多巴胺D2受体基因多态性与偏执型精神分裂症的关联研究
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摘要
精神分裂症是一种严重的精神疾病,全世界的群体发病率约为1%。研究表明遗传因素在其中起了十分重要的作用。药理学研究发现许多抗精神病药通过拮抗多巴胺D2受体发挥药理作用,提示DRD2基因与精神分裂症关联性。然而,多年大量研究结果提示DRD2基因上的与疾病相关的多态性位点很难在不同地理人群中被重复。该问题除了以遗传和表型异质性来解释外,也不能排除研究的样本量不够大、人群层化及一些其他混杂因素的干扰。
针对此问题,本研究仍围绕DRD2基因上的多态性位点,在前期工作的基础上展开。根据前期工作在小样本中所筛出杂合度较高的位点,继续在本研究所收集的大样本中国北方汉族人群(512名偏执型精神分裂症患者和480例正常对照)中,采用“病例-对照”关联分析,探讨这些SNPs(共10个)与精神分裂症的相关性。此外,还根据临床表型对病例组进一步分层。本研究希望通过增加样本量提高检验效力,并且希望通过表型分层,提高样本内部的同质性,增加阳性结果的可信度。
本研究结果发现:①单位点分析:无论是否进行了表型分层,这些SNPs与精神分裂症均无关,而且性别因素并不会影响它们与疾病的关联性。②多位点(单倍型)分析:阳性单倍型中大部分都包含rs2511521(C)-rs6275(C),而且部分与精神分裂症相关的单倍型在男性病例和对照组中的频率有显著差异(p＜0.001)。表型分层后,发现多数单倍型与阳性症状相关
从本工作中得到的结论:第一,在中国北方汉族人群中,我们所选取的SNPs均不与精神分裂症相关,该病的易感位点可能存在于阳性单倍型中。第二,性别因素影响疾病易感性。第三,单倍型分析结果高度提示疾病易感位点可能位于第4内含子和第7外显子之间。
Background:Schizophrenia is a complex multifactorial disorder with a worldwide lifetime prevalence of 1%.Particular attention has been focused on dopamine type D2 receptors(DRD2) due to the fact that they are the primary targets for some neuroleptic drugs.Polymorphisms of DRD2 have repeatedly been associated with schizophrenia; however,ethnic disparity seems to be a confounding factor in disease association.
Objective:1) To examine the association between the high heterozogosity SNPs of DRD2 gene screened from the previous work and schizophrenia in a larger sample from the Northern Chinese population.2) To explore the association of SNP(s) with certain phenotypes scaled by PANSS grading system.3) To specify the haplotypes within DRD2 that influences risk for schizophrenia.
Methods:We investigated the association of 10 polymorphisms,including -141C ins/del(rs1799732),Ser311Cys(rs1801028),His313His(rs6277),Pro319Pro(rs6275) in the DRD2 with schizophrenia using a case-control study,in 512 patients with DSM-IV diagnosis of paranoid schizophrenia and 480 unrelated mentally healthy controls.For quantitative trait analysis,we further stratified the patients by their phenotypes according to PANSS scale.
Results:1) In allelic and genotypic studies,no association of 10 polymorphisms with schizophrenia or any of its symptoms was found.2) In haplotypic study,haplotypes containing rs2511521(C)-rs6275(C) were associated with the disease,specifically in males(p＜0.001).3) The quantitative trait analysis revealed that haplotypes in DRD2 are associated with most of the positive syndromes of schizophrenia.
Conclusion:Our findings suggest that the haplotypes in DRD2 gene may associate with schizophrenia,and gender factor may take part in the pathogenesis of schizophrenia.A causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the fourth intron through seventh exons.
针对此问题,本研究仍围绕DRD2基因上的多态性位点,在前期工作的基础上展开。根据前期工作在小样本中所筛出杂合度较高的位点,继续在本研究所收集的大样本中国北方汉族人群(512名偏执型精神分裂症患者和480例正常对照)中,采用“病例-对照”关联分析,探讨这些SNPs(共10个)与精神分裂症的相关性。此外,还根据临床表型对病例组进一步分层。本研究希望通过增加样本量提高检验效力,并且希望通过表型分层,提高样本内部的同质性,增加阳性结果的可信度。
本研究结果发现:①单位点分析:无论是否进行了表型分层,这些SNPs与精神分裂症均无关,而且性别因素并不会影响它们与疾病的关联性。②多位点(单倍型)分析:阳性单倍型中大部分都包含rs2511521(C)-rs6275(C),而且部分与精神分裂症相关的单倍型在男性病例和对照组中的频率有显著差异(p＜0.001)。表型分层后,发现多数单倍型与阳性症状相关
从本工作中得到的结论:第一,在中国北方汉族人群中,我们所选取的SNPs均不与精神分裂症相关,该病的易感位点可能存在于阳性单倍型中。第二,性别因素影响疾病易感性。第三,单倍型分析结果高度提示疾病易感位点可能位于第4内含子和第7外显子之间。
Background:Schizophrenia is a complex multifactorial disorder with a worldwide lifetime prevalence of 1%.Particular attention has been focused on dopamine type D2 receptors(DRD2) due to the fact that they are the primary targets for some neuroleptic drugs.Polymorphisms of DRD2 have repeatedly been associated with schizophrenia; however,ethnic disparity seems to be a confounding factor in disease association.
Objective:1) To examine the association between the high heterozogosity SNPs of DRD2 gene screened from the previous work and schizophrenia in a larger sample from the Northern Chinese population.2) To explore the association of SNP(s) with certain phenotypes scaled by PANSS grading system.3) To specify the haplotypes within DRD2 that influences risk for schizophrenia.
Methods:We investigated the association of 10 polymorphisms,including -141C ins/del(rs1799732),Ser311Cys(rs1801028),His313His(rs6277),Pro319Pro(rs6275) in the DRD2 with schizophrenia using a case-control study,in 512 patients with DSM-IV diagnosis of paranoid schizophrenia and 480 unrelated mentally healthy controls.For quantitative trait analysis,we further stratified the patients by their phenotypes according to PANSS scale.
Results:1) In allelic and genotypic studies,no association of 10 polymorphisms with schizophrenia or any of its symptoms was found.2) In haplotypic study,haplotypes containing rs2511521(C)-rs6275(C) were associated with the disease,specifically in males(p＜0.001).3) The quantitative trait analysis revealed that haplotypes in DRD2 are associated with most of the positive syndromes of schizophrenia.
Conclusion:Our findings suggest that the haplotypes in DRD2 gene may associate with schizophrenia,and gender factor may take part in the pathogenesis of schizophrenia.A causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the fourth intron through seventh exons.
引文
1.Kraepelin E.Antischizophrenic drugs:chronic,Dementia praecox and pharaphrenis.(trans) New York,lnterntional Universities press Inc.,1950
2.Bleuler E.Dementia praecox or the Group of Schizophrenia,Zinldn J(trans) New York,Internation Universities press Inc.,1950
3.小鈅,中国精神障碍防治指南,北医大精研所中国精神分裂症防治指南(第二稿)2002:6-8
4.姜佐宁,现代精神病学[M],北京:人民卫生出版社,1999:550-558
5.Mowry B J,Nancarrow DJ.Molecular genetics of schizophrenia.Clin Exp Pharmacol Physiol,2001,28(1-2):66-69.
6.Semple D等原著:唐宏宇等主译.牛津临床精神病学手册.北京:人民卫生出版社,2006:152-163.
7.罗明强,高镇松,弓形虫感染与精神分裂症患者临床及血液流变学观察,中国热带医学.2006,6(3):410-411
8.Huber T J,Tettenbom C,Leifke E,et al.Sex hormones in psychotic men.Psychoneuroendocrinology 2005,30:111-114
9.Bergemann N,Mundt C,Parzer P,et al.Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics.Schizophr Res.2005,73:357-366
10.Davis KL,Kahn RS,Ko G,Davidson M.Dopamine in schizophrenia:a reveiw and reconceptualizaion.Am J Psychiatry 1991,148:1474-1486
11.Glenthoj BY,Hemmingsen R.Transmitter dysfunction during the process of schizophrenia.Acta Psychiatr Scand Suppl.1999,395:105-112.
12.Ahondzadeh S.The 5-HT hypothesis of schizophrenia.IDrugs 2001,4(3):295-300
13.Carlsson M,Carlsson A:Interactions between glutamatergic and monoaminergic systems within the basal ganglia--implications for schizophrenia and Parkinson's disease.Trends Neurosci 1990,13(7):272-276.
14.Luby ED,Cohen BD,Rosenbaum G,et al.Study of a new schizophrenomimetic drug;sernyl.AMA Arch Neurol Psychiatry 1959,81(3):363-369.
15.Lodge D,Aram JA,Church J,et al.Excitatory amino acids and phencyclidine-like drugs.In:Hicks TP,Lodge D,Mclennan H,editors.Excitory amino acid transmission.New York:Alan R.Liss Inc.1987,83-90
16.Olney JW,Farber NB.Glutamate receptor dysfunction and schizophrenia.Arch Gen Psychiatry 1995,52:998-1007
17.Greengard P,Nairn AC,Girault JA,et al.The DARPP-32/protein phosphatase-1 cascasde:a model for signal integration.Brain Res Rev.1998,26:274-284
18.Jeffrey A,Lieberman MD.Pathophysiologic mechanisms in the pathogenesis and clinical use of schizophrenia.J Clin Psychiatry,1999,60(supp 12):9
19.Davis KL,Buchs MS,Shihabudding L,et al.Ventricular enlargement in poor outcome schizophrenia.Comments Biol Psychiatry,1998,43:781
20.Noga Jl,Bartley A J,Jones DW,et al.Cortical gyral anatomy and gross brain dimensions in monozygotic twins discordant for schizophrenia.Schizophr Res.1996,22:27
21.王姗,精神分裂症与γ-氦基丁酸A受体相关基因的关联研究:[硕士学位论文].山西:山西医科大学,2007.
22.张萱,人类MHC class Ⅲ区域精神分裂症相关基因的遗传学研究:[博士学位论文].吉林:吉林大学,2003
23.Gillian CL,Todd J.,Strategies in complex disease mapping,Current Opinion in Genetics &Development.2000,10:330-334
24.Pritchard JK,Przeworski M,Linkage disequilibrium in humans:models and data,Am J Hum Gene.2001,69:1-14
25.Schaid DJ,Rowland C.Use of parents,sibs,and unrelated controls for detection of associations between genetic markers and disease.Am J Hum Genet.1998,63(5):1492-1506.
26.Spielman RS,Ewins WJ.The TDT and other family-based for linkage disequilibrium and association.Am J Hum Genet.1996,59(5):983-989.
27.Thomson G.Mapping disease genes:family-based association studies.Am J Hum Genet.1995,57:487-498
28.Bellodi L,Bussoleni C,Scorza-Smeraldi R,Grassi G,Zaechetti L,Smeraldi E.Family study of schizophrenia:exploratory analysis for relevant factors.Schizopr Bull.1986,12(1):120-128
29.Goldstein DB:Island of linkage disequilibrium.Nat Genet 2001,29:109-111
30.Totterdell S,Meredith GE.Topographical organization of projections from the entorhinal cortex to the striatum of the rat.Neuroscience,1997,78(3):715-729
31.彭代辉.精神分裂症患者多巴胺受体D2的相关研究.国外医学:精神病学分册,2001,28(3):185-189
32.Eubank JH,Djabali M,Selleri L,et al.Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11 q23.Genomics 1992(14):1010-1018.
33.Usiello A.,Balk JH.,et al.,Distinction function of the two isoforms of dopamine D2 receptors.Nature 2000,408:199-202
34.Ohara K,Nagai M,Tani K,et al.Functional polymorphism of-141C Ins/Del in the dopamine D2receptor gene promoter and schizophrenia.Psychiatry Res.1998,81:117-123.
35. Jonsson EG, Nothen MM, Neidt H, et al. Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia. Schizophr. Res. 1999 (40): 31-36.
36. Breen G., Brown J, Maude S, et al. -141 C del/ins polymorphism of the dopamine receptor 2 gene is associated with schizophrenia in a British population. Am J Med Genet. 1999 (88): 407-410
37. Duan J., Wainwright MS, Comeron JM, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum. Mol. Genet. 2003, 12: 205-216.
38. Lawford, BR, Young RM, Swagell CD, et al. The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia. Schizophr. Res. 2005, 73: 31-37.
39. Ritushree Kukreti, Sudipta Tripathi, Pallav Bhatnagar et al. Association of DRD2 genes variant with schizophrenia. Neuroscience Letters, 2006, 392: 68-71
40. Chen CH, Wei FC, Koong FJ, et al. Association of TaqI A polymorphism of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Biol Psychiatry 1997, 41 (7): 827-829
41. Hung A, Wong C, Buckle C, et al. Polymorphisms in dopamine receptors: what do they tell us? European Journal of Pharmacology, 2000, 410: 183-203
42. Seeman P, Targeting the dopamine D2 receptor in schizophrenia. Expert opin. ther. Target, 2006, 10(4): 515-531.
43. Arinami T, Itokawa M, Enguchi H, et al. Association of dopamine D2 receptor molecular variant with schizophrenia. Lancet 1994, 343: 703-704
44. Vergra M, Macciardi F, Pedrini S, et al. No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using as classical case control study and the haplotype relative risk. Schizophr Res. 1997,25: 117-121
45. Hori H, Ohmori O, Shinkai T, et al. Association analysis between two functional dopamine D2 receptor gene polymorphisms and schizophrenia. Am J Med Genet 2001, 105: 176-178
46. Laurent C, Bodeau-Pean S, Campion D, et al. No major role for the dopamine D2 receptor Ser→Cys311 mutation in schizophrenia. Psychiatr Genet 1994, 4: 229-230
47. Chen CH, Chien SH, Hwu HG No association of dopamine D2 receptor molecular variant Cys311 and schizophrenia in Chinese patients. Am J Med Genet 1996, 67: 418-420
48. Hanninen K, Katila H, Kampman O, et al. Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia. Neurosci. Lett. 2006, 407: 195-198
49. Hoenicka J, Aragues M, Rodriguez-Jimenez R, et al. C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients. Acta Psychiatr Scand 2005, 114: 435-438
50. Gorelova N, Yang CR. The course of neural projection from the prefrontal cortex to the nucleus accumbens in the rat. Neuroscience, 1997, 76 (3): 689-706
51. Glatt SJ, Faraone SV, Lasky-Su JA, et al. Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan.Mol.Psychiatr.2008:1-9[Epub ahead of print]
52.Arinami T,Gao M,Hamaguchi H,et al.A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia.Hum Mol Genet 1997,6:557-582
53.许琪,多巴胺代谢通路上的SNP型组合与偏执型精神分裂症的系统关联分析--一种研究复杂疾病的新策略:[博士学何论文].北京,协和医科大学,2004
54.Gabriel SB,Schaffner SF,Nguyen H,et al.The structure of haplotype blocks in the human genome.Science,2002,296(21):2225-2229
55.Daly M J,Rioux JD,Schaffner SF,et al.High-resolution haplotype structure in the human genome.Nat Genet.2001,29(2):229-232
56.Cardon LR,Bell J.Association study designs for complex diseases.Nat.Rev.Genet.2001,2:91-99
57.Gottesman Ⅱ,Gould TD.The endophenotype concept in psychiatry:Etymology and strategic intentions.American Journal of Psychiatry,2003,160:636-645
58.Gasperoni TL,Ekelund J,Huttunen M,et al.Genetic linkage and association between chromosome 1q and working memory function in schizophrenia.America Journal of Medical Genetics,2003,116:8-16
59.Hallmayer JF,Kalaydjieva L,Badcock J,et al.Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit.American Journal of Medical Genetics,2005,77:468-476
2.Bleuler E.Dementia praecox or the Group of Schizophrenia,Zinldn J(trans) New York,Internation Universities press Inc.,1950
3.小鈅,中国精神障碍防治指南,北医大精研所中国精神分裂症防治指南(第二稿)2002:6-8
4.姜佐宁,现代精神病学[M],北京:人民卫生出版社,1999:550-558
5.Mowry B J,Nancarrow DJ.Molecular genetics of schizophrenia.Clin Exp Pharmacol Physiol,2001,28(1-2):66-69.
6.Semple D等原著:唐宏宇等主译.牛津临床精神病学手册.北京:人民卫生出版社,2006:152-163.
7.罗明强,高镇松,弓形虫感染与精神分裂症患者临床及血液流变学观察,中国热带医学.2006,6(3):410-411
8.Huber T J,Tettenbom C,Leifke E,et al.Sex hormones in psychotic men.Psychoneuroendocrinology 2005,30:111-114
9.Bergemann N,Mundt C,Parzer P,et al.Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics.Schizophr Res.2005,73:357-366
10.Davis KL,Kahn RS,Ko G,Davidson M.Dopamine in schizophrenia:a reveiw and reconceptualizaion.Am J Psychiatry 1991,148:1474-1486
11.Glenthoj BY,Hemmingsen R.Transmitter dysfunction during the process of schizophrenia.Acta Psychiatr Scand Suppl.1999,395:105-112.
12.Ahondzadeh S.The 5-HT hypothesis of schizophrenia.IDrugs 2001,4(3):295-300
13.Carlsson M,Carlsson A:Interactions between glutamatergic and monoaminergic systems within the basal ganglia--implications for schizophrenia and Parkinson's disease.Trends Neurosci 1990,13(7):272-276.
14.Luby ED,Cohen BD,Rosenbaum G,et al.Study of a new schizophrenomimetic drug;sernyl.AMA Arch Neurol Psychiatry 1959,81(3):363-369.
15.Lodge D,Aram JA,Church J,et al.Excitatory amino acids and phencyclidine-like drugs.In:Hicks TP,Lodge D,Mclennan H,editors.Excitory amino acid transmission.New York:Alan R.Liss Inc.1987,83-90
16.Olney JW,Farber NB.Glutamate receptor dysfunction and schizophrenia.Arch Gen Psychiatry 1995,52:998-1007
17.Greengard P,Nairn AC,Girault JA,et al.The DARPP-32/protein phosphatase-1 cascasde:a model for signal integration.Brain Res Rev.1998,26:274-284
18.Jeffrey A,Lieberman MD.Pathophysiologic mechanisms in the pathogenesis and clinical use of schizophrenia.J Clin Psychiatry,1999,60(supp 12):9
19.Davis KL,Buchs MS,Shihabudding L,et al.Ventricular enlargement in poor outcome schizophrenia.Comments Biol Psychiatry,1998,43:781
20.Noga Jl,Bartley A J,Jones DW,et al.Cortical gyral anatomy and gross brain dimensions in monozygotic twins discordant for schizophrenia.Schizophr Res.1996,22:27
21.王姗,精神分裂症与γ-氦基丁酸A受体相关基因的关联研究:[硕士学位论文].山西:山西医科大学,2007.
22.张萱,人类MHC class Ⅲ区域精神分裂症相关基因的遗传学研究:[博士学位论文].吉林:吉林大学,2003
23.Gillian CL,Todd J.,Strategies in complex disease mapping,Current Opinion in Genetics &Development.2000,10:330-334
24.Pritchard JK,Przeworski M,Linkage disequilibrium in humans:models and data,Am J Hum Gene.2001,69:1-14
25.Schaid DJ,Rowland C.Use of parents,sibs,and unrelated controls for detection of associations between genetic markers and disease.Am J Hum Genet.1998,63(5):1492-1506.
26.Spielman RS,Ewins WJ.The TDT and other family-based for linkage disequilibrium and association.Am J Hum Genet.1996,59(5):983-989.
27.Thomson G.Mapping disease genes:family-based association studies.Am J Hum Genet.1995,57:487-498
28.Bellodi L,Bussoleni C,Scorza-Smeraldi R,Grassi G,Zaechetti L,Smeraldi E.Family study of schizophrenia:exploratory analysis for relevant factors.Schizopr Bull.1986,12(1):120-128
29.Goldstein DB:Island of linkage disequilibrium.Nat Genet 2001,29:109-111
30.Totterdell S,Meredith GE.Topographical organization of projections from the entorhinal cortex to the striatum of the rat.Neuroscience,1997,78(3):715-729
31.彭代辉.精神分裂症患者多巴胺受体D2的相关研究.国外医学:精神病学分册,2001,28(3):185-189
32.Eubank JH,Djabali M,Selleri L,et al.Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11 q23.Genomics 1992(14):1010-1018.
33.Usiello A.,Balk JH.,et al.,Distinction function of the two isoforms of dopamine D2 receptors.Nature 2000,408:199-202
34.Ohara K,Nagai M,Tani K,et al.Functional polymorphism of-141C Ins/Del in the dopamine D2receptor gene promoter and schizophrenia.Psychiatry Res.1998,81:117-123.
35. Jonsson EG, Nothen MM, Neidt H, et al. Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia. Schizophr. Res. 1999 (40): 31-36.
36. Breen G., Brown J, Maude S, et al. -141 C del/ins polymorphism of the dopamine receptor 2 gene is associated with schizophrenia in a British population. Am J Med Genet. 1999 (88): 407-410
37. Duan J., Wainwright MS, Comeron JM, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum. Mol. Genet. 2003, 12: 205-216.
38. Lawford, BR, Young RM, Swagell CD, et al. The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia. Schizophr. Res. 2005, 73: 31-37.
39. Ritushree Kukreti, Sudipta Tripathi, Pallav Bhatnagar et al. Association of DRD2 genes variant with schizophrenia. Neuroscience Letters, 2006, 392: 68-71
40. Chen CH, Wei FC, Koong FJ, et al. Association of TaqI A polymorphism of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Biol Psychiatry 1997, 41 (7): 827-829
41. Hung A, Wong C, Buckle C, et al. Polymorphisms in dopamine receptors: what do they tell us? European Journal of Pharmacology, 2000, 410: 183-203
42. Seeman P, Targeting the dopamine D2 receptor in schizophrenia. Expert opin. ther. Target, 2006, 10(4): 515-531.
43. Arinami T, Itokawa M, Enguchi H, et al. Association of dopamine D2 receptor molecular variant with schizophrenia. Lancet 1994, 343: 703-704
44. Vergra M, Macciardi F, Pedrini S, et al. No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using as classical case control study and the haplotype relative risk. Schizophr Res. 1997,25: 117-121
45. Hori H, Ohmori O, Shinkai T, et al. Association analysis between two functional dopamine D2 receptor gene polymorphisms and schizophrenia. Am J Med Genet 2001, 105: 176-178
46. Laurent C, Bodeau-Pean S, Campion D, et al. No major role for the dopamine D2 receptor Ser→Cys311 mutation in schizophrenia. Psychiatr Genet 1994, 4: 229-230
47. Chen CH, Chien SH, Hwu HG No association of dopamine D2 receptor molecular variant Cys311 and schizophrenia in Chinese patients. Am J Med Genet 1996, 67: 418-420
48. Hanninen K, Katila H, Kampman O, et al. Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia. Neurosci. Lett. 2006, 407: 195-198
49. Hoenicka J, Aragues M, Rodriguez-Jimenez R, et al. C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients. Acta Psychiatr Scand 2005, 114: 435-438
50. Gorelova N, Yang CR. The course of neural projection from the prefrontal cortex to the nucleus accumbens in the rat. Neuroscience, 1997, 76 (3): 689-706
51. Glatt SJ, Faraone SV, Lasky-Su JA, et al. Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan.Mol.Psychiatr.2008:1-9[Epub ahead of print]
52.Arinami T,Gao M,Hamaguchi H,et al.A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia.Hum Mol Genet 1997,6:557-582
53.许琪,多巴胺代谢通路上的SNP型组合与偏执型精神分裂症的系统关联分析--一种研究复杂疾病的新策略:[博士学何论文].北京,协和医科大学,2004
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55.Daly M J,Rioux JD,Schaffner SF,et al.High-resolution haplotype structure in the human genome.Nat Genet.2001,29(2):229-232
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