism. Am J Clin Nutr. 2010;91:1598–620.

Angela MR and Alexandre AT. Association between DRD4 genotype and Autistic Symptoms in DSM-IV ADHD. J Can Acad Child Adolesc Psychiatry. 2011;20:1.

20-Faraone SV, Khan SA. Candidate gene studies of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006;67(Suppl 8):13–20.

Mill J, Caspi A, Williams BS, Craig I, Taylor A, Polo-Tomas M. Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention deficit/ hyperactivity disorder: evidence from 2 birth cohorts. Arch Gen Psychiatry. 2006;63:462–9.

Ding YC, Chi HC, Grady DL. Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci USA. 2002;99:309–14

Esra G, Elvan Iseri, Sezen GEr, Emriye F P, Mehmet A E, Ozhan Y and Sahnur. The Correlation of Attention Deficit Hyperactivity Disorder with DRD4 Gene Polymorphism in Turkey. Int J Hum Genet. 2013;13(3):145-52.

Kaplan AS, Levitan RD, Yilmaz Z. A DRD4/BDNF gene-gene interaction associated with maximum BMI in women with bulimia nervosa. Int J Eat Disord 2008;41(1):22–28.

Emanuele E, Boso M, Cassola F. Increased dopamine DRD4 receptor mRNA expression in lymphocytes of musicians and autistic individuals: bridging the music-autism connection. Neuro Endocrinol Lett. 2010;31(1):122–5.

Lee KY, Joo EJ, Ji YI. Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses. Exp Mol Med 2011;43(1):44–52.

Lung FW, Yang MC, Shu BC. The interleukin 10 promoter haplotype ACA and the long-form variant of the DRD4 uVNTR polymorphism are associated with vulnerability to schizophrenia. Psychiatry Res. 2011;188(2):294–6.

Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL. The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 2004;74:931–44.

Demiralp T, Herrmann CS, Erdal ME, Ergenoglu T, Keskin YH, Ergen M. DRD4 and DAT1 polymorphisms modulate human gamma band responses. Cereb Cortex. 2007;17:1007–19.

Shahin O, Meguid NA, Raafat O, Dawood RM, Doss M, Bader el Din NG, et al. Polymorphism in Variable Number of Tandem Repeats of Dopamine D4 Gene Is a Genetic Risk Factor in Attention Deficit Hyperactive Egyptian Children: Pilot Study. Biomarker Insights 2015;10:33-8.




How to Cite

Kamal, M. M., Nady, G. H. E., Abushady, A. M., & Khalil, M. F. M. (2017). Association of dopamine D4 receptor gene variants with autism. International Journal of Research in Medical Sciences, 3(10), 2658–2663.



Original Research Articles