多巴胺D4受体基因启动子区多态性研究以及与慢性抽动障碍的关联研究
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摘要
目的
慢性抽动障碍(chronic tic disorder)是一种复杂的、慢性神经精神障碍，多起病于儿童期，以多种运动或发声抽动为主要临床表现。其患病率男性大于女性，常伴有强迫、多动等行为和情绪障碍。慢性抽动障碍的病因至今尚不十分明了，其病因学的研究近年来主要集中在分子生物学方面，目前比较公认的一个假说是抽动障碍的病因和多巴胺系统的紊乱有关系，涉及多巴胺能系统的代谢通路上的基因都成为了抽动障碍的候选基因，多巴胺受体基因也毫无争议的成为人们研究的重点对象，其中最为引人注目的是多巴胺D4受体基因。
目前，对多巴胺D4受体基因多态性的研究主要集中在第三外显子的48bpVNTR多态性与抽动障碍、ADHD等精神疾病相关性方面，但在中国辽宁地区，对于多巴胺D4受体基因启动子区的多态性分布特点及其与慢性抽动障碍的相关性研究均未见报道。为此，本课题选取多巴胺D4受体基因启动子区3个功能多态性位点(-1240L／S、-521C／T、-616C／G)，首先在辽宁汉族人群中进行多态性分析，然后采用病例-对照研究多巴胺D4受体基因启动子区的多态性与慢性抽动障碍发病风险的关系，在此基础上，构建含有不同多态性的pGL3-DRD4启动子的质粒，转染HeLa细胞，通过双荧光素酶报告系统，探讨多巴胺D4受体基因启动子区的多态性与慢性抽动障碍相关的可能机制。
方法
1．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点的遗传多态性分析
选择100名无血缘关系个体，提取静脉血白细胞基因组DNA，采用聚合酶链反应及等位基因特异性扩增技术，对DRD4基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点，进行基因型频率和等位基因频率分析，并进行Hardy-Weinberg平衡吻合度检验及连锁不平衡分析。然后将中国辽宁人群DRD4基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点的等位基因频率分布与文献报道的其他人群进行比较，并进行X~2检验。
2．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点与慢性抽动障碍的关联分析
选取无亲缘关系的慢性抽动障碍患儿84例以及无亲缘关系的健康个体100例为对照组，提取静脉血白细胞基因组DNA，采用聚合酶链反应及等位基因特异性扩增技术检测DRD4基因启动子区-1240L／S，-616C／G和-521C／T 3个功能位点的基因型。用SHEsis在线统计软件分析各位点等位基因、基因型、单倍型频率及其组间差异。
3．多巴胺D4受体基因启动子区-616C／G位点的功能分析
在上述实验中选择-616C／G位点分别为-616CC和-616GG的两个纯合子个体的基因组DNA为模板，构建多巴胺D4受体基因启动子区-616C／G位点的荧光素酶报告基因的表达载体，分别为重组质粒pGL3-D4C和pGL3-D4G。应用脂质体载体介导方法将重组质粒pGL3-D4C和pGL3-D4G转染到HeLa细胞中表达，以双荧光素酶报告基因检测系统检测多巴胺D4受体基因启动子区-616C／G位点的转录活性。
结果
1．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点的遗传多态性分析结果
DRD4基因启动子区-1240L／S的等位基因频率分别为60％和40％；-616C／G的等位基因频率分别为18％和82％；-521C／T的等位基因频率分别为39％和61％。X~2检验显示，基因型频率的观察值和期望值无显著性差异，提示
该群体符合Hardy-Weinberg遗传平衡法则。3个位点间存在较弱的连锁不平衡。中国辽宁地区人群与其他人群基因多态性分布频率对照研究发现，-1240L／S位点在辽宁和上海地区等位基因分布无差异，但与日本、欧洲白种人、加拿大白种人比较有显著性差异；-521C／T位点在辽宁和上海地区、日本、欧洲白种人、美国黑人等位基因分布比较均无显著性差异；-616C／G位点在辽宁和上海地区、日本、欧洲白种人、匈牙利白种人等位基因分布比较均有显著性差异。
2．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点与慢性抽动障碍的关联分析结果
-1240L／S和-521C／T位点的等位基因和基因型频率，在慢性抽动障碍组与正常对照组间比较，均无显著性差异；-616C／G位点的等位基因频率及其基因型频率在慢性抽动障碍组显著高于正常对照组(P=0.004，χ~2=8.419；P=0.020，χ~2=7.860)；DRD4基因-1240L／S，-616C／G和-521C／T组成的单倍型LCT的频率在慢性抽动障碍组显著高于正常对照组(p=0.012，χ~2=6.371)。
3．多巴胺D4受体基因启动子区-616C／G位点的功能分析结果
成功构建了重组质粒pGL3-D4C和pGL3-D4G。将pGL3-D4C和pGL3-D4G重组质粒分别与内参照质粒pRL-TK共转染HeLa细胞，利用双荧光素酶检测系统检测相对光强度，结果与pGL3-basic空载体相比，pGL3-D4C和pGL3-D4G重组质粒的相对光强度均明显增强，p＜0.05，表明-616C和-616G均具有启动报告基因转录的能力。在HeLa细胞中，pGL3-D4C和pGL3-D4G重组质粒的相对光强度与pGL3-basic空载体的相对光强度的比率分别为：7.6±0.5，34.7±1.5。pGL3-D4C比pGL3-D4G重组质粒的转录活性明显降低(p＜0.05)，pGL3-D4G的转录活性约是pGL3-D4C的4.6倍。
结论
1．多巴胺D4受体基因启动子区-1240L／S、-616C／G位点多态分布在世界范围内存在明显的种族差异；而-521C／T位点的多态性分布可能无明显的种族差异。
2．DRD4基因启动子区多态性与慢性抽动障碍易感性相关，DRD4基因-616C等位基因可能是决定慢性抽动障碍个体易感性的重要因素，而含有LCT单倍型的个体发生慢性抽动障碍的相对风险显著增高。
3．DRD4基因启动子区的-616 G＞C的变异可能在DRD4基因表达调控中起重要作用。
Objective
Chronic tic disorder is a childhood-onset neuropsychiatric disorder characterized by multiple motor or vocal tics lasting more than one year. The prevalence of tics occurs in more males than females. In addition, affected individuals frequently display symptoms such as obsessive-compulsive disorder, attention-deficit hyperactivity disorder and behaviors disorder. Despite evidence that chronic tic disorder is an inherited disorder, the exact genetic abnormality is unknown. Dopaminergic hypotheses have included abnormalities of both pre- and postsynaptic function in chronic tic disorder. Based on neurobiological theories, most of the candidate genes belong to the dopamine neurotransmitter system. In particular, the highly polymorphic dopamine D4 receptor (DRD4) gene has attracted increasing interest.
Currently, there were many studies about the 48-bp variable number of tandem repeats (VNTR) in the third exon polymorphism of the DRD4 gene and their relationship with tics, ADHD ect. neuropsychiatric disorder, but there is less reports concerning polymorphisms in the promoter region of the DRD4 gene distributing characteristics in liaoning, and association with chronic tic disorder. In our study, we test three polymorphisms in the promoter region (-1240L/S, -616C/G, -521C/T). Firstly, we study the distribution of the three gene polymorphisms in Chinese Han population Liaoning. Secondly, the association of polymorphisms in the promoter region with chronic tic disorder was studied using a case-control design. Finally, the functional activity of polymorphism was investigated through gene transfection and Dual-Luciferase Reporter assay system. To study whether there is an association of the three functional polymorphisms in the promoter region of dopamine D4 receptor (DRD4) gene with chronic tic disorder.
Methods
1. The three gene polymorphisms in the promoter of Dopamine D4 receptor in Chinese Han population Liaoning
Genomic DNA was isolated from venous blood leukocytes from 100 healthy unrelated individuals. Polymorphisms of DRD4, -1240L/S, -616C/G and -521C/T, were genotyped by PCR and allele specific amplification (ASA) techniques and tested Hardy-Weinberg equilibrium. Current results were compared with the data on other ethnic groups, and carried X~2 test.
2. Association between the polymorphisms in the promoter region of dopamine D4 receptor gene and chronic tic disorder
Genomic DNA was isolated from venous blood leukocytes from 84 unrelated patients with chronic tic disorder (Study group) and 100 healthy unrelated individuals as controls. Polymorphisms of DRD4, -1240L/S, -616C/G and -521C/T, were genotyped by allele-specific primer (ASP) PCR. The frequencies of genotypes, allele and haplotypes were analysed by SHEsis online.
3. The functional study of-616C/G in the promoter region of DRD4 gene Particular geneomes of two homozygotes of -616C/G, -616CC and -616GG respectively were templates in above-mentioned experiment. We constructed luciferase reporter gene express vectors of -616C/G in the promoter region of DRD4 gene, pGL3-D4Cand pGL3-D4G, and respetively. Constructed vectors pGL3-D4C and pGL3-D4G were transfected into HeLa cell through lipid vector. The transcriptional activity of-616C/G was determined by Dual-Luciferase reporter assay.
Results
1. The three gene polymorphisms in the promoter of Dopamine D4 receptor in Chinese Han population Liaoning
Within the 100 individuals tested, the frequencies of -1240L/S in the 5'promoter region of the DRD4 gene were found to be 60% and 40%, respectively, which met Hardy-Weinberg equilibrium. The frequencies of -616C/G were found to be 18% and 82%, respectively, which met Hardy-Weinberg equilibrium. The frequencies of -521C/T were found to be 39% and 61%, respectively, which met Hardy-Weinberg equilibrium. Chinese Liaoning populations comparing with other populations gene polymorphism distribute frequency contrasting studying find that -1240L/S no significant difference in allele frequencies between Liaoning and shanghai, but significant difference between Liaoning and Japan, Europe and Canada. There was significant difference in allele distributions of -616C/G of DRD4 between the Liaoning Han population and those of shanghai Japan, Europe and Hungary. The distribution of -521C/T of DRD4 gene has not exhibit ethnic heterogeneity.
2. Association between the polymorphisms in the promoter region of dopamine D4 receptor gene and chronic tic disorder
There were no significant differences in allele frequencies and genotypes frequencies of DRD4 -1240L/S and -521C/T between the Study and the Control groups. There were significant differences in allele frequencies and genotypes frequencies (x~2 =8.419, P<0.01; x~2=7.860, P<0.05 respectively) of DRD4-616C/G between the Study and the Control groups. The haplotypic frequencies of LCT (-1240L/S, -616C/G, -521C/T) in the Study group were noticeably higher than in the Control group (x~2 =6.371, P<0.05).
3. The functional study of -616C/G in the promoter region of DRD4 gene
We had constructed pGL3-D4C and pGL3-D4G vector successfully. Transfection efficiencies were normalized by cotransfection with the Renilla vector, pRL-TK. Both pGL3-basic and pGL3-Control were separately transfected into the HeLa cells, which served as negative and positive controls, respectively, within the assay. The transcriptional activity of -616C/G was determined by Dual- Luciferase reporter assay. The transcriptional luciferase activety of pGL3-D4C and pGL3-D4G wre calculated by taking the ratio of the firefly luciferase activity versus the Renilla luciferase activity. Significant differences in luciferase activity were observed between pGL3-D4C and pGL3-D4G constructs at p<0.05, There were transcriptional activity of -616C and -616G. These ratios were compared with that obtained for the pGL3-basic vector to produce fold values representing increments in transcriptional activity over basic for pGL3-D4C and pGL3-D4G as follows: 7.6±0.5, 34.7±1.5. The transcriptional activity of -616C was much lower than that of -616G, The transcriptional activity of -616G was 4.6 times to -616C.
Conclusion
1. The distributions of -1240L/S and -616C/G of DRD4 gene exhibit ethnic heterogeneity; but .the distribution of -521C/T of DRD4 gene has not exhibit ethnic heterogeneity.
2. There is an association between the DRD4-616C/G polymorphism and chronic tic disorder. The individuals with haplotype LCT (-1240L/S, -616C/G, -521C/T) are more susceptible to chronic tic disorder.
3. -616C/G may have a role in regulating the expression of the DRD4 gene.
慢性抽动障碍(chronic tic disorder)是一种复杂的、慢性神经精神障碍，多起病于儿童期，以多种运动或发声抽动为主要临床表现。其患病率男性大于女性，常伴有强迫、多动等行为和情绪障碍。慢性抽动障碍的病因至今尚不十分明了，其病因学的研究近年来主要集中在分子生物学方面，目前比较公认的一个假说是抽动障碍的病因和多巴胺系统的紊乱有关系，涉及多巴胺能系统的代谢通路上的基因都成为了抽动障碍的候选基因，多巴胺受体基因也毫无争议的成为人们研究的重点对象，其中最为引人注目的是多巴胺D4受体基因。
目前，对多巴胺D4受体基因多态性的研究主要集中在第三外显子的48bpVNTR多态性与抽动障碍、ADHD等精神疾病相关性方面，但在中国辽宁地区，对于多巴胺D4受体基因启动子区的多态性分布特点及其与慢性抽动障碍的相关性研究均未见报道。为此，本课题选取多巴胺D4受体基因启动子区3个功能多态性位点(-1240L／S、-521C／T、-616C／G)，首先在辽宁汉族人群中进行多态性分析，然后采用病例-对照研究多巴胺D4受体基因启动子区的多态性与慢性抽动障碍发病风险的关系，在此基础上，构建含有不同多态性的pGL3-DRD4启动子的质粒，转染HeLa细胞，通过双荧光素酶报告系统，探讨多巴胺D4受体基因启动子区的多态性与慢性抽动障碍相关的可能机制。
方法
1．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点的遗传多态性分析
选择100名无血缘关系个体，提取静脉血白细胞基因组DNA，采用聚合酶链反应及等位基因特异性扩增技术，对DRD4基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点，进行基因型频率和等位基因频率分析，并进行Hardy-Weinberg平衡吻合度检验及连锁不平衡分析。然后将中国辽宁人群DRD4基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点的等位基因频率分布与文献报道的其他人群进行比较，并进行X~2检验。
2．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点与慢性抽动障碍的关联分析
选取无亲缘关系的慢性抽动障碍患儿84例以及无亲缘关系的健康个体100例为对照组，提取静脉血白细胞基因组DNA，采用聚合酶链反应及等位基因特异性扩增技术检测DRD4基因启动子区-1240L／S，-616C／G和-521C／T 3个功能位点的基因型。用SHEsis在线统计软件分析各位点等位基因、基因型、单倍型频率及其组间差异。
3．多巴胺D4受体基因启动子区-616C／G位点的功能分析
在上述实验中选择-616C／G位点分别为-616CC和-616GG的两个纯合子个体的基因组DNA为模板，构建多巴胺D4受体基因启动子区-616C／G位点的荧光素酶报告基因的表达载体，分别为重组质粒pGL3-D4C和pGL3-D4G。应用脂质体载体介导方法将重组质粒pGL3-D4C和pGL3-D4G转染到HeLa细胞中表达，以双荧光素酶报告基因检测系统检测多巴胺D4受体基因启动子区-616C／G位点的转录活性。
结果
1．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点的遗传多态性分析结果
DRD4基因启动子区-1240L／S的等位基因频率分别为60％和40％；-616C／G的等位基因频率分别为18％和82％；-521C／T的等位基因频率分别为39％和61％。X~2检验显示，基因型频率的观察值和期望值无显著性差异，提示
该群体符合Hardy-Weinberg遗传平衡法则。3个位点间存在较弱的连锁不平衡。中国辽宁地区人群与其他人群基因多态性分布频率对照研究发现，-1240L／S位点在辽宁和上海地区等位基因分布无差异，但与日本、欧洲白种人、加拿大白种人比较有显著性差异；-521C／T位点在辽宁和上海地区、日本、欧洲白种人、美国黑人等位基因分布比较均无显著性差异；-616C／G位点在辽宁和上海地区、日本、欧洲白种人、匈牙利白种人等位基因分布比较均有显著性差异。
2．多巴胺D4受体基因启动子区3个功能多态性-1240L／S、-616C／G、-521C／T位点与慢性抽动障碍的关联分析结果
-1240L／S和-521C／T位点的等位基因和基因型频率，在慢性抽动障碍组与正常对照组间比较，均无显著性差异；-616C／G位点的等位基因频率及其基因型频率在慢性抽动障碍组显著高于正常对照组(P=0.004，χ~2=8.419；P=0.020，χ~2=7.860)；DRD4基因-1240L／S，-616C／G和-521C／T组成的单倍型LCT的频率在慢性抽动障碍组显著高于正常对照组(p=0.012，χ~2=6.371)。
3．多巴胺D4受体基因启动子区-616C／G位点的功能分析结果
成功构建了重组质粒pGL3-D4C和pGL3-D4G。将pGL3-D4C和pGL3-D4G重组质粒分别与内参照质粒pRL-TK共转染HeLa细胞，利用双荧光素酶检测系统检测相对光强度，结果与pGL3-basic空载体相比，pGL3-D4C和pGL3-D4G重组质粒的相对光强度均明显增强，p＜0.05，表明-616C和-616G均具有启动报告基因转录的能力。在HeLa细胞中，pGL3-D4C和pGL3-D4G重组质粒的相对光强度与pGL3-basic空载体的相对光强度的比率分别为：7.6±0.5，34.7±1.5。pGL3-D4C比pGL3-D4G重组质粒的转录活性明显降低(p＜0.05)，pGL3-D4G的转录活性约是pGL3-D4C的4.6倍。
结论
1．多巴胺D4受体基因启动子区-1240L／S、-616C／G位点多态分布在世界范围内存在明显的种族差异；而-521C／T位点的多态性分布可能无明显的种族差异。
2．DRD4基因启动子区多态性与慢性抽动障碍易感性相关，DRD4基因-616C等位基因可能是决定慢性抽动障碍个体易感性的重要因素，而含有LCT单倍型的个体发生慢性抽动障碍的相对风险显著增高。
3．DRD4基因启动子区的-616 G＞C的变异可能在DRD4基因表达调控中起重要作用。
Objective
Chronic tic disorder is a childhood-onset neuropsychiatric disorder characterized by multiple motor or vocal tics lasting more than one year. The prevalence of tics occurs in more males than females. In addition, affected individuals frequently display symptoms such as obsessive-compulsive disorder, attention-deficit hyperactivity disorder and behaviors disorder. Despite evidence that chronic tic disorder is an inherited disorder, the exact genetic abnormality is unknown. Dopaminergic hypotheses have included abnormalities of both pre- and postsynaptic function in chronic tic disorder. Based on neurobiological theories, most of the candidate genes belong to the dopamine neurotransmitter system. In particular, the highly polymorphic dopamine D4 receptor (DRD4) gene has attracted increasing interest.
Currently, there were many studies about the 48-bp variable number of tandem repeats (VNTR) in the third exon polymorphism of the DRD4 gene and their relationship with tics, ADHD ect. neuropsychiatric disorder, but there is less reports concerning polymorphisms in the promoter region of the DRD4 gene distributing characteristics in liaoning, and association with chronic tic disorder. In our study, we test three polymorphisms in the promoter region (-1240L/S, -616C/G, -521C/T). Firstly, we study the distribution of the three gene polymorphisms in Chinese Han population Liaoning. Secondly, the association of polymorphisms in the promoter region with chronic tic disorder was studied using a case-control design. Finally, the functional activity of polymorphism was investigated through gene transfection and Dual-Luciferase Reporter assay system. To study whether there is an association of the three functional polymorphisms in the promoter region of dopamine D4 receptor (DRD4) gene with chronic tic disorder.
Methods
1. The three gene polymorphisms in the promoter of Dopamine D4 receptor in Chinese Han population Liaoning
Genomic DNA was isolated from venous blood leukocytes from 100 healthy unrelated individuals. Polymorphisms of DRD4, -1240L/S, -616C/G and -521C/T, were genotyped by PCR and allele specific amplification (ASA) techniques and tested Hardy-Weinberg equilibrium. Current results were compared with the data on other ethnic groups, and carried X~2 test.
2. Association between the polymorphisms in the promoter region of dopamine D4 receptor gene and chronic tic disorder
Genomic DNA was isolated from venous blood leukocytes from 84 unrelated patients with chronic tic disorder (Study group) and 100 healthy unrelated individuals as controls. Polymorphisms of DRD4, -1240L/S, -616C/G and -521C/T, were genotyped by allele-specific primer (ASP) PCR. The frequencies of genotypes, allele and haplotypes were analysed by SHEsis online.
3. The functional study of-616C/G in the promoter region of DRD4 gene Particular geneomes of two homozygotes of -616C/G, -616CC and -616GG respectively were templates in above-mentioned experiment. We constructed luciferase reporter gene express vectors of -616C/G in the promoter region of DRD4 gene, pGL3-D4Cand pGL3-D4G, and respetively. Constructed vectors pGL3-D4C and pGL3-D4G were transfected into HeLa cell through lipid vector. The transcriptional activity of-616C/G was determined by Dual-Luciferase reporter assay.
Results
1. The three gene polymorphisms in the promoter of Dopamine D4 receptor in Chinese Han population Liaoning
Within the 100 individuals tested, the frequencies of -1240L/S in the 5'promoter region of the DRD4 gene were found to be 60% and 40%, respectively, which met Hardy-Weinberg equilibrium. The frequencies of -616C/G were found to be 18% and 82%, respectively, which met Hardy-Weinberg equilibrium. The frequencies of -521C/T were found to be 39% and 61%, respectively, which met Hardy-Weinberg equilibrium. Chinese Liaoning populations comparing with other populations gene polymorphism distribute frequency contrasting studying find that -1240L/S no significant difference in allele frequencies between Liaoning and shanghai, but significant difference between Liaoning and Japan, Europe and Canada. There was significant difference in allele distributions of -616C/G of DRD4 between the Liaoning Han population and those of shanghai Japan, Europe and Hungary. The distribution of -521C/T of DRD4 gene has not exhibit ethnic heterogeneity.
2. Association between the polymorphisms in the promoter region of dopamine D4 receptor gene and chronic tic disorder
There were no significant differences in allele frequencies and genotypes frequencies of DRD4 -1240L/S and -521C/T between the Study and the Control groups. There were significant differences in allele frequencies and genotypes frequencies (x~2 =8.419, P<0.01; x~2=7.860, P<0.05 respectively) of DRD4-616C/G between the Study and the Control groups. The haplotypic frequencies of LCT (-1240L/S, -616C/G, -521C/T) in the Study group were noticeably higher than in the Control group (x~2 =6.371, P<0.05).
3. The functional study of -616C/G in the promoter region of DRD4 gene
We had constructed pGL3-D4C and pGL3-D4G vector successfully. Transfection efficiencies were normalized by cotransfection with the Renilla vector, pRL-TK. Both pGL3-basic and pGL3-Control were separately transfected into the HeLa cells, which served as negative and positive controls, respectively, within the assay. The transcriptional activity of -616C/G was determined by Dual- Luciferase reporter assay. The transcriptional luciferase activety of pGL3-D4C and pGL3-D4G wre calculated by taking the ratio of the firefly luciferase activity versus the Renilla luciferase activity. Significant differences in luciferase activity were observed between pGL3-D4C and pGL3-D4G constructs at p<0.05, There were transcriptional activity of -616C and -616G. These ratios were compared with that obtained for the pGL3-basic vector to produce fold values representing increments in transcriptional activity over basic for pGL3-D4C and pGL3-D4G as follows: 7.6±0.5, 34.7±1.5. The transcriptional activity of -616C was much lower than that of -616G, The transcriptional activity of -616G was 4.6 times to -616C.
Conclusion
1. The distributions of -1240L/S and -616C/G of DRD4 gene exhibit ethnic heterogeneity; but .the distribution of -521C/T of DRD4 gene has not exhibit ethnic heterogeneity.
2. There is an association between the DRD4-616C/G polymorphism and chronic tic disorder. The individuals with haplotype LCT (-1240L/S, -616C/G, -521C/T) are more susceptible to chronic tic disorder.
3. -616C/G may have a role in regulating the expression of the DRD4 gene.
引文
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2. Paterson AD, Sunohara GA, Kennedy JL. Dapamine D4 receptor gene: novelty or nonsense. Neuropsychopharm. 1999; 21: 3-16.
3. D'Souza UM, Russ C, Tahir E, et al. Functional effects of a tandem duplication polymorphism in the 5'flanking region of the DRD4 gene. Biol Psychiatry. 2004; 56(9): 691-697.
4. Okuyama Y, Ishiguro H, Tom M, et al. A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem Biophys Res Coraraun. 1999; 258(2): 292-295.
5. Okuyama Y, Ishiguro H, Nankai M, et al. Identification of a polymorphism in the promoter region of DRD4 associated with the human novelty seeking personality trait. Mol Psychiatry. 2000; 5: 64-69
6. Ronai Z, Szekely A, Nemoda Z, et al. Association between novelty seeking and the-521C/T polymorphism in the promoter region of the DRD4 gene. Mol Psychiatry. 2001; 6: 35-38
7．赵书平，张俊洁，杨玉红，等．用碘化钾提取基因组DNA临床检验杂志，2000，18(1)：38-39
8. Seaman MI, Fisher JB, Chang F, et al. Tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4). Am J Med Genet B Neuropsychiatr Genet, 1999, 88(6): 705-709.
9. Ronai Z, Szantai E, Szmola R, et al. A novel A/G SNP in the-615th position of the dopamine D4 receptor promoter region as a source of misgenotyping of the-616C/G SNP. Am J Med Genet B Neuropsychiatr Genet, 2004, 126(1): 74-78.
10. Ronai Z, Barta C, Guttman A, et al. Genotyping the-521C/T functional polymorphism in the promoter region of dopamine D4 receptor (DRD4) gene. Electrophoresis, 2001, 22(6): 1102-1105.
11. Xing QH, Wu SN, Lin ZG, et al. Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene in schizophrenia. Schizophr Res. 2003;65(1):9-14.
12. Barr CL, Feng Y, Wigg KG, et al. 5'-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. Am J Med Genet. 2001; 105( 1 ):84-90.
13. Paterson AD, Ying DJ, Petronis A, et al. A Pst I restriction fragment length polymorphism in the 5' untranslated region of DRD4 is not associated with schizophrenia. Psychiatr Genet, 1996,6(4): 191-193
14. Mitsuyasu H, Ozawa H, Takeda Y, et al. Novel polymorphisms in the upstream region of the human dopamine D4 receptor (DRD4) gene. J Hum Genet. 1999; 44(6):416-418.
15. Bookman EB, Taylor RE, Adams-Campbell L, et al. DRD4 promoter SNPs and gender effects on Extraversion in African Americans. Mol Psychiatry. 2002;7(7):786-789.
16. Lowe N, Kirley A, Mullins C, et al. Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP-616. Am J Med Genet B Neuropsychiatr Genet, 2004, 131(1): 33 -37.
17. Kendler KS, MacLean CJ, Ma Y, et al. Marker-to-marker linkage disequilibrium on chromosomes 5q, 6p, and 8p in Irish high-density schizophrenia pedigrees. Am J Med Genet, 1999; 88:29-33.
18. Dawson E, Abecasis GR, Bumpstead S, et al. A first-generation linkage disequilibrium map of human chromosome 22. Nature, 2002; 418: 544-548.
19. Apter A, Pauls DL, Bleich A, et al. An epidemiologic study of Gilles de la Tourette's syndrome in Israel. Arch Gen Psychiatry, 1993, 50:734-738.
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