Association Study Between The Methylation Of Promoter Region Of NR3C1 And NR3C2 Genes And Aggressive Behavior

Objective:To study the association between methylation status in the promoter region of NR3C1and NR3C2 genes and aggressive behavior,and to reveal the epigenetic regulation mechanism of aggression,so as to provide theoretical basis for the prevention and control of violence.Methods:The CpG islands in the promoter region of NR3C1 and NR3C2 genes of 104 adult males with aggressive behavior?54 physical aggression,50 property aggression?and correspondingly 106 healthy individuals were detected via sodium bisulfite treatment combined with MethylTarget method.To evaluate the aggressiveness and impulsiveness of aggression group and control group by Buss-Perry Aggression Questionaire and Barratt Impulsivity Scale.The statistical analysis was performed using statistical software like SPSS 20.0.Results:1.Age compositionThe average age of the aggression group was 33.88±12.39 years old,while that of the control group was 32.96±10.87 years old,with the largest number in the 18-40 age group.There was no significant difference in age between the aggression group and the control group?P>0.05?.2.Evaluation of aggression and impulsiveness scale and its correlation with DNA methylation levelThe total score and subscale score of Buss-Perry Aggression Questionaire and Barratt Impulsivity Scale were significantly different between the aggression group and the control group?P<0.05?,and the score of the aggression group were significantly higher than the control group.The results showed that the methylation level of NR3C1₁F region in the Buss-Perry Aggression Questionaire was positively correlated with the score of physical aggression subscale?r=0.140,P=0.048?and hostility subscale?r=0.143,P=0.04?.The methylation status of NR3C2₄ region was also positively correlated with the scores of hostility subscale?r=0.166,P=0.018?and pointing to self-aggression subscale?r=0.159,P=0.024?.Barratt Impulsivity Scale showed that there was a positive correlation between the methylation level of NR3C2₄ region and the score of unplannned impulsivity subscale?r=0.154,P=0.028?.3.The analysis results of risk factors of aggressive behaviorPeople with lower educated?P<0.001,OR[95%CI]:8.687[3.957-19.069]??single?P<0.001,OR[95%CI]:3.415[1.881-6.201]?and smoking?P-0.006,OR[95%CI]:2.500[1.305-4.788]?had a higher risk of aggressive behavior than those with higher educated?married and non-smoking.4.The relationship between DNA methylation of the promoter region of NR3C1 and aggressive behaviorIn this study,there were 4 regions?including NR3C1₁D,1B,1F,1H?and 83 CpGs sites were detected.It was found that 2 regions?NR3C1₁B and NR3C1₁F?and 14 CpGs sites?ID CpG-1.1B CpG-2,CpG-5,CpG-6,CpG-7,CpG-8,CpG-11,CpG-12,CpG-16.1FCpG-12,CpG-20,CpG-21,CpG-26,CpG-28?had significant difference in methylation level between the aggression group and the control group,and the methylation level in the aggression group was higher than that in the control group.The NR3C1₁B region and NR3C1₁B CpG-12 site were still significant when corrected by Bonferroni.The aggression group was divided into physical aggression subgroup and property aggression subgroup,and pairwise comparision was made among physical aggression subgroup,property aggression subgroup and control group.It was found that there was significant difference in the methylation level of NR3Cl₁B regions between the physical aggression subgroup,the property aggression subgroup and control group?P<0.001?,and the methylation levels were higher than those of the control group.The methylation level of NR3C1₁B CpG-2 site between the property aggression subgroup and the control group was significantly higher than that of the control group?P=0.003?.The methylation level of NR3C1₁B CpG-4 in the property aggression subgroup was significantly higher than that in the control group?P=0.012?and physical aggression subgroup?P=0.014?.The methylation level of NR3C1₁B CpG-12 in the physical aggression subgroup?P=0.014?and the property aggression subgroup?P<0.001?were significantly higher than those in the control group.The methylation level of NR3C1₁F CpG-32in the property aggression subgroup was significantly lower than that in the control group?P=0.015?and physical aggression subgroup?P=0.039?.The methylation level of NR3C1₁H CpG-9 in the property aggression subgroup was significantly lower than that in the control group?P=0.049?and the physical aggression subgroup?P--0.004?.The methylation level of NR3C1₁H CpG-11 in the physical aggression subgroup was lower than that in the property aggression subgroup?P=0.025?.After Bonferroni correction,there was no significant difference in NR3C11FCpG-32 methylation level between property aggression subgroup and physical aggression subgroup,NR3C1₁HCpG-9 methylation level had no significant difference between property aggression subgroup and control group,and NR3C1₁HCpG-11 methylation level had no significant difference between physical aggression subgroup and property aggression subgroup.5.The relationship between DNA methylation of the promoter region of NR3C2 and aggressive behaviorIn this study,there were 4 regions?including NR3C2₁,2,3,4?and 75 CpGs sites were detected.It was found that 1 region?NR3C2₄?and 7 CpGs sites?NR3C2 1 CpG-5 NR3C2₂ CpG-4,CpG-11.NR3C2₃ CpG-17.NR3C2₄ CpG-11,CpG-19,CpG-22?had significant difference in methylation level between the aggression group and the control group,and the methylation level in the aggression group was higher than that in the control group.The NR3C2₄ region and NR3C2₂ CpG-11 sites were still significant when corrected by Bonferroni.A pairwise comparison was made among the physical aggression subgroup,property aggression subgroup and control group.It was found that there was a significant difference in the methylation level of NR3C2₄ region between the property aggression subgroup and the control group?P=0.005?,and the methylation level of the property aggression subgroup was higher than that of the control group.The methylation levels of NR3C2₂ CpG-11 in the physical aggression subgroup?P=0.013?and the property aggression subgroup?P=0.012?were significantly higher than those in the control group.The methylation level of NR3C2 3 CpG-5 physical aggression subgroup was significantly lower than that of control group?P=0.033?and property aggression subgroup?P=0.019?.The methylation level of NR3C2₄ CpG-19 in the property aggression subgroup was significantly higher than that in the control group?P=0.028?.After Bonferroni correction,there was no significant difference in the methylation level of NR3C2₃ CpG-5 site and NR3C2₄ CpG-19 site.6.The relationship between education,marital status?smoking and DNA methylationThe methylation level of lower educated group was significantly higher than higher educated group in NR3C1₁B region?P<0.05?.The methylation level of smoking group was significantly higher than no smoking group in NR3C2₄ region?P<0.05?.Further analysis,the methylation of NR3C1₁B region in lower educated groups and NR3C2₁ region in higher educated groups were significantly higher in the aggression group than the control group;the methylation of NR3C1₁F?NR3C1₁B?NR3C2₁?NRC2₃ region in the single groups and NR3C1₁B?NR3C2₄ region in the married groups were significantly higher than those in the control group;the methylation of NR3C1₁B region in somkers and NR3C1₁B?NR3C1₁F region in non-somkers were significantly higher than those in the control group.In the aggression group,there were no significant difference in the methylation levels of different educational levels and marital status.The methylation of NR3C2₂ region showed a significant difference between smoking and non-smoking groups?P=0.036?,while the methylation levels of other region showed no significant difference between smoking and non-smoking groups.Conclusions:1.The hypermethylation status of NR3C1 gene and NR3C2 gene was associated with aggressive behavior,and the hypermethylation state was more aggressive and impulsive.2.The epigenetic regulation mechanisms of physical aggression?personal attacks directed at others?and property aggression?attacks directed to property?may be different.3.The lower educated?singleness and smoking were risk factors for aggressive behavior,and interaction with aggressive behavior affects the methylation level of aggressive behavior.