注意缺陷多动障碍的遗传方式以及与儿茶酚-O-甲基转移酶基因和多巴胺β羟化酶基因的关联分析
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摘要
目的
1．研究ADHD可能的遗传方式，探讨遗传因素在ADHD发生中的地位和作用。
2．分析COMT基因和DβH基因多态性与ADHD的关联以及两基因之间的相互作用；寻找ADHD的易感基因；探讨血浆DβH活性水平与DβH基因型之间的关系。
方法
1．第一部分：采用家系调查方法，对54个ADHD家系的各级患病亲属的患病类型、ADHD的患病率等进行了分析，并采用分离分析对家系进行单基因显、隐性遗传以及X、Y连锁遗传的单基因遗传方式分析，采用多基因阈值模型理论方法，对家系进行多基因遗传方式分析，并对各级亲属遗传度、疾病易患性和ADHD再病风险进行估计。
2．第二部分：采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)和扩增片段长度多态性(Amp-FLP)的分子遗传学技术，检测ADHD患者及其父母和正常对照者COMT基因Val158Met多态性和DβH基因(GT)n重复序列多态性的基因型和等位基因频率，运用病例对照研究和核心家系的关联分析(HRR和TDT)方法分别进行分析；并对血浆DβH活性进行了测定。
结果
第一部分
1．先证者的一、二、三级亲属ADHD患病率分别为29.63％，3.25％和4.42％，其中，一级亲属患病率明显高于群体患病率；一、二级亲属患病率随着与先证者的亲缘关系级数递增而剧减。
2．各级ADHD患病亲属中有较明显的共病现象，童年期以共病学习障碍和品行障碍为主，成年期患病类型有各类人格障碍、病态赌博和酒依赖等。
3．一级亲属中，男性亲属患病人数多于女性亲属患病人数
巾＜0刀1入 男女性患病亲属在疾病亚型（＊8＊－w）构成上差异无显
著性：先证者的父亲患病人数明显多于母亲患病人数中叨刀1人
4．ADHD的遗传方式既不符合常染色体显、隐性遗传，也不符
合X．Y连锁遗传，可能是具有主基因的多基因遗传。估算其加权平
均遗传度为门．47士9．78）％。
5．由加权平均遗传度估计ADHD再病风险，显示各级亲属预期
患病率分别为23．0％，8．9％和5．0％，其中，一级亲属患病风险明显
增高；各级亲属患病率随着与先证者的亲属关系级数递增而剧减，先
证者各级亲属的实际患病率与预期患病率之间差异无显著性
中J刀5人支持AD HD具有家族聚集性。
第二部分
1．COMT基因Vat158Met多态性各基因型频率和等位基因频率
在ADHD组与对照组以及核心家系中的分布差异均无显著性（均
尸＞0．05人 ADHD注意缺陷为主型患儿 COMT基因的 G／G型频率和 G
等位基因频率明显高于混合型的GIG型频率和G等位基因频率
巾＜0．05人 ADHD混合型患儿的 GIA型明显增多巾＜0．05入 A等
位基因与ADHD的某些临床症状如注意问题、违纪行为、攻击行为
等相关。
2．DOH基因（GT）n重复序列多态性的各基因型频率和等位基
因频率在ADHD组与对照组以及核心家系中的分布差异均无显著性
（均尸＞0．05人DgH基因（GT）＞重复序列多态性A4等位基因在本
研究对象中出现的频率较低。单纯ADHD患儿AZ等位基因频率明
显高于共病患几中＜0刀5人AZ／A 3型在＊B＊L的社交问题、注意问
题、攻击行为得分以及行为总分得分上均明显高于A3／A3 型
中＜0．05人NHD组与对照组健康儿童D a H活性差异无显著性
（尸＞O．05）。
3．在ADHD中未发现COMT基因和D6H基因之间有相互作用。
结论
第一部分
1．ADHD具有家族聚集性；ADHD的一级亲属患病风险明显增’
高。
2．ADHD可能在童年期易于与学习障碍、品行障碍共病，成年
11
期患病类型有各类人格障碍、病态赌博和酒依赖等，ADHD可能与
这些疾病的发生有关。
3．一级亲属中ADHD的患病可能存在性别差异，男性多于女性。
4．ADHD的遗传方式可能是具有主基因的多基因遗传。估算其
加权平均遗传度为 （10．47土9．78）％。其遗传因素在决定ADHD易
患性变异上可能有重要作用，除了微效的累加的多对基因外，可能还
存在着主基因。
第二部分
l．CO皿基因可能与ADHD缺乏关联。COMT基因可能与
ADHD临床亚型或症状有关。G等位基因可能是注意缺陷为主型的
一个风险因子，A等位基因可能是该亚型的一个保护因于。G／A型可
能与混合型有关。
2．D6H基因可能与ADHD缺乏关联。A4等位基因在本研究对
象中出现的频率较低。AZ可能与单纯ADHD有关。DgH基因（GT）
n重复序列多态性可能与ADHD的某些临床特征有关。
3．ADHD中COMT基因和D6H基因之间无相互作用。
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
1．研究ADHD可能的遗传方式，探讨遗传因素在ADHD发生中的地位和作用。
2．分析COMT基因和DβH基因多态性与ADHD的关联以及两基因之间的相互作用；寻找ADHD的易感基因；探讨血浆DβH活性水平与DβH基因型之间的关系。
方法
1．第一部分：采用家系调查方法，对54个ADHD家系的各级患病亲属的患病类型、ADHD的患病率等进行了分析，并采用分离分析对家系进行单基因显、隐性遗传以及X、Y连锁遗传的单基因遗传方式分析，采用多基因阈值模型理论方法，对家系进行多基因遗传方式分析，并对各级亲属遗传度、疾病易患性和ADHD再病风险进行估计。
2．第二部分：采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)和扩增片段长度多态性(Amp-FLP)的分子遗传学技术，检测ADHD患者及其父母和正常对照者COMT基因Val158Met多态性和DβH基因(GT)n重复序列多态性的基因型和等位基因频率，运用病例对照研究和核心家系的关联分析(HRR和TDT)方法分别进行分析；并对血浆DβH活性进行了测定。
结果
第一部分
1．先证者的一、二、三级亲属ADHD患病率分别为29.63％，3.25％和4.42％，其中，一级亲属患病率明显高于群体患病率；一、二级亲属患病率随着与先证者的亲缘关系级数递增而剧减。
2．各级ADHD患病亲属中有较明显的共病现象，童年期以共病学习障碍和品行障碍为主，成年期患病类型有各类人格障碍、病态赌博和酒依赖等。
3．一级亲属中，男性亲属患病人数多于女性亲属患病人数
巾＜0刀1入 男女性患病亲属在疾病亚型（＊8＊－w）构成上差异无显
著性：先证者的父亲患病人数明显多于母亲患病人数中叨刀1人
4．ADHD的遗传方式既不符合常染色体显、隐性遗传，也不符
合X．Y连锁遗传，可能是具有主基因的多基因遗传。估算其加权平
均遗传度为门．47士9．78）％。
5．由加权平均遗传度估计ADHD再病风险，显示各级亲属预期
患病率分别为23．0％，8．9％和5．0％，其中，一级亲属患病风险明显
增高；各级亲属患病率随着与先证者的亲属关系级数递增而剧减，先
证者各级亲属的实际患病率与预期患病率之间差异无显著性
中J刀5人支持AD HD具有家族聚集性。
第二部分
1．COMT基因Vat158Met多态性各基因型频率和等位基因频率
在ADHD组与对照组以及核心家系中的分布差异均无显著性（均
尸＞0．05人 ADHD注意缺陷为主型患儿 COMT基因的 G／G型频率和 G
等位基因频率明显高于混合型的GIG型频率和G等位基因频率
巾＜0．05人 ADHD混合型患儿的 GIA型明显增多巾＜0．05入 A等
位基因与ADHD的某些临床症状如注意问题、违纪行为、攻击行为
等相关。
2．DOH基因（GT）n重复序列多态性的各基因型频率和等位基
因频率在ADHD组与对照组以及核心家系中的分布差异均无显著性
（均尸＞0．05人DgH基因（GT）＞重复序列多态性A4等位基因在本
研究对象中出现的频率较低。单纯ADHD患儿AZ等位基因频率明
显高于共病患几中＜0刀5人AZ／A 3型在＊B＊L的社交问题、注意问
题、攻击行为得分以及行为总分得分上均明显高于A3／A3 型
中＜0．05人NHD组与对照组健康儿童D a H活性差异无显著性
（尸＞O．05）。
3．在ADHD中未发现COMT基因和D6H基因之间有相互作用。
结论
第一部分
1．ADHD具有家族聚集性；ADHD的一级亲属患病风险明显增’
高。
2．ADHD可能在童年期易于与学习障碍、品行障碍共病，成年
11
期患病类型有各类人格障碍、病态赌博和酒依赖等，ADHD可能与
这些疾病的发生有关。
3．一级亲属中ADHD的患病可能存在性别差异，男性多于女性。
4．ADHD的遗传方式可能是具有主基因的多基因遗传。估算其
加权平均遗传度为 （10．47土9．78）％。其遗传因素在决定ADHD易
患性变异上可能有重要作用，除了微效的累加的多对基因外，可能还
存在着主基因。
第二部分
l．CO皿基因可能与ADHD缺乏关联。COMT基因可能与
ADHD临床亚型或症状有关。G等位基因可能是注意缺陷为主型的
一个风险因子，A等位基因可能是该亚型的一个保护因于。G／A型可
能与混合型有关。
2．D6H基因可能与ADHD缺乏关联。A4等位基因在本研究对
象中出现的频率较低。AZ可能与单纯ADHD有关。DgH基因（GT）
n重复序列多态性可能与ADHD的某些临床特征有关。
3．ADHD中COMT基因和D6H基因之间无相互作用。
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
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