| OBJECTIVE: Internet addiction disorder should be viewed as a serious public health problem,and which is a behavioral addiction with health,psychological,social,emotional,economic,and legal consequences.Identification of contributing genes and pathways may improve understanding of aetiology,facilitate therapy and prevention.This study will assess the association with single nucleotide polymorphisms in DRD1,DRD2,DRD3,HTR2 A,COMT,BDNF,CHRNA4 genes and internet addiction disorder susceptibility.The environmental factors and gene-environment interactions were also evaluated.METHODS: A case control study was conducted to genotype the SNPs loci including rs686 and rs4532 in DRD1 gene,rs1800497 and rs6277 in DRD2 gene,rs6280 in DRD3 gene,rs6313 and rs6311 in HTR2 A gene,rs4680 in COMT gene,rs6265 in BDNF gene,rs1044396 in CHRNA4 gene.207 students with a diagnosis of internet addiction disorder and 339 controls according to the Kimberly Young Internet Addiction Impairment Index were recruited in Chinese vocational school.Oral exfoliated cells were collected and SNP genotyping were accomplished by using an ABI3730 XL DNA sequencer.The Adolescent Self-rating Life Events Checklist was used to measure negative life event,the Childhood Trauma Questionnaire-Short Form was used to measure childhood maltreatment experiences,including abuse and neglect,subjective social support,perceived social support and social support utilization was assessed with the Chinese Social Support Rating Scale.Statistical analysis of the association between SNPs and internet addiction disorder was performed using the chi-squared test and SPSS software.The genetic distributions of each group were tested for Hardy-Weinberg equilibrium(HWE).Haplo View 4.2 software was used to calculate linkage disequilibrium blocks and haplotype association risk.Logistic regression was used to assess two factors interaction between gene and gene,gene and environmental factor with odds ratios(ORs)and 95% confidence intervals(95%CIs).Additive interaction between gene and environmental factors was estimated using relative excess risk due to interaction(RERI),attributable proportion due to interaction(AP),and synergy index(S).Significant RERI> 0,AP> 0,and S> 1 indicated additive interaction.Gene-gene interaction and gene-gene interaction were analyzed by Generalized Multifactor Dimensionality Reduetion(GMDR).RESULTS: Genotype frequencies for all SNPs were in Hardy-Weinberg equilibrium(P>0.05).1.The genotype distribution of rs4532 in DRD1 gene was not significantly different between IAD group and controls group after the Bonferroni correction,the frequencies of TT genotype were significantly higher in IAD group than in control group(TT vs CT+CC: OR=1.753,95%CI: 1.174~2.616,P=0.006),the T allele of rs4532 was found significantly associated with increased risk of IAD(OR=1.590,95%CI: 1.109~2.281,P=0.011).2.The genotype distribution of DRD2 gene rs1800497 was significantly different between IAD group and controls group(χ2=11.908,P=0.003),the frequencies of GG genotype were significantly higher in IAD group than in control group(GG vs AA+GA: OR=1.727,95%CI: 1.187~2.511,P=0.004),the G allele of rs1800497 was found significantly associated with increased risk of IAD(OR=1.518,95%CI: 1.182~1.949,P=0.001). 3.The genotype distribution of HTR2 A gene rs6313,rs6311 were significantly different between IAD group and controls group(χ2=9.004,P=0.011;χ2=11.150,P=0.004),the frequencies of rs6313 TT genotype were significantly higher in IAD group than in control group(TT vs CT+CC: OR=1.726,95%CI: 1.195~2.493,P=0.003),the frequencies of rs6311 TT genotype were significantly higher in IAD group than in control group(TT vs CT+CC: OR=1.824,95%CI: 1.263~2.634,P=0.001),the T allele of rs6313 was not significantly associated with IAD(χ2=4.485,P=0.034),and the T allele of rs6311 was not significantly associated with IAD(χ2=5.247,P=0.022).4.We found no significant association between polymorphisms of rs686,rs6277,rs6280,rs4680,rs6265,rs1044396 and IAD.5.Haplotype analysis demonstrated that there was a strong linkage disequilibrium(LD)between rs686 and rs4532(IAD group: D’=1.0,r2 =0.89,control group: D’=0.98,r2 =0.96),rs6313 and rs6311(IAD group: D’=0.99,r2 =0.97,control group: D’=0.99,r2 =0.97),weak LD between rs1800497 and rs6277(IAD group: D’=0.63,r2 =0.02,control group: D’=0.56,r2 =0.02).6.Haplotypes containing rs686(G)-rs4532(C)in DRD1 gene was found significantly associated with decreased risk of IAD(OR=0.653,95%CI: 0.455~0.939),rs686(A)-rs4532(T),rs6313(T)-rs6311(T)and rs6313(C)-rs6311(C)were not significantly associated with IAD.7.Using Logistic regression model to analyze the interaction between SNPs,the results showed that rs1800497 and rs6313,rs1800497 and rs6311 have multiplicative interaction,subjects with GA of rs1800497 and CT of rs6313 genotype have the highest IAD risk,compared to subjects with GG of rs1800497 and CC of rs6313 genotype,OR(95%CI)was 4.441(1.472~13.399),subjects with GA of rs1800497 and CT of rs6311 genotype have the highest IAD risk,compared to subjects with GG of rs1800497 and CC of rs6311 genotype,OR(95%CI)was 4.572(1.516~13.792).GMDR analysis indicated that there was a significant three-locus model(P=0.001)involving rs686,rs1800497 and rs6311.8.Logistic regression analysis show that relationship pressure(OR=1.575,95%CI: 1.037~2.391,adjusted P=0.033),adaption problem(OR=2.533,95%CI: 1.672~3.837,adjusted P<0.001),physical abuse(OR=1.825,95%CI: 1.168~2.853,adjusted P=0.008)were associated with IAD.9.Analysis of first-order interaction with four loci and environmental factors by Logistic regression model showed that there was no significant relationship between each other.GMDR analysis indicated that there was a significant three factors model(P=0.001)involving rs1800497,rs6311 and adaption problem.CONCLUSIONS: DRD1 gene,DRD2 gene and HTR2 A gene may be susceptibility genes of IAD.Gene-gene interaction effect was found between DRD2 gene and HTR2 A gene.Gene-environment interaction effect was also found between DRD2 gene,HTR2 A gene and negative life events. |
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