Attention Deficit Hyperactivity Disorder: Studies Of Genetic Model And Associations With COMT And D β H Polymorphisms

Objectives( i ) To analysis the genetic model of attention deficit hyperactivity disorder (ADHD) and to explore the role of the genetic factors in the etiology of ADHD.(ii) To analysis the association between polymorphisms in human catechol-0-methyltransferase gene and dopamine -hydroxylase gene and ADHD. To understand the interaction between COMT gene and D H gene in ADHD. To find the disease-perdisposing genes of ADHD. To explore the relationship between D H activity in plasma and genotypes of D H gene. Methods( i ) The ADHD prevalence and disease types of degree relatives of probands children in 54 ADHD families were measured using family -based analysis. The single-gene segregation analysis was used to analysis the family data to prove the genetic mode of autosomal inheritance or X-linked inheritance of ADHD, and the polygenic multiple threshold model was used to explore the polygenic mode and to estimate the heritability, the liability of ADHD and the recurrence risk of ADHD in each degree relatives.(ii) Genotypes and allele frequencies of VaH58Met polymorphism at COMT gene and polymorphic (GT) n repeat at D H gene in ADHD probands, their parents, and normal controls were examined by PCR, RFLP and Amp-FLP techniques. Both case-control association study and family-based association study (HRR and TDT analysis) were used. Plasma D H activity was photometrically assayed.Results Part 1(i) Prevalences of ADHD in the first-, second- and third-degree relatives of ADHD probands were 29.63%, 3.25% and 4.42%, respectively. The prevalence of ADHD in the first-degree relatives was significantly higher than that of the general population.The ADHD prevalences of the first- and the second-degree relatives were rapidly decreased with the increased magnitude of consanguineous relationships of each degree relatives and ADHD probands.(ii) There were comorbid conditions among affected relatives in each degree of families. The comorbid disorders were Learning Disorders and Conduct Disorder in childhood, and the patterns of psychiatric disorders were Personality Disorders, Gambling and Alcohol Dependence in adulthood.(iii) Among the first-degree relatives of probands children, the prevalence of male affected relatives was significantly higher than that of female affected relatives (p<0.01). There was no statistical significance in percentage of each subtype of ADHD (DSM-IV Criteria) between male and female relatives. In addition that, sum of ADHD fathers of ADHD probands were significantly more than that of ADHD mothers of ADHD probands.(iv) The genetic model of ADHD was probably polygenic inheritance with major genes, while other models such as autosomal inheritance or X-linked inheritance could be rejected. The weighted mean value of heritability of ADHD was (102.47 9.78) %.(v) The expected prevalences of ADHD in each degree relatives were 23.0%, 8.9% and 5.0%, respectively. The first-degree relatives of probands children were in high risk for ADHD. The ADHD prevalence of each degree relatives rapidly decreased with the increased magnitude of consanguineous relationships of each degree relatives and ADHD probands. No differences were found between actual prevalence and expected prevalence of ADHD in each degree relatives of probands children (p<0.05), which suggested that ADHD was a familial disorder.Part 2( i ) No differences in genotypes and allele frequencies of Vall58Met polymorphism at COMT gene were observed between ADHD group and control group (p>0.05), and in nuclear families (p>0.05). The frequencies of genotype G/G and G allele of Vall58Met polymorphism at COMT gene in ADHD predominantly inattention subtype were significantly higher than those in combined subtype (p<0.05). The G/A frequency in combined subtype significantly increased (p<0.05) .A allele was associated with certain clinical manifestations (attention problems, delinquent behavior and aggressive behavior).( ii ) No differences in genotypes and allele frequencies of polymorphic (GT) n r...