Abstract
Dysfunctions of the neurotransmitter system are related to the development of many psychological diseases including autism spectrum disorder (ASD). Single nucleotide polymorphisms (SNPs) are correlated with varied susceptibility of ASD and response to treatments. The association between SNPs in genes encoding serotonin and dopamine receptors and childhood ASD was examined in a Chinese Han population. Both autistic children (n = 319) and age-and gender-matched healthy controls (n = 347) were recruited from a local district. Disease severity was evaluated by the childhood autism rating scale (CARS). SNPs of rs6311 and rs6313 in the serotonin receptor HTR2A gene, rs4630328 in the dopamine receptor D2 (DRD2) gene and rs167771 in the DRD3 gene were examined. The CC genotype of rs6311 was significantly associated with an increased risk of ASD (odds ratio (OD) = 1.8 vs TT, 95% confidence interval (CI): 1.2–2.8, P = 0.0085). Carriers of the C allele of rs6311 had a significantly higher risk of childhood ASD (OD =1.3, 95% CI = 1.1–1.7, P = 0.0094). A strong linkage disequilibrium was observed between rs6311 and rs6313 (D′ = 0.93, r2 = 0.86). There were significant correlations between haplotypes (T-A and C-G of rs6311-rs6313) and risk of childhood ASD. In contrast, the frequencies of genotypes and alleles of rs6313, rs4630328 and rs167771 were not significantly different between the case and control groups. All the SNPs examined were not associated with severity of the disease. Our study demonstrates that certain SNPs in the HTR2A gene, but not the DRD2 and DRD3, are associated with susceptibility to childhood ASD.
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The datasets used during the current study are available from the corresponding author on reasonable request.
References
Abdulamir HA, Abdul-Rasheed OF, Abdulghani EA (2018) Serotonin and serotonin transporter levels in autistic children. Saudi Med J 39:487–494. https://doi.org/10.15537/smj.2018.5.21751
Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, Howes OD (2017) The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry 22:666–679. https://doi.org/10.1038/mp.2017.16
Belujon P, Grace AA (2017) Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol 20:1036–1046. https://doi.org/10.1093/ijnp/pyx056
Chadman KK, Guariglia SR, Yoo JH (2012) New directions in the treatment of autism spectrum disorders from animal model research. Expert Opin Drug Discov 7:407–416. https://doi.org/10.1517/17460441.2012.678828
Cho IH, Yoo HJ, Park M, Lee YS, Kim SA (2007) Family-based association study of 5-HTTLPR and the 5-HT2A receptor gene polymorphisms with autism spectrum disorder in Korean trios. Brain Res 1139:34–41. https://doi.org/10.1016/j.brainres.2007.01.002
Cieślińska A, Fiedorowicz E, JarmpBowska B, Kordulewska N, Kostyra E, MoszyDska M, Savelkoul HFJ (2019) Polymorphisms rs6313 and rs6314 in serotonin receptor gene (HTR2A) and serotonin concentration in autistic children. Neuropsychiatry 9:2021–2028. https://doi.org/10.4172/Neuropsychiatry.1000547
de Krom M et al (2009) A common variant in DRD3 receptor is associated with autism spectrum disorder. Biol Psychiatry 65:625–630. https://doi.org/10.1016/j.biopsych.2008.09.035
Gadow KD, Smith RM, Pinsonneault JK (2014) Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder. Cogn Behav Neurol 27:107–116. https://doi.org/10.1097/WNN.0000000000000028
Goldberg J, Anderson GM, Zwaigenbaum L, Hall GB, Nahmias C, Thompson A, Szatmari P (2009) Cortical serotonin type-2 receptor density in parents of children with autism spectrum disorders. J Autism Dev Disord 39:97–104. https://doi.org/10.1007/s10803-008-0604-4
Gong P, Liu J, Blue PR, Li S, Zhou X (2015) Serotonin receptor gene (HTR2A) T102C polymorphism modulates individuals’ perspective taking ability and autistic-like traits. Front Hum Neurosci 9:575. https://doi.org/10.3389/fnhum.2015.00575
Guhathakurta S, Singh AS, Sinha S, Chatterjee A, Ahmed S, Ghosh S, Usha R (2009) Analysis of serotonin receptor 2A gene (HTR2A): association study with autism spectrum disorder in the Indian population and investigation of the gene expression in peripheral blood leukocytes. Neurochem Int 55:754–759. https://doi.org/10.1016/j.neuint.2009.07.008
Hranilovic D, Bujas-Petkovic Z, Vragovic R, Vuk T, Hock K, Jernej B (2007) Hyperserotonemia in adults with autistic disorder. J Autism Dev Disord 37:1934–1940. https://doi.org/10.1007/s10803-006-0324-6
Hranilovic D, Blazevic S, Babic M, Smurinic M, Bujas-Petkovic Z, Jernej B (2010) 5-HT2A receptor gene polymorphisms in Croatian subjects with autistic disorder. Psychiatry Res 178:556–558. https://doi.org/10.1016/j.psychres.2010.04.007
Khanzada NS, Butler MG, Manzardo AM (2017) GeneAnalytics pathway analysis and genetic overlap among autism Spectrum disorder, bipolar disorder and schizophrenia. Int J Mol Sci 18:527. https://doi.org/10.3390/ijms18030527
Kolevzon A, Mathewson KA, Hollander E (2006) Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry 67:407–414
Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28:402–412. https://doi.org/10.1038/sj.npp.1300057
McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH (1996) Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 53:993–1000. https://doi.org/10.1001/archpsyc.1996.01830110029004
Moul C, Dobson-Stone C, Brennan J, Hawes D, Dadds M (2013) An exploration of the serotonin system in antisocial boys with high levels of callous-unemotional traits. PLoS One 8:e56619. https://doi.org/10.1371/journal.pone.0056619
Nyffeler J, Walitza S, Bobrowski E, Gundelfinger R, Grunblatt E (2014) Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism. J Mol Psychiatry 2:1. https://doi.org/10.1186/2049-9256-2-1
Paval D (2017) A dopamine hypothesis of autism spectrum disorder. Dev Neurosci 39:355–360. https://doi.org/10.1159/000478725
Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98. https://doi.org/10.1038/sj.cr.7290272
Smith RM, Banks W, Hansen E, Sadee W, Herman GE (2014) Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder. Autism Res 7:459–467. https://doi.org/10.1002/aur.1383
Staal WG (2015) Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge. Eur Neuropsychopharmacol 25:1421–1426. https://doi.org/10.1016/j.euroneuro.2014.08.011
Toma C, Hervás A, Balmaña N, Salgado M, Maristany M, Vilella E, Aguilera F, Orejuela C, Cuscó I, Gallastegui F, Pérez-Jurado LA, Caballero-Andaluz R, Diego-Otero Y, Guzmán-Alvarez G, Ramos-Quiroga JA, Ribasés M, Bayés M, Cormand B (2013) Neurotransmitter systems and neurotrophic factors in autism: association study of 37 genes suggests involvement of DDC. World J Biol Psychiatry 14:516–527. https://doi.org/10.3109/15622975.2011.602719
Unschuld PG et al (2007) Polymorphisms in the serotonin receptor gene HTR2A are associated with quantitative traits in panic disorder. Am J Med Genet B Neuropsychiatr Genet 144B:424–429. https://doi.org/10.1002/ajmg.b.30412
Yu H, Liu J, Yang A, Yang G, Yang W, Lei H, Quan J, Zhang Z (2016) Lack of association between polymorphisms in Dopa decarboxylase and dopamine Receptor-1 genes with childhood autism in Chinese Han population. J Child Neurol 31:560–564. https://doi.org/10.1177/0883073815601496
Yu H, Zhang Z, Liu J, Hu P, Liu Z (2020) Association study between genetic variants in vitamin D metabolism related genes and childhood autism spectrum disorder. Metab Brain Dis 35(6):971–978. https://doi.org/10.1007/s11011-020-00570-x
Acknowledgments
We are greatly thankful to Dr. Kristin Best for her review of our manuscript. This work was supported by Xiaoshan District Science & Technology Bureau of Hangzhou City (2019224), Science Technology Department of Zhejiang Province (LGF19H090004), and Health Commission of Zhejiang Province (2018ZD038). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Conceptualization, J.L. and H.Y.; Methodology, J.L.; Formal Analysis, H.F. and J.K.; Investigation, H.F, J.K. H.Y. and Z.Z.; Resources, J.K.; Data Curation, H.Y., Z.Z. and J.L.; Writing – Original Draft Preparation, H.F. and J.L.; Writing – Review & Editing, H.F., J.K., H.Y., Z.Z. and J.L.; Supervision, J.L.; Funding Acquisition, J.L. Z.Z and H.Y.
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Liu, J., Fu, H., Kong, J. et al. Association between autism spectrum disorder and polymorphisms in genes encoding serotine and dopamine receptors. Metab Brain Dis 36, 865–870 (2021). https://doi.org/10.1007/s11011-021-00699-3
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DOI: https://doi.org/10.1007/s11011-021-00699-3