| Objective We aimed to systematically explore the relationship between genetic variations of serotonin receptor genes and childhood ADHD, so as to provide a theoretical basis for the pathogenesis of ADHD.Methods(1) An association study with case-control design was performed for the novel candidate genes of HTR1A、HTR1E and HTR3 A in ADHD. The case group consisted of 192 ADHD children who were diagnosed with DSM-IV criteria in Hunan Children’s Hospital from July2013 to August 2014, and 192 normal children who came to the hospital for health examination in the same period were enrolled in control group. All enrolled children were tested by Wechsler intelligence quotient(IQ) test and continuous attention test(CAT), and all the parents of enrolled children filled out a questionnaire for basic demographic characteristics and a Conners parent symptom questionnaire(PSQ). Genomic DNA was extracted from the 2-ml of peripheral blood sample. Candidate SNPs(rs6295, rs1406946, rs1062613) were genotyped using Mass ARRAY technology(Sequenom). F test, χ2 test, Logistic regression were used respectively to examine the association between genetic polymorphisms and PSQ score, CAT result, ADHD risk. All statistical analyses were conducted by using SPSS 20.0 software.(2)A meta analysis was performed to explore the association candidate genes HTR1B, HTR2 A, HTR2 C and new HTR1 A gene with ADHD. Databases were searched to collect all relevant references and available references in high quality were selected before 2016 March. Statistical analysis was conducted by using R 3.1.3 software metaphor package.Results(1)Association study: the average age and the Wechsler intelligence test score in controls were significantly greater than the case group(P = 0.000 and P = 0.019). Significant differences were observed in the genotype(χ2=7.235, P=0.027) or allele(χ2=7.003, P=0.008) frequencies of the HTR1 A rs6295 polymorphism between cases and controls. After adjustment for age, gender and IQ factors, rs6295 were significantly or marginally associated with ADHD both in a recessive model(GG vs. CG+CC: OR=2.00, 95%CI=1.23-3.28, P=0.005) and allele model(G vs. C: OR=1.77,95%CI=1.16-2.72, P= 0.008) with G as a risk allele. There were statistically significant difference in impulsivity-hyperactivity factor score of PSQ scale among different genotypes of rs6295(F=4.490, P=0.012). The correlations of HTR1 E rs1406946 polymorphism and HTR3 A rs1062613 polymorphism respectively with ADHD susceptibility, with PSQ hyperactivity factor score and total score, with attention test results, were not statistically significant(P>0.05).(2)Meta analysis: HTR1 B gene rs6296 G allele could significantly increase the ADHD risk(random effect model:OR=1.16,95% CI=1.04-1.29, P<0.01)with no publication bias, and this positive association result by sensitive analysis and cumulative meta-analysis showed stable and highly reliable. HTR2 C gene rs518147 polymorphism(fixed effect model:OR=1.69,95% CI=1.38-2.07, P<0.01)and rs3813929 polymorphism(fixed effect model:OR=1.57,95% CI=1.25-1.97, P<0.52)were both statistically correlated with the risk of ADHD; None of the HTR2 A gene rs6314 polymorphism(random effect model:OR=1.09,95% CI=0.77-1.54, P=0.62), rs6313 polymorphism(random effect model:OR=0.96,95% CI=0.85-1.08,P=0.52)and rs6311 polymorphism(fixed effect model:OR=0.96,95% CI=0.86-1.07,P=0.45) were statistically associated with ADHD susceptibility.Conclusion(1) HTR1 A gene rs6295 polymorphism is associated with ADHD susceptibility in Chinese Han children, and the GG genotype and-1019 G allele are risk factors;(2) HTR1 B gene rs6296 polymorphism is associated with the risk of ADHD, and the 861 G allele is a risk factor;(3) HTR2 C gene rs518147 and rs3813929 polymorphisms were probably associated with ADHD susceptibility;(4) HTR2 A gene rs4314, rs6313, and rs6311 polymorphisms may have no relationship with ADHD susceptibility. |
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