Association Between Genetic Variations Of Stress Response Gene And Attention Deficit Hyperactivity Disorder In Children

Objective: To investigate the association between genetic variations of stress response gene and ADHD in children so as to provide novel thought and theoretical basis for the pathogenesis of ADHD.Methods: A case-control study strategy was used in this research.All of the 406 cases and 432 controls were recruited from Wuhan.The cases were new medication-free cases diagnosed by Swanson,Nolan,and Pelham-IV Questionnaire(SNAP-IV),and the controls were healthy children conducted physical checkups during the same period.A Chinese Wechsler Intelligence Scale for children was administered to all participants,and the IQs were above 70.SNAP-IV,Parent Symptom Questionnaire(PSQ),Continuous Performance Test(CPT)and electroencephalogram(EEG)were conducted to measure the clinical characteristics of all participants.Fill out Life Events Scale for Pregnant Women(LESPW)and collect 2ml venous blood in each child.Genotyping of candidate genes was performed using the Sequenom Mass ARRAY.The t test and χ2 test were performed to examine the difference of demographic characteristic and SNPs between cases and controls in SPSS 21.0.The risk of clinical symptoms with SNPs was explored by t test and ANOVA.Multivariate logistic regression models were conducted to analyze the association of SNPs with ADHD.Bonferroni correction was performed for multiple comparison corrections for association analysis.Logistic regression analysis was used to analyze the risk of maternal stress during pregnancy in ADHD.Gene-gene and gene-environment interactions between the positive association SNPs and maternal stress during pregnancy were investigated by both additive and multiplicative model to explore their effect in ADHD.Results: 1.With the Bonferroni correction,the results of association analysis showed that NR3C1 rs6191 and SLC4A4 rs25531 were both significantly associated with ADHD.rs6191 was relative to ADHD in codominant model(OR=0.566,95%CI=0.380-0.844),dominant model(OR=0.564,95%CI=0.389-0.819)and addictive model(OR=0.694,95%CI=0.458-0.858).rs6191 was also associated with clinical symptoms like attention deficit(P=0.006),ADHD-C subtypes(P=0.006)and comorbid anxiety-depression disorder(P=0.007).rs25531 was relative to ADHD in dominant model(OR=1.573,95%CI=1.120-1.938)and addictive model(OR=1.380,95%CI=1.111-1.714).rs25531 was in connection with attention deficit(P=0.003)and ADHD-I subtypes(P=0.007).2.Maternal stress during pregnancy(OR=2.388,95%CI=1.575-3.620)was a risk factor for ADHD.Children carry both rs6191(CA+AA)and rs25531(AG+GG)genotypes had 1.153 times more risk to suffer ADHD.There were also interactions between rs6191/rs25531 and maternal stress during pregnancy(OR=2.433,95%CI=1.181-1.739;OR=2.630,95%CI=1.317-2.039).Conclusions: NR3C1 rs6191 and SLC6A4 rs25531 were associated with susceptibility of ADHD in children.There was an interaction between two SNPs and maternal stress during pregnancy in the pathogenesis of ADHD.The positive associations found need to be verified in different regions and populations,and their biological functions also should be further identified.