精神发育迟滞和脑卒中候选基因的连锁不平衡分析
|
摘要
本论文运用连锁不平衡分析方法研究了两种复杂性遗传疾病(精神发育迟滞和脑卒中)的候选基因。在对精神发育迟滞的研究中,笔者研究了位于下丘脑-垂体-甲状腺轴上的一个重要的转录因子POU1F1基因和神经传递过程中对突触的可塑性起着重要作用的RAB3A基因。笔者在来自秦巴山区的中国汉族人群中对这两个基因展开了病例对照的连锁不平衡分析。结果发现在女性组中,POU1F1基因的rs300996(P=0.0003), snp-7057(P=0.0001)和rs300977(P=0.0005)三个位点的等位基因以及所构成的单倍型频率(global P= 0.0050)相对于总病例和对照组中表现出更强的显著差异;数量性状分析也表明,位点rs300996的等位基因频率(P=0.0301)和由rs300996、snp-7057、rs300977构成的单倍型频率(P=0.0397)分布在女性样本中也表现出显著性差异。在笔者选取的能基本覆盖整个RAB3A基因的遗传标记中,没有发现任何等位基因,基因型以及单倍型频率在病例和对照中有差异。我们的研究结果首次表明POU1F1对精神发育迟滞的作用有性别依赖性,而RAB3A基因在汉族人群中不是精神发育迟滞的易感基因。
ALOX5AP和PDE4D基因是在冰岛人群中通过大规模的全基因组连锁分析定位后,进一步通过连锁不平衡分析精细定位找到的脑卒中的候选基因。笔者在来自中国东部地区的汉族人群中开展连锁不平衡分析,旨在研究这两个基因是否是中国人群脑卒中的相关基因。对ALOX5AP的研究发现,在男性病例对照组中,位点SG13S114的频率分布在病例和对照中表现出显著性差异(P= 0.0295),snp-10267, SG13S377, SG13S114和SG13S32构成的整体单倍型(P=0.0239)和单个单倍型(P= 0.0016)的频率分布在病例组和对照组中也有显著性差异。对PDE4D的研究发现,位点SNP83的等位基因频率分布在心源性和颈动脉性脑卒中病例和对照中表现出显著性差异(P=0.0060);在脑内小动脉阻塞性脑卒中组进行研究的时候,由rs152312和SNP56构成的整体单倍型(P = 0.0034)和单个单倍型(P=0.0009)的频率分布在病例组和对照组中表现出显著性差异。我们的研究结果进一步表明,ALOX5AP和PDE4D在中国人群中也是脑卒中的易感基因。
This thesis uses the linkage disequilibrium analysis to study the candidate gens of two kinds of common diseases: mental retardation (MR) and stroke. In the study of MR, we investigated the POU1F1 gene, an important transcription factor in the hypothalamus-pituitary-thyroid gland axis and the RAB3A gene, a key molecule in modulating basal neurotransmission and synaptic plasticity. We performed case-control linkage disequilibrium studies in the Chinese Han population from Qin-Ba mountain region. For POU1F1, in females, we found significant differences between cases and controls in the allele frequency distribution of rs300996, snp-7057 (P=0.0001) and rs300977 (P=0.0005) respectively, and their combined haplotype (global P=0.0050). The P-value was 0.0301 for rs300996 and 0.0397 for the haplotype combination of rs300996-snp-7057-rs300977 in the analysis of the quantitative effects of the alleles and haplotypes on IQ in females. However, there were no significant differences with RAB3A detected in the same sample at all. Our data first suggest that POU1F1 may affect MR through a gender specific mechanism, but RAB3A doesn’t.
ALOX5AP and PDE4D are promising candidate genes in relation to stroke, given its positional and functional involvement. In the linkage disequilibrium studies, we explored the role of these genes in the incidence of stroke in the Chinese Han population of eastern China. For ALOX5AP, in the analysis of the male group, SG13S114 showed significant differences between cases and controls (P=0.0295); the global P value for the frequencies of the haplotypes in snp-10267, SG13S377 SG13S114 and SG13S32 was 0.0239, and the frequency of haplotype G-G-T-C was higher in cases than in controls (P=0.0016). For PDE4D, in the analysis of the combined cardiogenic and carotid stroke group, both the allele (P=0.0060) and genotype (P=0.0160) frequencies between cases and controls at SNP83 showed significant differences; in the analysis of the small-artery occlusive stroke group, the global haplotype frequency in rs152312 and SNP56 showed significant differences between cases and controls (P=0.0034), and the frequency of haplotype C-A was higher in cases than in controls (P=0.0009). Our findings well support that both ALOX5AP and PDE4D are associated with an increased risk for ischemic stroke in the Chinese population.
ALOX5AP和PDE4D基因是在冰岛人群中通过大规模的全基因组连锁分析定位后,进一步通过连锁不平衡分析精细定位找到的脑卒中的候选基因。笔者在来自中国东部地区的汉族人群中开展连锁不平衡分析,旨在研究这两个基因是否是中国人群脑卒中的相关基因。对ALOX5AP的研究发现,在男性病例对照组中,位点SG13S114的频率分布在病例和对照中表现出显著性差异(P= 0.0295),snp-10267, SG13S377, SG13S114和SG13S32构成的整体单倍型(P=0.0239)和单个单倍型(P= 0.0016)的频率分布在病例组和对照组中也有显著性差异。对PDE4D的研究发现,位点SNP83的等位基因频率分布在心源性和颈动脉性脑卒中病例和对照中表现出显著性差异(P=0.0060);在脑内小动脉阻塞性脑卒中组进行研究的时候,由rs152312和SNP56构成的整体单倍型(P = 0.0034)和单个单倍型(P=0.0009)的频率分布在病例组和对照组中表现出显著性差异。我们的研究结果进一步表明,ALOX5AP和PDE4D在中国人群中也是脑卒中的易感基因。
This thesis uses the linkage disequilibrium analysis to study the candidate gens of two kinds of common diseases: mental retardation (MR) and stroke. In the study of MR, we investigated the POU1F1 gene, an important transcription factor in the hypothalamus-pituitary-thyroid gland axis and the RAB3A gene, a key molecule in modulating basal neurotransmission and synaptic plasticity. We performed case-control linkage disequilibrium studies in the Chinese Han population from Qin-Ba mountain region. For POU1F1, in females, we found significant differences between cases and controls in the allele frequency distribution of rs300996, snp-7057 (P=0.0001) and rs300977 (P=0.0005) respectively, and their combined haplotype (global P=0.0050). The P-value was 0.0301 for rs300996 and 0.0397 for the haplotype combination of rs300996-snp-7057-rs300977 in the analysis of the quantitative effects of the alleles and haplotypes on IQ in females. However, there were no significant differences with RAB3A detected in the same sample at all. Our data first suggest that POU1F1 may affect MR through a gender specific mechanism, but RAB3A doesn’t.
ALOX5AP and PDE4D are promising candidate genes in relation to stroke, given its positional and functional involvement. In the linkage disequilibrium studies, we explored the role of these genes in the incidence of stroke in the Chinese Han population of eastern China. For ALOX5AP, in the analysis of the male group, SG13S114 showed significant differences between cases and controls (P=0.0295); the global P value for the frequencies of the haplotypes in snp-10267, SG13S377 SG13S114 and SG13S32 was 0.0239, and the frequency of haplotype G-G-T-C was higher in cases than in controls (P=0.0016). For PDE4D, in the analysis of the combined cardiogenic and carotid stroke group, both the allele (P=0.0060) and genotype (P=0.0160) frequencies between cases and controls at SNP83 showed significant differences; in the analysis of the small-artery occlusive stroke group, the global haplotype frequency in rs152312 and SNP56 showed significant differences between cases and controls (P=0.0034), and the frequency of haplotype C-A was higher in cases than in controls (P=0.0009). Our findings well support that both ALOX5AP and PDE4D are associated with an increased risk for ischemic stroke in the Chinese population.
引文
1. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet. 2003;33 Suppl:228-37.
2. Dipple KM, McCabe ERB. Modifier Genes Convert "Simple" Mendelian Disorders to Complex Traits. Mol Genet Metab. 2000;71:43-50.
3. Terwilliger JD, Weiss KM. Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr Opin Biotechnol. 1998;9:578-94.
4. Thornton-Wells TA, Moore JH, Haines JL. Genetics, statistics and human disease: analytical retooling for complexity. Trends Genet. 2004;20:640-7.
5. Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet. 2001;2:91-9.
6. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860-921.
7. Crawford DC, Nickerson DA. Definition and clinical importance of haplotypes. Annu Rev Med. 2005;56:303-20.
8. Ardlie KG, Kruglyak L, Seielstad M. Patterns of linkage disequilibrium in the human genome. Nat Rev Genet. 2002;3:299-309.
9. Zollner S, von Haeseler A. A coalescent approach to study linkage disequilibrium between single-nucleotide polymorphisms. Am J Hum Genet. 2000;66:615-28.
10. Morton NE. Sequential tests for the detection of linkage. Am J Hum Genet. 1955;7:277-318.
11. Elston RC, Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21:523-42.
12. Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974;26:588-97.
13. Chotai J. On the lod score method in linkage analysis. Ann Hum Genet. 1984;48:359-78.
14. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516-7.
15. Clark AG. Finding genes underlying risk of complex disease by linkage disequilibrium mapping. Curr Opin Genet Dev. 2003;13:296-302.
16. Boehnke M. Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes. Am J Hum Genet. 1994;55:379-90.
17. Kruglyak L, Lander ES. High-resolution genetic mapping of complex traits. Am J Hum Genet. 1995;56:1212-23.
18. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994;3:569-74.
19. Tsai MS, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, Ivnik RJ, Thibodeau SN. Apolipoprotein E: risk factor for Alzheimer disease. Am J Hum Genet. 1994;54:643-9.
20. Lucotte G, Visvikis S, Leininger-Muler B, David F, Berriche S, Reveilleau S, Couderc R, Babron MC, Aguillon D, Siest G. Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer's disease. Am J Med Genet. 1994;54:286-8.
21. Cordell HJ, Clayton DG. Genetic association studies. Lancet. 2005;366:1121-31.
22. Sham P. Statistics in Human Genetics. Arnold. 1998.
23. Jeffreys AJ, Kauppi L, Neumann R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet. 2001;29:217-22.
24. Ardlie K, Liu-Cordero SN, Eberle MA, Daly M, Barrett J, Winchester E, Lander ES, Kruglyak L. Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. Am J Hum Genet. 2001;69:582-9.
25. Frisse L, Hudson RR, Bartoszewicz A, Wall JD, Donfack J, Di Rienzo A. Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet. 2001;69:831-43.
26. Quintana PJ, Neuwirth EA, Grosovsky AJ. Interchromosomal gene conversion at an endogenous human cell locus. Genetics. 2001;158:757-67.
27. Terwilliger JD, Zollner S, Laan M, Paabo S. Mapping genes through the use of linkage disequilibrium generated by genetic drift: 'drift mapping' in small populations with no demographic expansion. Hum Hered. 1998;48:138-54.
28. Chakraborty R, Weiss KM. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci U S A. 1988;85:9119-23.
29. Stephens JC, Briscoe D, O'Brien SJ. Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am J Hum Genet. 1994;55:809-24.
30. Wilson JF, Goldstein DB. Consistent long-range linkage disequilibrium generated by admixture in a Bantu-Semitic hybrid population. Am J Hum Genet. 2000;67:926-35.
31. Pfaff CL, Parra EJ, Bonilla C, Hiester K, McKeigue PM, Kamboh MI, Hutchinson RG, Ferrell RE, Boerwinkle E, Shriver MD. Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium. Am J Hum Genet. 2001;68:198-207.
32. Parsch J, Meiklejohn CD, Hartl DL. Patterns of DNA sequence variation suggest the recent action of positive selection in the janus-ocnus region of Drosophila simulans. Genetics. 2001;159:647-57.
33. Verrelli BC, Eanes WF. Clinal variation for amino acid polymorphisms at the Pgm locus in Drosophila melanogaster. Genetics. 2001;157:1649-63.
34. Charlesworth B, Morgan MT, Charlesworth D. The effect of deleterious mutations on neutral molecular variation. Genetics. 1993;134:1289-303.
35. Cannon GB. The effects of natural selection on linkage disequilibrium and relative fitness in experimental populations of Drosophila melanogaster. Genetics. 1963;48:1201-16.
36. Lewontin RC. The Interaction of Selection and Linkage. Ii. Optimum Models. Genetics. 1964;50:757-82.
37. Pritchard JK, Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet. 2001;69:1-14.
38. Weiss KM, Clark AG. Linkage disequilibrium and the mapping of complex human traits. Trends Genet. 2002;18:19-24.
39. Przeworski M, Wall JD. Why is there so little intragenic linkage disequilibrium in humans? Genet Res. 2001;77:143-51.
40. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999;22:139-44.
41. Fearnhead P, Donnelly P. Estimating recombination rates from population genetic data.Genetics. 2001;159:1299-318.
42. Hudson RR. Properties of a neutral allele model with intragenic recombination. Theor Popul Biol. 1983;23:183-201.
43. Kuhner MK, Yamato J, Felsenstein J. Maximum likelihood estimation of recombination rates from population data. Genetics. 2000;156:1393-401.
44. Long AD, Langley CH. The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res. 1999;9:720-31.
45. Nielsen R. Estimation of population parameters and recombination rates from single nucleotide polymorphisms. Genetics. 2000;154:931-42.
46. Wall JD. A comparison of estimators of the population recombination rate. Mol Biol Evol. 2000;17:156-63.
47. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES. Linkage disequilibrium in the human genome. Nature. 2001;411:199-204.
48. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES. High-resolution haplotype structure in the human genome. Nat Genet. 2001;29:229-32.
49. van den Oord EJ, Neale BM. Will haplotype maps be useful for finding genes? Mol Psychiatry. 2004;9:227-36.
50. Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003;4:587-97.
51. Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA. Haplotype tagging for the identification of common disease genes. Nat Genet. 2001;29:233-7.
52. Integrating ethics and science in the International HapMap Project. Nat Rev Genet. 2004;5:467-75.
53. A haplotype map of the human genome. Nature. 2005;437:1299-320.
54. Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17:502-10.
55. Smith DJ, Lusis AJ. The allelic structure of common disease. Hum Mol Genet. 2002;11:2455-61.
56. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921-3.
57. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76-80.
58. Becker KG. The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses. 2004;62:309-17.
59. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SFA, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR,Stefansson K. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet.2004;36:233-239.
60. Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet. 2000;26:151-7.
61. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001;69:124-37.
62. Falk CT, Rubinstein P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet. 1987;51 ( Pt 3):227-33.
63. Terwilliger JD, Ott J. A haplotype-based 'haplotype relative risk' approach to detecting allelic associations. Hum Hered. 1992;42:337-46.
64. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993;52:506-16.
65. Sham PC, Curtis D. An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet. 1995;59:323-36.
66. Spielman RS, Ewens WJ. A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet. 1998;62:450-8.
67. Curtis D. Use of siblings as controls in case-control association studies. Ann Hum Genet. 1997;61:319-33.
68. Martin ER, Kaplan NL, Weir BS. Tests for linkage and association in nuclear families. Am J Hum Genet. 1997;61:439-48.
69. Allison DB. Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet. 1997;60:676-90.
70. Rabinowitz D. A transmission disequilibrium test for quantitative trait loci. Hum Hered. 1997;47:342-50.
71. Abecasis GR, Cardon LR, Cookson WO. A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000;66:279-92.
72. Martin ER, Monks SA, Warren LL, Kaplan NL. A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet. 2000;67:146-54.
73. Morton NE, Collins A. Tests and estimates of allelic association in complex inheritance. Proc Natl Acad Sci U S A. 1998;95:11389-93.
74. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220-8.
75. Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997-1004.
76. Bacanu SA, Devlin B, Roeder K. The power of genomic control. Am J Hum Genet. 2000;66:1933-44.
77. Pritchard JK, Stephens M, Donnelly P. Inference of population structure using multilocus genotype data. Genetics. 2000;155:945-59.
78. Collins A, Lonjou C, Morton NE. Genetic epidemiology of single-nucleotide polymorphisms. Proc Natl Acad Sci U S A. 1999;96:15173-7.
79. Eaves IA, Merriman TR, Barber RA, Nutland S, Tuomilehto-Wolf E, Tuomilehto J, Cucca F, Todd JA. The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes. Nat Genet. 2000;25:320-3.
80. Taillon-Miller P, Bauer-Sardina I, Saccone NL, Putzel J, Laitinen T, Cao A, Kere J, Pilia G,Rice JP, Kwok PY. Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nat Genet. 2000;25:324-8.
81. Wright AF, Carothers AD, Pirastu M. Population choice in mapping genes for complex diseases. Nat Genet. 1999;23:397-404.
82. Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, Shkolny D, Einarsson G, Gudjonsdottir HM, Valdimarsson EM, Einarsson OB, Thorgeirsson G, Hadzic R, Jonsdottir S, Reynisdottir ST, Bjarnadottir SM, Gudmundsdottir T, Gudlaugsdottir GJ, Gill R, Lindpaintner K, Sainz J, Hannesson HH, Sigurdsson GT, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet. 2002;70:593-603.
83. Jorde LB. Linkage disequilibrium and the search for complex disease genes. Genome Res. 2000;10:1435-44.
84. Perneger TV. What's wrong with Bonferroni adjustments. Bmj. 1998;316:1236-8.
85. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A. 2003;100:9440-5.
86. Goldsmith LJ. Power and sample size considerations in molecular biology. Methods Mol Biol. 2002;184:111-30.
87. J. C. Statistical power analysis for the behavioral sciences. 2nd edition ed: Hillsdle, New Jersey, Lawrence Erlbaum Association.; 1988.
88. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35-41.
89. Sun Y, Zhang F, Gao J, Gao X, Guo T, Zhang K, Shi Y, Zheng Z, Tang W, Zheng Y, Li S, Li X, Feng G, Shen X, He L. Positive association between POU1F1 and mental retardation in young females in the Chinese Han population. Hum Mol Genet. 2006;15:1237-43.
90. American Psychiatric Association: Task Force on DSM-IV: diagnostic and statistical manual of mental disorders: DSM-IV. 1994.
91. Leonard H, Wen XY. The epidemiology of mental retardation: Challenges and opportunities in the new millennium. Mental Retardation and Developmental Disabilities Research Reviews. 2002;8:117-134.
92. Retardation AAotM. Mental Retardation :definition ,classification and systems of supports-workbook. Washington, DC: American Association on Mental Retardation; 1992.
93. Accardo PJ. Overview: Mental retardation. Mental Retardation and Developmental Disabilities Research Reviews 4; 1998.
94. Lubinski D. Introduction to the special section on cognitive abilities: 100 years after Spearman's (1904) "'General intelligence,' objectively determined and measured". J Pers Soc Psychol. 2004;86:96-111.
95. Plomin R. The genetics of g in human and mouse. Nat Rev Neurosci. 2001;2:136-41.
96. Ruth Luckasson JDSB-D. Mental Retardation Definition, Classification, and Systems of Supports. 10th Edition ed; 2002.
97. Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T. Genetics and pathophysiology of mental retardation. Eur J Hum Genet. 2006;14:701-13.
98. 郑子健,曹蓉,张富昌. 秦巴山区弱智儿童的社会文化成因及防治对策. 西北大学学报(哲学社会科学版). 1999;29:107-110.
99. Bartels M, Rietveld MJ, Van Baal GC, Boomsma DI. Genetic and environmental influences on the development of intelligence. Behav Genet. 2002;32:237-49.
100. Yeargin-Allsopp M, Murphy CC, Cordero JF, Decoufle P, Hollowell JG. Reported biomedical causes and associated medical conditions for mental retardation among 10-year-old children, metropolitan Atlanta, 1985 to 1987. Dev Med Child Neurol. 1997;39:142-9.
101. Yeargin-Allsopp M, Murphy CC, Oakley GP, Sikes RK. A multiple-source method for studying the prevalence of developmental disabilities in children: the Metropolitan Atlanta Developmental Disabilities Study. Pediatrics. 1992;89:624-30.
102. Yeargin-Allsopp M, Drews CD, Decoufle P, Murphy CC. Mild mental retardation in black and white children in metropolitan Atlanta: a case-control study. Am J Public Health. 1995;85:324-8.
103. Murray. RJHC. The Bell Curve: Intelligence and Class Structure in American Life: Free Press; 1999.
104. Wilson RS, Matheny AP, Jr. Retardation and twin concordance in infant mental development: a reassessment. Behav Genet. 1976;6:353-8.
105. Trouton A, Spinath FM, Plomin R. Twins early development study (TEDS): a multivariate, longitudinal genetic investigation of language, cognition and behavior problems in childhood. Twin Res. 2002;5:444-8.
106. Rijsdijk FV, Vernon PA, Boomsma DI. Application of hierarchical genetic models to Raven and WAIS subtests: a Dutch twin study. Behav Genet. 2002;32:199-210.
107. Benyamin B, Wilson V, Whalley LJ, Visscher PM, Deary IJ. Large, consistent estimates of the heritability of cognitive ability in two entire populations of 11-year-old twins from Scottish mental surveys of 1932 and 1947. Behav Genet. 2005;35:525-34.
108. Posthuma D, Baare WFC, Pol HEH, Kahn RS, Boomsma DI, De Geus EJC. Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Research. 2003;6:131-139.
109. Alarcon M, Plomin R, Fulker DW, Corley R, DeFries JC. Multivariate path analysis of specific cognitive abilities data at 12 years of age in the Colorado Adoption Project. Behavior Genetics. 1998;28:255-264.
110. Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, Winter RM, Bolton P, Flint J. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet. 1999;354:1676-81.
111. Bocian E, Helias-Rodzewicz Z, Suchenek K, Obersztyn E, Kutkowska-Kazmierczak A, Stankiewicz P, Kostyk E, Mazurczak T. Subtelomeric rearrangements: results from FISH studies in 84 families with idiopathic mental retardation. Med Sci Monit. 2004;10:CR143-51.
112. Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet. 1995;9:132-40.
113. De Vries BB, Winter R, Schinzel A, van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003;40:385-98.
114. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36:955-7.
115. Bi W, Saifi GM, Shaw CJ, Walz K, Fonseca P, Wilson M, Potocki L, Lupski JR. Mutations ofRAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet. 2004;115:515-24.
116. Nicholls RD. The impact of genomic imprinting for neurobehavioral and developmental disorders. J Clin Invest. 2000;105:413-8.
117. Petersen MB, Brondum-Nielsen K, Hansen LK, Wulff K. Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. Am J Med Genet. 1995;60:261-2.
118. Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M. Autism in Angelman syndrome: a population-based study. Pediatr Neurol. 1996;14:131-6.
119. Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001;2:153-75.
120. Inlow JK, Restifo LL. Molecular and comparative genetics of mental retardation. Genetics. 2004;166:835-81.
121. Luciano M, Wright MJ, Duffy DL, Wainwright MA, Zhu G, Evans DM, Geffen GM, Montgomery GW, Martin NG. Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q. Behav Genet. 2006;36:45-55.
122. Posthuma D, Luciano M, Geus EJ, Wright MJ, Slagboom PE, Montgomery GW, Boomsma DI, Martin NG. A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. Am J Hum Genet. 2005;77:318-26.
123. Huntsman MM, Tran BV, Potkin SG, Bunney WE, Jr., Jones EG. Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc Natl Acad Sci U S A. 1998;95:15066-71.
124. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet. 2001;69:570-81.
125. Addington AM, Gornick M, Duckworth J, Sporn A, Gogtay N, Bobb A, Greenstein D, Lenane M, Gochman P, Baker N, Balkissoon R, Vakkalanka RK, Weinberger DR, Rapoport JL, Straub RE. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry. 2005;10:581-8.
126. Plomin R, Turic DM, Hill L, Turic DE, Stephens M, Williams J, Owen MJ, O'Donovan MC. A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability. Mol Psychiatry. 2004;9:582-6.
127. Plomin R, Hill L, Craig IW, McGuffin P, Purcell S, Sham P, Lubinski D, Thompson LA, Fisher PJ, Turic D, Owen MJ. A genome-wide scan of 1842 DNA markers for allelic associations with general cognitive ability: a five-stage design using DNA pooling and extreme selected groups. Behav Genet. 2001;31:497-509.
128. Butcher LM, Meaburn E, Knight J, Sham PC, Schalkwyk LC, Craig IW, Plomin R. SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children. Hum Mol Genet. 2005;14:1315-25.
129. Zhang LF, Yang J, Hong Z, Yuan GG, Zhou BF, Zhao LC, Huang YN, Chen J, Wu YF. Proportion of different subtypes of stroke in China. Stroke. 2003;34:2091-6.
130. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2:43-53.
131. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and Natural-History of Clinically Identifiable Subtypes of Cerebral Infarction. Lancet. 1991;337:1521-1526.
132. Yang QD, Niu Q, Zhou YH, Liu YH, Xu HW, Gu WP, Tian FF, Xie YQ, Zhang L, Xia J. Incidence of cerebral hemorrhage in the Changsha community. A prospective study from 1986 to 2000. Cerebrovasc Dis. 2004;17:303-13.
133. 粟秀初,孔繁元,范学文. 现代脑血管病学. 第一版 ed. 北京: 人民军医出版社; 2003.
134. 吴兆苏,姚崇华,赵冬. 我国人群脑卒中发病率、死亡率的流行病学研究. 中华流行病学杂志. 2003;24:236-239.
135. Wu Z, Yao C, Zhao D, Wu G, Wang W, Liu J, Zeng Z, Wu Y. Sino-MONICA Project : A Collaborative Study on Trends and Determinants in Cardiovascular Diseases in China, Part I: Morbidity and Mortality Monitoring. Circulation. 2001;103:462-468.
136. 全军脑血管病流行病学协作组. 中国脑血管病流行病学研究. 北京: 人民军医出版社; 1993.
137. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, Degraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37:1583-633.
138. Hrubec Z, Robinette CD. The study of human twins in medical research. N Engl J Med. 1984;310:435-41.
139. Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD. A study of twins and stroke. Stroke. 1992;23:221-3.
140. Carmelli D, DeCarli C, Swan GE, Jack LM, Reed T, Wolf PA, Miller BL. Evidence For Genetic Variance in White Matter Hyperintensity Volume in Normal Elderly Male Twins. Stroke. 1998;29:1177-1181.
141. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke. 2002;33:769-74.
142. Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E. Parental History of Cardiovascular Disease and Risk of Stroke : A Prospective Follow-up of 14 371 Middle-aged Men and Women in Finland. Stroke. 1997;28:1361-1366.
143. Howard G, Evans GW, Toole JF, Tell G, Rose LA, Espeland M, Truscott BL. Characteristics of Stroke Victims Associated with Early Cardiovascular Mortality in Their Children. J Clin Epidemiol. 1990;43:49-54.
144. Welin L, Svardsudd K, Wilhelmsen L, Larsson B, Tibblin G. Analysis of risk factors for stroke in a cohort of men born in 1913. N Engl J Med. 1987;317:521-6.
145. Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH. Familial aggregation of stroke. The Framingham Study. Stroke. 1993;24:1366-71.
146. MacClellan LR, Mitchell BD, Cole JW, Wozniak MA, Stern BJ, Giles WH, Brown DW, Sparks MJ, Kittner SJ. Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study. Genet Epidemiol. 2006;30:602-8.
147. Liao D, Myers R, Hunt S, Shahar E, Paton C, Burke G, Province M, Heiss G. Familial history of stroke and stroke risk. The Family Heart Study. Stroke. 1997;28:1908-12.
148. Khaw K-T, Barrett-Connor E. Family history of stroke as an independent predictor of ischiemtc heart disease in men and stroke in women. Am. J. Epidemiol. 1986;123:59-66.
149. Rastenyte D, Tuomilehto J, Sarti C. Genetics of stroke - a review. Journal of the Neurological Sciences. 1998;153:132-145.
150. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K. Genetic liability in stroke - A long-term follow-up study of Danish twins. Stroke. 2002;33:769-774.
151. Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD. A Study of Twins and Stroke. Stroke. 1992;23:221-223.
152. Brass LM, Page WF, Lichtman JH. Stroke in twins III: A follow-up study. Stroke. 1999;30:256-256.
153. Jamrozik K, Broadhurst R, Anderson C, Stewart-Wynne E. The role of lifestyle factors in the etiology of stroke. A population- based case-control study in Perth, Western Australia. Stroke. 1994;25:51-59.
154. Flossmann E, Schulz UG, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke. 2004;35:212-27.
155. Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Lohr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet. 2005;366:1794-6.
156. Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006;5:501-12.
157. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383:707-10.
158.Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731-9.
159. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127:2533-9.
160. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350:1511-5.
161. Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005;62:1091-4.
162. Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, Ferrari MD, Breuning MH, Haan J. Cerebral microbleeds in CADASIL. Neurology. 2001;57:1066-70.
163. Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, Uttner I, Crispin A, Ludwig H, Gasser T, Yousry TA. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999;52:1361-7.
164. Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031-8.
165. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, Schiffmann R. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology.1998;50:1746-9.
166. Grewal RP. Stroke in Fabry's disease. J Neurol. 1994;241:153-6.
167. Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996;40:8-17.
168. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288-94.
169. Stockman JA, Nigro MA, Mishkin MM, Oski FA. Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med. 1972;287:846-9.
170. Pavlakis SG, Bello J, Prohovnik I, Sutton M, Ince C, Mohr JP, Piomelli S, Hilal S, De Vivo DC. Brain infarction in sickle cell anemia: magnetic resonance imaging correlates. Ann Neurol. 1988;23:125-30.
171. Schatz J, White DA, Moinuddin A, Armstrong M, DeBaun MR. Lesion burden and cognitive morbidity in children with sickle cell disease. J Child Neurol. 2002;17:891-5.
172. Driscoll MC, Hurlet A, Styles L, McKie V, Files B, Olivieri N, Pegelow C, Berman B, Drachtman R, Patel K, Brambilla D. Stroke risk in siblings with sickle cell anemia. Blood. 2003;101:2401-4.
173. Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet. 2005;37:435-40.
174. Steinberg MH, Adewoye AH. Modifier genes and sickle cell anemia. Curr Opin Hematol. 2006;13:131-6.
175. Taylor JGt, Tang DC, Savage SA, Leitman SF, Heller SI, Serjeant GR, Rodgers GP, Chanock SJ. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood. 2002;100:4303-9.
176. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5-11.
177. Bellamy MF, McDowell IF. Putative mechanisms for vascular damage by homocysteine. J Inherit Metab Dis. 1997;20:307-15.
178. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis. N Engl J Med. 1996;334:763-8.
179. Hassan A, Hunt BJ, O'Sullivan M, Bell R, D'Souza R, Jeffery S, Bamford JM, Markus HS. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127:212-219.
180. Lee SJ, Lee DH, Yoo HW, Koo SK, Park ES, Park JW, Lim HG, Jung SC. Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria. J Hum Genet. 2005;50:648-54.
181. Kraus JP, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo MP, Sebastio G, de Franchis R, Andria G, Kluijtmans LA, Blom H, Boers GH, Gordon RB, Kamoun P, Tsai MY, Kruger WD, Koch HG, Ohura T, Gaustadnes M. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat. 1999;13:362-75.
182. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. AnnNeurol. 1984;16:481-8.
183. Martinez-Fernandez E, Gil-Peralta A, Garcia-Lozano R, Chinchon I, Aguilera I, Fernandez-Lopez O, Arenas J, Campos Y, Bautista J. Mitochondrial disease and stroke. Stroke. 2001;32:2507-10.
184. Yoneda M, Maeda M, Kimura H, Fujii A, Katayama K, Kuriyama M. Vasogenic edema on MELAS: a serial study with diffusion-weighted MR imaging. Neurology. 1999;53:2182-4.
185. Clark JM, Marks MP, Adalsteinsson E, Spielman DM, Shuster D, Horoupian D, Albers GW. MELAS: Clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy. Neurology. 1996;46:223-7.
186. Judge DP, Dietz HC. Marfan's syndrome. Lancet. 2005;366:1965-76.
187. Nollen GJ, Mulder BJM. What is new in the Marfan syndrome? International Journal of Cardiology. 2004;97:103-108.
188. Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407-11.
189. Wityk RJ, Zanferrari C, Oppenheimer S. Neurovascular complications of marfan syndrome: a retrospective, hospital-based study. Stroke. 2002;33:680-4.
190. Spittell PC, Spittell JA, Jr., Joyce JW, Tajik AJ, Edwards WD, Schaff HV, Stanson AW. Clinical features and differential diagnosis of aortic dissection: experience with 236 cases (1980 through 1990). Mayo Clin Proc. 1993;68:642-51.
191. Schievink WI, Michels VV, Piepgras DG. Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke. 1994;25:889-903.
192. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673-80.
193. North KN, Whiteman DA, Pepin MG, Byers PH. Cerebrovascular complications in Ehlers-Danlos syndrome type IV. Ann Neurol. 1995;38:960-4.
194. van den Berg JS, Hennekam RC, Cruysberg JR, Steijlen PM, Swart J, Tijmes N, Limburg M. Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum. Cerebrovasc Dis. 2000;10:315-9.
195. Ikezaki K, Han DH, Kawano T, Kinukawa N, Fukui M. A clinical comparison of definite moyamoya disease between South Korea and Japan. Stroke. 1997;28:2513-7.
196. Hallemeier CL, Rich KM, Grubb RL, Jr., Chicoine MR, Moran CJ, Cross DT, 3rd, Zipfel GJ, Dacey RG, Jr., Derdeyn CP. Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke. 2006;37:1490-6.
197. Fukui M. Current state of study on moyamoya disease in Japan. Surg Neurol. 1997;47:138-43.
198. Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet. 1999;64:533-7.
199. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, Inoue T, Ikezaki K, Matsushima T, Fukui M. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke. 2000;31:930-5.
200. Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, Arinami T. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet. 2004;49:278-81.
201. Celentano A, Mancini FP, Crivaro M, Palmieri V, Ferrara LA, De Stefano V, Di Minno G, de Simone G. Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension. Am J Cardiol. 1999;83:1196-200.
202. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Bmj. 2002;325:1202.
203. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005;365:224-32.
204. Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004;61:1652-61.
205. Humphries SE, Morgan L. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol. 2004;3:227-35.
206. Slooter AJ, Rosendaal FR, Tanis BC, Kemmeren JM, van der Graaf Y, Algra A. Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. J Thromb Haemost. 2005;3:1213-7.
207. Dikmen M, Ozbabalik D, Gunes HV, Degirmenci I, Bal C, Ozdemir G, Basaran A. Acute stroke in relation to homocysteine and methylenetetrahydrofolate reductase gene polymorphisms. Acta Neurol Scand. 2006;113:307-14.
208. Grossmann R, Geisen U, Merati G, Mullges W, Schambeck CM, Walter U, Schwender S. Genetic risk factors in young adults with 'cryptogenic' ischemic cerebrovascular disease. Blood Coagul Fibrinolysis. 2002;13:583-90.
209. Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke. 2005;36:1581-7.
210. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J, Jr. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-77.
211. Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006;98:1123-33.
212. Brenner D, Labreuche J, Poirier O, Cambien F, Amarenco P. Renin-angiotensin-aldosterone system in brain infarction and vascular death. Ann Neurol. 2005;58:131-8.
213. Rubattu S, Di Angelantonio E, Stanzione R, Zanda B, Evangelista A, Pirisi A, De Paolis P, Cota L, Brunetti E, Volpe M. Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant. J Hypertens. 2004;22:2129-34.
214. Tuncer N, Tuglular S, Kilic G, Sazci A, Us O, Kara I. Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. J Clin Neurosci. 2006;13:224-7.
215. Hassan A, Markus HS. Genetics and ischaemic stroke. Brain. 2000;123 ( Pt 9):1784-812.
216. Sethi AA, Tybjaerg-Hansen A, Gronholdt ML, Steffensen R, Schnohr P, Nordestgaard BG. Angiotensinogen mutations and risk for ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. Six case-control studies from the Copenhagen City Heart Study. Ann Intern Med. 2001;134:941-54.
217. Schmidt H, Fazekas F, Kostner GM, van Duijn CM, Schmidt R. Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study. Stroke. 2001;32:405-12.
218. Lalouschek W, Schillinger M, Hsieh K, Endler G, Tentschert S, Lang W, Cheng S, Mannhalter C. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke.2005;36:1405-9.
219. Rubattu S, Speranza R, Ferrari M, Evangelista A, Beccia M, Stanzione R, Assenza GE, Volpe M, Rasura M. A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study. Eur J Neurol. 2005;12:989-93.
220. Santamaria A, Oliver A, Borrell M, Mateo J, Belvis R, Marti-Fabregas J, Ortin R, Tirado I, Souto JC, Fontcuberta J. Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels. Stroke. 2003;34:2387-91.
221. Aznar J, Mira Y, Vaya A, Corella D, Ferrando F, Villa P, Estelles A. Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke. Thromb Haemost. 2004;91:1031-4.
222. Jood K, Ladenvall P, Tjarnlund-Wolf A, Ladenvall C, Andersson M, Nilsson S, Blomstrand C, Jern C. Fibrinolytic gene polymorphism and ischemic stroke. Stroke. 2005;36:2077-81.
223. Wiklund PG, Nilsson L, Ardnor SN, Eriksson P, Johansson L, Stegmayr B, Hamsten A, Holmberg D, Asplund K. Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts. Stroke. 2005;36:1661-5.
224. van Goor ML, Garcia EG, Leebeek F, Brouwers GJ, Koudstaal P, Dippel D. The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke. A case-control study. Thromb Haemost. 2005;93:92-6.
225. Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood. 2002;100:3-10.
226. Lai J, Zhou D, Xia S, Shang Y, Zhu J, Pan J, Hua B, Zhu Y, Cui L. Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population. Neurol India. 2006;54:366-9.
227. Seripa D, Dobrina A, Margaglione M, Matera MG, Gravina C, Vecile E, Fazio VM. Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke. Cerebrovasc Dis. 2003;15:276-81.
228. Couderc R, Mahieux F, Bailleul S, Fenelon G, Mary R, Fermanian J. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study. Stroke. 1993;24:661-4.
229. de Andrade M, Thandi I, Brown S, Gotto A, Jr., Patsch W, Boerwinkle E. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet. 1995;56:1379-90.
230. Schmidt R, Schmidt H, Fazekas F, Schumacher M, Niederkorn K, Kapeller P, Weinrauch V, Kostner GM. Apolipoprotein E polymorphism and silent microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study. Stroke. 1997;28:951-6.
231. Pedro-Botet J, Senti M, Nogues X, Rubies-Prat J, Roquer J, D'Olhaberriague L, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992;23:1556-62.
232. Kessler C, Spitzer C, Stauske D, Mende S, Stadlmuller J, Walther R, Rettig R. The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol. 1997;17:2880-4.
233. Margaglione M, Seripa D, Gravina C, Grandone E, Vecchione G, Cappucci G, Merla G, Papa S, Postiglione A, Di Minno G, Fazio VM. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian Case-Control Study. Stroke. 1998;29:399-403.
234. MO MC, Muir KW, Weir CJ, Dyker AG, Bone I, Nicoll JA, Lees KR. The apolipoprotein E epsilon4 allele and outcome in cerebrovascular disease. Stroke. 1998;29:1882-7.
235. Alberts MJ, Graffagnino C, McClenny C, DeLong D, Strittmatter W, Saunders AM, Roses AD. ApoE genotype and survival from intracerebral haemorrhage. Lancet. 1995;346:575.
236. Teasdale GM, Nicoll JA, Murray G, Fiddes M. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet. 1997;350:1069-71.
237. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D. Cerebrovascular disease, the apolipoprotein e4 allele, and cognitive decline in a community-based study of elderly men. Stroke. 1996;27:2230-5.
238. White RP, Deane C, Vallance P, Markus HS. Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia. Stroke. 1998;29:467-72.
239. Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA. Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab. 1994;14:175-92.
240. White RP, Vallance P, Markus HS. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci (Lond). 2000;99:555-60.
241. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774-7.
242. Hassan A, Gormley K, O'Sullivan M, Knight J, Sham P, Vallance P, Bamford J, Markus H. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke. 2004;35:654-659.
243. Hou L, Osei-Hyiaman D, Yu H, Ren Z, Zhang Z, Wang B, Harada S. Association of a 27-bp repeat polymorphism in ecNOS gene with ischemic stroke in Chinese patients. Neurology. 2001;56:490-496.
244. Yahashi Y, Kario K, Shimada K, Matsuo M. The 27-bp repeat polymorphism in intron 4 of the endothelial cell nitric oxide synthase gene and ischemic stroke in a Japanese population. Blood Coagul Fibrinolysis. 1998;9:405-9.
245. Elbaz A, Poirier O, Moulin T, Chedru F, Cambien F, Amarenco P. Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. Stroke. 2000;31:1634-1639.
246. Markus HS, Ruigrok Y, Ali N, Powell JF. Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke. 1998;29:1908-1911.
247. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003;35:131-8.
248. Song Q, Cole JW, O'Connell JR, Stine OC, Gallagher M, Giles WH, Mitchell BD, Wozniak MA, Stern BJ, Sorkin JD, McArdle PF, Naj AC, Xu Q, Gibbons GH, Kittner SJ. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study. Hum Mol Genet. 2006;15:2468-78.
249. Bevan S, Porteous L, Sitzer M, Markus HS. Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis. Stroke. 2005;36:949-53.
250. Lohmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, Meitinger T, Dichgans M. ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients. Stroke. 2005;36:731-736.
251. Nilsson-Ardnor S, Wiklund PG, Lindgren P, Nilsson AK, Janunger T, Escher SA, Hallbeck B, Stegmayr B, Asplund K, Holmberg D. Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population. Stroke. 2005;36:1666-71.
252. Meschia JF, Brott TG, Brown RD, Jr., Crook R, Worrall BB, Kissela B, Brown WM, Rich SS, Case LD, Evans EW, Hague S, Singleton A, Hardy J. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol. 2005;58:351-61.
253. van Rijn MJ, Slooter AJ, Schut AF, Isaacs A, Aulchenko YS, Snijders PJ, Kappelle LJ, van Swieten JC, Oostra BA, van Duijn CM. Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population. Neurology. 2005;65:1203-9.
254. Saleheen D, Bukhari S, Haider SR, Nazir A, Khanum S, Shafqat S, Anis MK, Frossard P. Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Stroke. 2005;36:2275-7.
255. Nakayama T, Asai S, Sato N, Soma M. Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese: a case-control study. Stroke. 2006;37:69-76.
256. Woo D, Kaushal R, Kissela B, Sekar P, Wolujewicz M, Pal P, Alwell K, Haverbusch M, Ewing I, Miller R, Kleindorfer D, Flaherty M, Chakraborty R, Deka R, Broderick J. Association of Phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Stroke. 2006;37:371-6.
257. Kuhlenbaumer G, Berger K, Huge A, Lange E, Kessler C, John U, Funke H, Nabavi DG, Stogbauer F, Ringelstein EB, Stoll M. Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort. J Neurol Neurosurg Psychiatry. 2006;77:521-4.
258. Brophy VH, Ro SK, Rhees BK, Lui LY, Lee JM, Umblas N, Bentley LG, Li J, Cheng S, Browner WS, Erlich HA. Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status. Stroke. 2006;37:1385-90.
259. Zee RYL, Cheng S, Hegener HH, Erlich HA, Ridker PM. Genetic Variants of Arachidonate 5-Lipoxygenase-Activating Protein, and Risk of Incident Myocardial Infarction and Ischemic Stroke: A Nested Case-Control Approach. Stroke. 2006;37:2007-2011.
260. Rosand J, Bayley N, Rost N, de Bakker PIW. Many hypotheses but no replication for the association between PDE4D and stroke. 2006;38:1091-1092.
261. Helgadottir A, Gretarsdottir S, St Clair D, Manolescu A, Cheung J, Thorleifsson G, Pasdar A, Grant SF, Whalley LJ, Hakonarson H, Thorsteinsdottir U, Kong A, Gulcher J, Stefansson K, MacLeod MJ. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet. 2005;76:505-9.
262. Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggstrom JZ. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006;103:8161-6.
263. Helgadottir A, Manolescu A, Helgason A, Thorleifsson G, Thorsteinsdottir U, Gudbjartsson DF, Gretarsdottir S, Magnusson KP, Gudmundsson G, Hicks A, Jonsson T, Grant SF, Sainz J, O'Brien SJ, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Levey AI, Abramson JL, Reilly MP,Vaccarino V, Wolfe ML, Gudnason V, Quyyumi AA, Topol EJ, Rader DJ, Thorgeirsson G, Gulcher JR, Hakonarson H, Kong A, Stefansson K. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet. 2006;38:68-74.
264. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet. 1996;13:429-34.
265. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gauguier D, Reid JL, Macrae IM, Dominiczak AF. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet. 1997;16:364-7.
266. Hassan A, Ali N, Dong Y, Carter ND, Markus HS. Atrial natriuretic peptide gene G664A polymorphism and the risk of ischemic cerebrovascular disease. Neurology. 2001;57:1726-8.
267. Rubattu S, Stanzione R, Di Angelantonio E, Zanda B, Evangelista A, Tarasi D, Gigante B, Pirisi A, Brunetti E, Volpe M. Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans. Stroke. 2004;35:814-8.
268. Zuo Q, Zhang Z, Lei Z. Adaptive scale of infant and children: Medical University of China, Beijing, China; 1988.
269. Gong Y, Dai X. Chinese-Wechsler young children scale of intelligence (C-WYCSI): Map Press, Hunan, China; 1992.
270. Gong Y, Cai T. Wechsler intelligence scale for children, Chinese revision (C-WISC): Map Press, Hunan, China; 1993.
271. Psychiatry CAo. Chinese classification of mental disorders,2nd revision. In. Nanking: Southeast University Press; 1995.
272. Organization TWH. The ICD-10 classification of mental and behavioral disorders: clinical descriptions and diagnostic guidelines. Geneva, Switzerland: WHO; 1992.
273. Wang HY, Zhang FC, Gao JJ, Fan JB, Liu P, Zheng ZJ, Xi H, Sun Y, Gao XC, Huang TZ, Ke ZJ, deficiency disorder in China. Molecular Psychiatry. 2000;5:363-368.
274. Li F, Yan F, Han z, Yang W, Li X, Li Y. A study of the relationship between health care during labour and children's mental retardation in QinBa mountain area, Shaanxi province. J Xi'an Med Univ. 1999;20:100-102.
275. Oppenheimer JH, Schwartz HL. Molecular Basis of Thyroid Hormone-Dependent Brain Development. Endocr Rev. 1997;18:462-475.
276. Anderson GW. Thyroid hormones and the brain. Front Neuroendocrinol. 2001;22:1-17.
277. Winter WE, Signorino MR. Review: molecular thyroidology. Ann Clin Lab Sci. 2001;31:221-44.
278. Cushman LJ, Showalter AD, Rhodes SJ. Genetic defects in the development and function of the anterior pituitary gland. Ann Med. 2002;34:179-91.
279. De Felice M, Postiglione MP, Di Lauro R. Minireview: thyrotropin receptor signaling in development and differentiation of the thyroid gland: insights from mouse models and human diseases. Endocrinology. 2004;145:4062-7.
280. Li S, Crenshaw EB, 3rd, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature. 1990;347:528-33.
281. Rhodes SJ, DiMattia GE, Rosenfeld MG. Transcriptional mechanisms in anterior pituitary cell differentiation. Curr Opin Genet Dev. 1994;4:709-17.
282. Noguchi T, Sugisaki T, Tsukada Y. Postnatal action of growth and thyroid hormones on theretarded cerebral myelinogenesis of Snell dwarf mice (dw). J Neurochem. 1982;38:257-63.
283. Sekiguchi M, Abe H, Moriya M, Tanaka O, Nowakowski RS. Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse. J Comp Neurol. 1998;400:363-74.
284. Lin S, Li S, Drolet D, Rosenfeld M. Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development. 1994;120:515-522.
285. Cohen LE, Radovick S. Molecular Basis of Combined Pituitary Hormone Deficiencies. Endocr Rev. 2002;23:431-442.
286. Blankenstein O, Muhlenberg R, Kim C, Wuller S, Pfaffle R, Heimann G. A new C-terminal located mutation (V272ter) in the PIT-1 gene manifesting with severe congenital hypothyroidism. Possible functionality of the PIT-1 C-terminus. Horm Res. 2001;56:81-6.
287. de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van den Berghe G, Martial JA. The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab. 1995;80:3127-30.
288. Guo TW, Zhang FC, Gao JJ, Bian L, Gao XC, Ma J, Yang M, Ji Q, Duan SW, Zheng ZJ, Li RL, 14q31 are not associated with mental retardation in the iodine-deficient areas of China. Neurosci Lett. 2005;382:179-84.
289. Sham PC, Curtis D. Monte-Carlo tests for associations between disease and alleles at highly polymorphic loci. Annals of Human Genetics. 1995;59:97-105.
290. Zapata C, Carollo C, Rodriguez S. Sampling variance and distribution of the D ' measure of overall gametic disequilibrium between multiallelic loci. Ann Hum Genet. 2001;65:395-406.
291. Xie X, Ott J. Testing linkage disequilibrium between a disease gene and marker loci. Am J Hum Genet. 1993;53:1107-1107.
292. Zhao JH, Curtis D, Sham PC. Model-free analysis and permutation tests for allelic associations. Hum Hered. 2000;50:133-139.
293. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15:97-8.
294. Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol. 2003;25:115-21.
295. Erdfelder E, Faul F, Buchner A. G*Power: a general power analysis program. Behav Res Methods Instrum Comput. 1996;28:1-11.
296. Zhang Z, Wang Z, Zhang R, Gong F, Wang Z. The iodine nutritive status of the pregnant women and wet nurses in Qin-Ba mountain areas. Chin J Endemiol. 2001;20:201-203.
297. Rajas F, Delhase M, De La Hoya M, Verdood P, Castrillo JL, Hooghe-Peters EL. Nuclear factor 1 regulates the distal silencer of the human PIT1/GHF1 gene. Biochem J. 1998;333 ( Pt 1):77-84.
298. Lew D, Brady H, Klausing K, Yaginuma K, Theill LE, Stauber C, Karin M, Mellon PL. GHF-1-promoter-targeted immortalization of a somatotropic progenitor cell results in dwarfism in transgenic mice. Genes Dev. 1993;7:683-93.
299. Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin SC, Yu VC, Rosenfeld MG. A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene. Genes Dev. 1993;7:913-32.
300. Delhase M, Vila V, Hooghe-Peters EL, Castrillo J. A novel pituitary transcription factor is produced by alternative splicing of the human GHF-1/PIT-1 gene. Gene. 1995;155:273-275.
301. Collins A, Morton NE. Mapping a disease locus by allelic association. Proc Natl Acad Sci U S A.1998;95:1741-5.
302. Kuiper GG, Shughrue PJ, Merchenthaler I, Gustafsson JA. The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol. 1998;19:253-86.
303. Mitchner NA, Garlick C, Ben-Jonathan N. Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland. Endocrinology. 1998;139:3976-83.
304. Zhu YS, Pfaff DW. Differential regulation of AP-1 DNA binding activity in rat hypothalamus and pituitary by estrogen. Brain Res Mol Brain Res. 1998;55:115-25.
305. Delhase M, Castrillo JL, de la Hoya M, Rajas F, Hooghe-Peters EL. AP-1 and Oct-1 transcription factors down-regulate the expression of the human PIT1/GHF1 gene. J Biol Chem. 1996;271:32349-58.
306. Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler GB, Jr. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J Clin Invest. 1994;94:2475-80.
307. Lorey FW, Cunningham GC. Birth prevalence of primary congenital hypothyroidism by sex and ethnicity. Hum Biol. 1992;64:531-8.
308. Devos H, Rodd C, Gagne N, Laframboise R, Van Vliet G. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab. 1999;84:2502-6.
309. Pomeroy SL, Kim JY. Biology and pathobiology of neuronal development. Ment Retard Dev Disabil Res Rev. 2000;6:41-6.
310. Schaller RH. Membrane trafficking in the presynaptic nerve terminal. Neuron. 1995;14:893-897.
311. Renieri A, Pescucci C, Longo I, Ariani F, Mari F, Meloni I. Non-syndromic X-linked mental retardation: from a molecular to a clinical point of view. J Cell Physiol. 2005;204:8-20.
312. Stenmark H, Olkkonen VM. The Rab GTPase family. Genome Biol. 2001;2:reviews3007.
313. Thakker-Varia S, Alder J, Crozier RA, Plummer MR, Black IB. Rab3A is required for brain-derived neurotrophic factor-induced synaptic plasticity: Transcriptional analysis at the population and single-cell levels. Journal of Neuroscience. 2001;21:6782-6790.
314. Geppert M, Bolshakov VY, Siegelbaum SA, Takei K, De Camilli P, Hammer RE, Sudhof TC. The role of Rab3A in neurotransmitter release. Nature. 1994;369:493-497.
315. Geppert M, Goda Y, Stevens CF, Sudhof TC. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature. 1997;387:810-4.
316. Castillo PE, Janz R, Sdhof TC, Tzounopoulos T, Malenka RC, Nicoll RA. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature. 1997;388:590-593.
317. Leenders AGM, da Silva FHL, Ghijsen WEJM, Verhage M. Rab3A is involved in transport of synaptic vesicles to the active zone in mouse brain nerve terminals. Mol. Biol. Cell. 2001;12:3095-3102.
318. Basel-Vanagaite L, Alkelai A, Straussberg R, Magal N, Inbar D, Mahajna M, Shohat M. Mapping of a new locus for autosomal recessive non-syndromic mental retardation in the chromosomal region 19p13.12-p13.2: further genetic heterogeneity. Journal of Medical Genetics. 2003;40:729-732.
319. Sullivan M, Olsen AS, Houslay MD. Genomic organisation of the human cyclic AMP-specific phosphodiesterase PDE4C gene and its chromosomal localisation to 19p13.1, between RAB3A and JUND. Cellular Signalling. 1999;11:735-742.
320. Milatovich A, Bolger G, Michaeli T, Francke U. Chromosome localizations of genes for fivecAMP-specific phosphodiesterases in man and mouse. Somat Cell Mol Genet. 1994;20:75-86.
321. Bienvenu T, des Portes V, Saint Martin A, McDonell N, Billuart P, Carrie A, Vinet M, Couvert P, Toniolo D, Ropers H, Moraine C, van Bokhoven H, Fryns J, Kahn A, Beldjord C, Chelly J. Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. Hum. Mol. Genet. 1998;7:1311-1315.
322. D'Adamo P, Menegon A, Lo Nigro C, Grasso M, Gulisano M, Tamanini F, Bienvenu T, Gedeon AK, Oostra B, Wu SK, Tandon A, Valtorta F, Balch WE, Chelly J, Toniolo D. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet. 1998;19:134-9.
323. Nokelainen P, Flint J. Genetic effects on human cognition: lessons from the study of mental retardation syndromes. J Neurol Neurosurg Psychiatry. 2002;72:287-96.
324. Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, Hoffmann K, Maina EN, Morgan NV, Tee L, Morton J, Ainsworth JR, Horn D, Rosser E, Cole TRP, Stolte-Dijkstra I, Fieggen K, Clayton-Smith J, Megarbane A, Shield JP, Newbury-Ecob R, Dobyns WB, Graham JM, Kjaer KW, Warburg M, Bond J, Trembath RC, Harris LW, Takai Y, Mundlos S, Tannahill D, Woods CG, Maher ER. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet. 2005;37:221-224.
325. Chelly J, Mandel J-L. Monogenic causes of X-linked mental retardation. Nat Rev Genet. 2001;2:669-680.
326. Dichgans M. Genetics of ischaemic stroke. Lancet Neurol. 2007;6:149-61.
327. Zee RY, Brophy VH, Cheng S, Hegener HH, Erlich HA, Ridker PM. Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke. 2006;37:2012-7.
328. The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. WHO MONICA Project Principal Investigators. J Clin Epidemiol. 1988;41:105-14.
329. Germer S, Holland MJ, Higuchi R. High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res. 2000;10:258-66.
330. Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, Kelsoe JR. Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet. 2001;105:145-51.
331. Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001;29:E88-8.
332. Storey JD, Tibshirani R. Statistical significance for genomewide studies. PNAS. 2003;100:9440-9445.
333. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1-18.
334. Liu H, Maurice DH. Phosphorylation-mediated activation and translocation of the cyclic AMP-specific phosphodiesterase PDE4D3 by cyclic AMP-dependent protein kinase and mitogen-activated protein kinases. A potential mechanism allowing for the coordinated regulation of PDE4D activity and targeting. J Biol Chem. 1999;274:10557-65.
335. Miro X, Casacuberta JM, Gutierrez-Lopez MD, de Landazuri MO, Puigdomenech P. Phosphodiesterases 4D and 7A splice variants in the response of HUVEC cells to TNF-alpha(1). Biochem Biophys Res Commun. 2000;274:415-21.
336. Shepherd MC, Baillie GS, Stirling DI, Houslay MD. Remodelling of the PDE4 cAMPphosphodiesterase isoform profile upon monocyte-macrophage differentiation of human U937 cells. Br J Pharmacol. 2004;142:339-51.
337. Ariga M, Neitzert B, Nakae S, Mottin G, Bertrand C, Pruniaux MP, Jin SL, Conti M. Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation. J Immunol. 2004;173:7531-8.
338. Lorenowicz MJ, Fernandez-Borja M, Hordijk PL. cAMP Signaling in Leukocyte Transendothelial Migration. Arterioscler Thromb Vasc Biol. 2007.
339.Ichiki T. Role of cAMP response element binding protein in cardiovascular remodeling: good, bad, or both? Arterioscler Thromb Vasc Biol. 2006;26:449-55.
340. Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M, O'Donnell JM. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology. 2002;27:587-95.
341. Kato H, Araki T, Itoyama Y, Kogure K. Rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, reduces neuronal damage following cerebral ischemia in the gerbil. Eur J Pharmacol. 1995;272:107-10.
342. Block F, Tondar A, Schmidt W, Schwarz M. Delayed treatment with rolipram protects against neuronal damage following global ischemia in rats. Neuroreport. 1997;8:3829-32.
343. Bok J, Zha XM, Cho YS, Green SH. An extranuclear locus of cAMP-dependent protein kinase action is necessary and sufficient for promotion of spiral ganglion neuronal survival by cAMP. J Neurosci. 2003;23:777-87.
344. Wang X, Tang X, Li M, Marshall J, Mao Z. Regulation of neuroprotective activity of myocyte-enhancer factor 2 by cAMP-protein kinase A signaling pathway in neuronal survival. J Biol Chem. 2005;280:16705-13.
345. Nakagawa S, Kim JE, Lee R, Malberg JE, Chen J, Steffen C, Zhang YJ, Nestler EJ, Duman RS. Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci. 2002;22:3673-82.
346. Sasaki T, Kitagawa K, Omura-Matsuoka E, Todo K, Terasaki Y, Sugiura S, Hatazawa J, Yagita Y, Hori M. The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia. Stroke. 2007;38:1597-1605.
347. De Caterina R, Zampolli A. From asthma to atherosclerosis--5-lipoxygenase, leukotrienes, and inflammation. N Engl J Med. 2004;350:4-7.
348. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171-6.
349. Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature. 1990;343:282-4.
350. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983;220:568-75.
351. Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z, Funk CD, Lusis AJ. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002;91:120-6.
352. Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ. Expanding expression of the 5-lipoxygenase pathway within thearterial wall during human atherogenesis. Proc Natl Acad Sci U S A. 2003;100:1238-43.
353. Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350:29-37.
354. Aiello RJ, Bourassa PA, Lindsey S, Weng W, Freeman A, Showell HJ. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol. 2002;22:443-9.
355. Ghazalpour A, Wang X, Lusis AJ, Mehrabian M. Complex inheritance of the 5-lipoxygenase locus influencing atherosclerosis in mice. Genetics. 2006;173:943-51.
356.Kajimoto K, Shioji K, Ishida C, Iwanaga Y, Kokubo Y, Tomoike H, Miyazaki S, Nonogi H, Goto Y, Iwai N. Validation of the association between the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a Japanese population. Circ J. 2005;69:1029-34.
357. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263-5.
2. Dipple KM, McCabe ERB. Modifier Genes Convert "Simple" Mendelian Disorders to Complex Traits. Mol Genet Metab. 2000;71:43-50.
3. Terwilliger JD, Weiss KM. Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr Opin Biotechnol. 1998;9:578-94.
4. Thornton-Wells TA, Moore JH, Haines JL. Genetics, statistics and human disease: analytical retooling for complexity. Trends Genet. 2004;20:640-7.
5. Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet. 2001;2:91-9.
6. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860-921.
7. Crawford DC, Nickerson DA. Definition and clinical importance of haplotypes. Annu Rev Med. 2005;56:303-20.
8. Ardlie KG, Kruglyak L, Seielstad M. Patterns of linkage disequilibrium in the human genome. Nat Rev Genet. 2002;3:299-309.
9. Zollner S, von Haeseler A. A coalescent approach to study linkage disequilibrium between single-nucleotide polymorphisms. Am J Hum Genet. 2000;66:615-28.
10. Morton NE. Sequential tests for the detection of linkage. Am J Hum Genet. 1955;7:277-318.
11. Elston RC, Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21:523-42.
12. Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974;26:588-97.
13. Chotai J. On the lod score method in linkage analysis. Ann Hum Genet. 1984;48:359-78.
14. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516-7.
15. Clark AG. Finding genes underlying risk of complex disease by linkage disequilibrium mapping. Curr Opin Genet Dev. 2003;13:296-302.
16. Boehnke M. Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes. Am J Hum Genet. 1994;55:379-90.
17. Kruglyak L, Lander ES. High-resolution genetic mapping of complex traits. Am J Hum Genet. 1995;56:1212-23.
18. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994;3:569-74.
19. Tsai MS, Tangalos EG, Petersen RC, Smith GE, Schaid DJ, Kokmen E, Ivnik RJ, Thibodeau SN. Apolipoprotein E: risk factor for Alzheimer disease. Am J Hum Genet. 1994;54:643-9.
20. Lucotte G, Visvikis S, Leininger-Muler B, David F, Berriche S, Reveilleau S, Couderc R, Babron MC, Aguillon D, Siest G. Association of apolipoprotein E allele epsilon 4 with late-onset sporadic Alzheimer's disease. Am J Med Genet. 1994;54:286-8.
21. Cordell HJ, Clayton DG. Genetic association studies. Lancet. 2005;366:1121-31.
22. Sham P. Statistics in Human Genetics. Arnold. 1998.
23. Jeffreys AJ, Kauppi L, Neumann R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet. 2001;29:217-22.
24. Ardlie K, Liu-Cordero SN, Eberle MA, Daly M, Barrett J, Winchester E, Lander ES, Kruglyak L. Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. Am J Hum Genet. 2001;69:582-9.
25. Frisse L, Hudson RR, Bartoszewicz A, Wall JD, Donfack J, Di Rienzo A. Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet. 2001;69:831-43.
26. Quintana PJ, Neuwirth EA, Grosovsky AJ. Interchromosomal gene conversion at an endogenous human cell locus. Genetics. 2001;158:757-67.
27. Terwilliger JD, Zollner S, Laan M, Paabo S. Mapping genes through the use of linkage disequilibrium generated by genetic drift: 'drift mapping' in small populations with no demographic expansion. Hum Hered. 1998;48:138-54.
28. Chakraborty R, Weiss KM. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci U S A. 1988;85:9119-23.
29. Stephens JC, Briscoe D, O'Brien SJ. Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am J Hum Genet. 1994;55:809-24.
30. Wilson JF, Goldstein DB. Consistent long-range linkage disequilibrium generated by admixture in a Bantu-Semitic hybrid population. Am J Hum Genet. 2000;67:926-35.
31. Pfaff CL, Parra EJ, Bonilla C, Hiester K, McKeigue PM, Kamboh MI, Hutchinson RG, Ferrell RE, Boerwinkle E, Shriver MD. Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium. Am J Hum Genet. 2001;68:198-207.
32. Parsch J, Meiklejohn CD, Hartl DL. Patterns of DNA sequence variation suggest the recent action of positive selection in the janus-ocnus region of Drosophila simulans. Genetics. 2001;159:647-57.
33. Verrelli BC, Eanes WF. Clinal variation for amino acid polymorphisms at the Pgm locus in Drosophila melanogaster. Genetics. 2001;157:1649-63.
34. Charlesworth B, Morgan MT, Charlesworth D. The effect of deleterious mutations on neutral molecular variation. Genetics. 1993;134:1289-303.
35. Cannon GB. The effects of natural selection on linkage disequilibrium and relative fitness in experimental populations of Drosophila melanogaster. Genetics. 1963;48:1201-16.
36. Lewontin RC. The Interaction of Selection and Linkage. Ii. Optimum Models. Genetics. 1964;50:757-82.
37. Pritchard JK, Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet. 2001;69:1-14.
38. Weiss KM, Clark AG. Linkage disequilibrium and the mapping of complex human traits. Trends Genet. 2002;18:19-24.
39. Przeworski M, Wall JD. Why is there so little intragenic linkage disequilibrium in humans? Genet Res. 2001;77:143-51.
40. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999;22:139-44.
41. Fearnhead P, Donnelly P. Estimating recombination rates from population genetic data.Genetics. 2001;159:1299-318.
42. Hudson RR. Properties of a neutral allele model with intragenic recombination. Theor Popul Biol. 1983;23:183-201.
43. Kuhner MK, Yamato J, Felsenstein J. Maximum likelihood estimation of recombination rates from population data. Genetics. 2000;156:1393-401.
44. Long AD, Langley CH. The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res. 1999;9:720-31.
45. Nielsen R. Estimation of population parameters and recombination rates from single nucleotide polymorphisms. Genetics. 2000;154:931-42.
46. Wall JD. A comparison of estimators of the population recombination rate. Mol Biol Evol. 2000;17:156-63.
47. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES. Linkage disequilibrium in the human genome. Nature. 2001;411:199-204.
48. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES. High-resolution haplotype structure in the human genome. Nat Genet. 2001;29:229-32.
49. van den Oord EJ, Neale BM. Will haplotype maps be useful for finding genes? Mol Psychiatry. 2004;9:227-36.
50. Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003;4:587-97.
51. Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA. Haplotype tagging for the identification of common disease genes. Nat Genet. 2001;29:233-7.
52. Integrating ethics and science in the International HapMap Project. Nat Rev Genet. 2004;5:467-75.
53. A haplotype map of the human genome. Nature. 2005;437:1299-320.
54. Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17:502-10.
55. Smith DJ, Lusis AJ. The allelic structure of common disease. Hum Mol Genet. 2002;11:2455-61.
56. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921-3.
57. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76-80.
58. Becker KG. The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses. 2004;62:309-17.
59. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SFA, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR,Stefansson K. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet.2004;36:233-239.
60. Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet. 2000;26:151-7.
61. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001;69:124-37.
62. Falk CT, Rubinstein P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet. 1987;51 ( Pt 3):227-33.
63. Terwilliger JD, Ott J. A haplotype-based 'haplotype relative risk' approach to detecting allelic associations. Hum Hered. 1992;42:337-46.
64. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993;52:506-16.
65. Sham PC, Curtis D. An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet. 1995;59:323-36.
66. Spielman RS, Ewens WJ. A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet. 1998;62:450-8.
67. Curtis D. Use of siblings as controls in case-control association studies. Ann Hum Genet. 1997;61:319-33.
68. Martin ER, Kaplan NL, Weir BS. Tests for linkage and association in nuclear families. Am J Hum Genet. 1997;61:439-48.
69. Allison DB. Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet. 1997;60:676-90.
70. Rabinowitz D. A transmission disequilibrium test for quantitative trait loci. Hum Hered. 1997;47:342-50.
71. Abecasis GR, Cardon LR, Cookson WO. A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000;66:279-92.
72. Martin ER, Monks SA, Warren LL, Kaplan NL. A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet. 2000;67:146-54.
73. Morton NE, Collins A. Tests and estimates of allelic association in complex inheritance. Proc Natl Acad Sci U S A. 1998;95:11389-93.
74. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220-8.
75. Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997-1004.
76. Bacanu SA, Devlin B, Roeder K. The power of genomic control. Am J Hum Genet. 2000;66:1933-44.
77. Pritchard JK, Stephens M, Donnelly P. Inference of population structure using multilocus genotype data. Genetics. 2000;155:945-59.
78. Collins A, Lonjou C, Morton NE. Genetic epidemiology of single-nucleotide polymorphisms. Proc Natl Acad Sci U S A. 1999;96:15173-7.
79. Eaves IA, Merriman TR, Barber RA, Nutland S, Tuomilehto-Wolf E, Tuomilehto J, Cucca F, Todd JA. The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes. Nat Genet. 2000;25:320-3.
80. Taillon-Miller P, Bauer-Sardina I, Saccone NL, Putzel J, Laitinen T, Cao A, Kere J, Pilia G,Rice JP, Kwok PY. Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nat Genet. 2000;25:324-8.
81. Wright AF, Carothers AD, Pirastu M. Population choice in mapping genes for complex diseases. Nat Genet. 1999;23:397-404.
82. Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, Shkolny D, Einarsson G, Gudjonsdottir HM, Valdimarsson EM, Einarsson OB, Thorgeirsson G, Hadzic R, Jonsdottir S, Reynisdottir ST, Bjarnadottir SM, Gudmundsdottir T, Gudlaugsdottir GJ, Gill R, Lindpaintner K, Sainz J, Hannesson HH, Sigurdsson GT, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet. 2002;70:593-603.
83. Jorde LB. Linkage disequilibrium and the search for complex disease genes. Genome Res. 2000;10:1435-44.
84. Perneger TV. What's wrong with Bonferroni adjustments. Bmj. 1998;316:1236-8.
85. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A. 2003;100:9440-5.
86. Goldsmith LJ. Power and sample size considerations in molecular biology. Methods Mol Biol. 2002;184:111-30.
87. J. C. Statistical power analysis for the behavioral sciences. 2nd edition ed: Hillsdle, New Jersey, Lawrence Erlbaum Association.; 1988.
88. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35-41.
89. Sun Y, Zhang F, Gao J, Gao X, Guo T, Zhang K, Shi Y, Zheng Z, Tang W, Zheng Y, Li S, Li X, Feng G, Shen X, He L. Positive association between POU1F1 and mental retardation in young females in the Chinese Han population. Hum Mol Genet. 2006;15:1237-43.
90. American Psychiatric Association: Task Force on DSM-IV: diagnostic and statistical manual of mental disorders: DSM-IV. 1994.
91. Leonard H, Wen XY. The epidemiology of mental retardation: Challenges and opportunities in the new millennium. Mental Retardation and Developmental Disabilities Research Reviews. 2002;8:117-134.
92. Retardation AAotM. Mental Retardation :definition ,classification and systems of supports-workbook. Washington, DC: American Association on Mental Retardation; 1992.
93. Accardo PJ. Overview: Mental retardation. Mental Retardation and Developmental Disabilities Research Reviews 4; 1998.
94. Lubinski D. Introduction to the special section on cognitive abilities: 100 years after Spearman's (1904) "'General intelligence,' objectively determined and measured". J Pers Soc Psychol. 2004;86:96-111.
95. Plomin R. The genetics of g in human and mouse. Nat Rev Neurosci. 2001;2:136-41.
96. Ruth Luckasson JDSB-D. Mental Retardation Definition, Classification, and Systems of Supports. 10th Edition ed; 2002.
97. Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T. Genetics and pathophysiology of mental retardation. Eur J Hum Genet. 2006;14:701-13.
98. 郑子健,曹蓉,张富昌. 秦巴山区弱智儿童的社会文化成因及防治对策. 西北大学学报(哲学社会科学版). 1999;29:107-110.
99. Bartels M, Rietveld MJ, Van Baal GC, Boomsma DI. Genetic and environmental influences on the development of intelligence. Behav Genet. 2002;32:237-49.
100. Yeargin-Allsopp M, Murphy CC, Cordero JF, Decoufle P, Hollowell JG. Reported biomedical causes and associated medical conditions for mental retardation among 10-year-old children, metropolitan Atlanta, 1985 to 1987. Dev Med Child Neurol. 1997;39:142-9.
101. Yeargin-Allsopp M, Murphy CC, Oakley GP, Sikes RK. A multiple-source method for studying the prevalence of developmental disabilities in children: the Metropolitan Atlanta Developmental Disabilities Study. Pediatrics. 1992;89:624-30.
102. Yeargin-Allsopp M, Drews CD, Decoufle P, Murphy CC. Mild mental retardation in black and white children in metropolitan Atlanta: a case-control study. Am J Public Health. 1995;85:324-8.
103. Murray. RJHC. The Bell Curve: Intelligence and Class Structure in American Life: Free Press; 1999.
104. Wilson RS, Matheny AP, Jr. Retardation and twin concordance in infant mental development: a reassessment. Behav Genet. 1976;6:353-8.
105. Trouton A, Spinath FM, Plomin R. Twins early development study (TEDS): a multivariate, longitudinal genetic investigation of language, cognition and behavior problems in childhood. Twin Res. 2002;5:444-8.
106. Rijsdijk FV, Vernon PA, Boomsma DI. Application of hierarchical genetic models to Raven and WAIS subtests: a Dutch twin study. Behav Genet. 2002;32:199-210.
107. Benyamin B, Wilson V, Whalley LJ, Visscher PM, Deary IJ. Large, consistent estimates of the heritability of cognitive ability in two entire populations of 11-year-old twins from Scottish mental surveys of 1932 and 1947. Behav Genet. 2005;35:525-34.
108. Posthuma D, Baare WFC, Pol HEH, Kahn RS, Boomsma DI, De Geus EJC. Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Research. 2003;6:131-139.
109. Alarcon M, Plomin R, Fulker DW, Corley R, DeFries JC. Multivariate path analysis of specific cognitive abilities data at 12 years of age in the Colorado Adoption Project. Behavior Genetics. 1998;28:255-264.
110. Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, Winter RM, Bolton P, Flint J. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet. 1999;354:1676-81.
111. Bocian E, Helias-Rodzewicz Z, Suchenek K, Obersztyn E, Kutkowska-Kazmierczak A, Stankiewicz P, Kostyk E, Mazurczak T. Subtelomeric rearrangements: results from FISH studies in 84 families with idiopathic mental retardation. Med Sci Monit. 2004;10:CR143-51.
112. Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet. 1995;9:132-40.
113. De Vries BB, Winter R, Schinzel A, van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003;40:385-98.
114. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36:955-7.
115. Bi W, Saifi GM, Shaw CJ, Walz K, Fonseca P, Wilson M, Potocki L, Lupski JR. Mutations ofRAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet. 2004;115:515-24.
116. Nicholls RD. The impact of genomic imprinting for neurobehavioral and developmental disorders. J Clin Invest. 2000;105:413-8.
117. Petersen MB, Brondum-Nielsen K, Hansen LK, Wulff K. Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. Am J Med Genet. 1995;60:261-2.
118. Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M. Autism in Angelman syndrome: a population-based study. Pediatr Neurol. 1996;14:131-6.
119. Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001;2:153-75.
120. Inlow JK, Restifo LL. Molecular and comparative genetics of mental retardation. Genetics. 2004;166:835-81.
121. Luciano M, Wright MJ, Duffy DL, Wainwright MA, Zhu G, Evans DM, Geffen GM, Montgomery GW, Martin NG. Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q. Behav Genet. 2006;36:45-55.
122. Posthuma D, Luciano M, Geus EJ, Wright MJ, Slagboom PE, Montgomery GW, Boomsma DI, Martin NG. A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. Am J Hum Genet. 2005;77:318-26.
123. Huntsman MM, Tran BV, Potkin SG, Bunney WE, Jr., Jones EG. Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc Natl Acad Sci U S A. 1998;95:15066-71.
124. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet. 2001;69:570-81.
125. Addington AM, Gornick M, Duckworth J, Sporn A, Gogtay N, Bobb A, Greenstein D, Lenane M, Gochman P, Baker N, Balkissoon R, Vakkalanka RK, Weinberger DR, Rapoport JL, Straub RE. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry. 2005;10:581-8.
126. Plomin R, Turic DM, Hill L, Turic DE, Stephens M, Williams J, Owen MJ, O'Donovan MC. A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability. Mol Psychiatry. 2004;9:582-6.
127. Plomin R, Hill L, Craig IW, McGuffin P, Purcell S, Sham P, Lubinski D, Thompson LA, Fisher PJ, Turic D, Owen MJ. A genome-wide scan of 1842 DNA markers for allelic associations with general cognitive ability: a five-stage design using DNA pooling and extreme selected groups. Behav Genet. 2001;31:497-509.
128. Butcher LM, Meaburn E, Knight J, Sham PC, Schalkwyk LC, Craig IW, Plomin R. SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children. Hum Mol Genet. 2005;14:1315-25.
129. Zhang LF, Yang J, Hong Z, Yuan GG, Zhou BF, Zhao LC, Huang YN, Chen J, Wu YF. Proportion of different subtypes of stroke in China. Stroke. 2003;34:2091-6.
130. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2:43-53.
131. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and Natural-History of Clinically Identifiable Subtypes of Cerebral Infarction. Lancet. 1991;337:1521-1526.
132. Yang QD, Niu Q, Zhou YH, Liu YH, Xu HW, Gu WP, Tian FF, Xie YQ, Zhang L, Xia J. Incidence of cerebral hemorrhage in the Changsha community. A prospective study from 1986 to 2000. Cerebrovasc Dis. 2004;17:303-13.
133. 粟秀初,孔繁元,范学文. 现代脑血管病学. 第一版 ed. 北京: 人民军医出版社; 2003.
134. 吴兆苏,姚崇华,赵冬. 我国人群脑卒中发病率、死亡率的流行病学研究. 中华流行病学杂志. 2003;24:236-239.
135. Wu Z, Yao C, Zhao D, Wu G, Wang W, Liu J, Zeng Z, Wu Y. Sino-MONICA Project : A Collaborative Study on Trends and Determinants in Cardiovascular Diseases in China, Part I: Morbidity and Mortality Monitoring. Circulation. 2001;103:462-468.
136. 全军脑血管病流行病学协作组. 中国脑血管病流行病学研究. 北京: 人民军医出版社; 1993.
137. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, Degraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37:1583-633.
138. Hrubec Z, Robinette CD. The study of human twins in medical research. N Engl J Med. 1984;310:435-41.
139. Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD. A study of twins and stroke. Stroke. 1992;23:221-3.
140. Carmelli D, DeCarli C, Swan GE, Jack LM, Reed T, Wolf PA, Miller BL. Evidence For Genetic Variance in White Matter Hyperintensity Volume in Normal Elderly Male Twins. Stroke. 1998;29:1177-1181.
141. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke. 2002;33:769-74.
142. Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E. Parental History of Cardiovascular Disease and Risk of Stroke : A Prospective Follow-up of 14 371 Middle-aged Men and Women in Finland. Stroke. 1997;28:1361-1366.
143. Howard G, Evans GW, Toole JF, Tell G, Rose LA, Espeland M, Truscott BL. Characteristics of Stroke Victims Associated with Early Cardiovascular Mortality in Their Children. J Clin Epidemiol. 1990;43:49-54.
144. Welin L, Svardsudd K, Wilhelmsen L, Larsson B, Tibblin G. Analysis of risk factors for stroke in a cohort of men born in 1913. N Engl J Med. 1987;317:521-6.
145. Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH. Familial aggregation of stroke. The Framingham Study. Stroke. 1993;24:1366-71.
146. MacClellan LR, Mitchell BD, Cole JW, Wozniak MA, Stern BJ, Giles WH, Brown DW, Sparks MJ, Kittner SJ. Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study. Genet Epidemiol. 2006;30:602-8.
147. Liao D, Myers R, Hunt S, Shahar E, Paton C, Burke G, Province M, Heiss G. Familial history of stroke and stroke risk. The Family Heart Study. Stroke. 1997;28:1908-12.
148. Khaw K-T, Barrett-Connor E. Family history of stroke as an independent predictor of ischiemtc heart disease in men and stroke in women. Am. J. Epidemiol. 1986;123:59-66.
149. Rastenyte D, Tuomilehto J, Sarti C. Genetics of stroke - a review. Journal of the Neurological Sciences. 1998;153:132-145.
150. Bak S, Gaist D, Sindrup SH, Skytthe A, Christensen K. Genetic liability in stroke - A long-term follow-up study of Danish twins. Stroke. 2002;33:769-774.
151. Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD. A Study of Twins and Stroke. Stroke. 1992;23:221-223.
152. Brass LM, Page WF, Lichtman JH. Stroke in twins III: A follow-up study. Stroke. 1999;30:256-256.
153. Jamrozik K, Broadhurst R, Anderson C, Stewart-Wynne E. The role of lifestyle factors in the etiology of stroke. A population- based case-control study in Perth, Western Australia. Stroke. 1994;25:51-59.
154. Flossmann E, Schulz UG, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke. 2004;35:212-27.
155. Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Lohr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet. 2005;366:1794-6.
156. Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006;5:501-12.
157. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383:707-10.
158.Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731-9.
159. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127:2533-9.
160. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350:1511-5.
161. Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005;62:1091-4.
162. Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, Ferrari MD, Breuning MH, Haan J. Cerebral microbleeds in CADASIL. Neurology. 2001;57:1066-70.
163. Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, Uttner I, Crispin A, Ludwig H, Gasser T, Yousry TA. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999;52:1361-7.
164. Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031-8.
165. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, Schiffmann R. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology.1998;50:1746-9.
166. Grewal RP. Stroke in Fabry's disease. J Neurol. 1994;241:153-6.
167. Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996;40:8-17.
168. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288-94.
169. Stockman JA, Nigro MA, Mishkin MM, Oski FA. Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med. 1972;287:846-9.
170. Pavlakis SG, Bello J, Prohovnik I, Sutton M, Ince C, Mohr JP, Piomelli S, Hilal S, De Vivo DC. Brain infarction in sickle cell anemia: magnetic resonance imaging correlates. Ann Neurol. 1988;23:125-30.
171. Schatz J, White DA, Moinuddin A, Armstrong M, DeBaun MR. Lesion burden and cognitive morbidity in children with sickle cell disease. J Child Neurol. 2002;17:891-5.
172. Driscoll MC, Hurlet A, Styles L, McKie V, Files B, Olivieri N, Pegelow C, Berman B, Drachtman R, Patel K, Brambilla D. Stroke risk in siblings with sickle cell anemia. Blood. 2003;101:2401-4.
173. Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet. 2005;37:435-40.
174. Steinberg MH, Adewoye AH. Modifier genes and sickle cell anemia. Curr Opin Hematol. 2006;13:131-6.
175. Taylor JGt, Tang DC, Savage SA, Leitman SF, Heller SI, Serjeant GR, Rodgers GP, Chanock SJ. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood. 2002;100:4303-9.
176. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5-11.
177. Bellamy MF, McDowell IF. Putative mechanisms for vascular damage by homocysteine. J Inherit Metab Dis. 1997;20:307-15.
178. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis. N Engl J Med. 1996;334:763-8.
179. Hassan A, Hunt BJ, O'Sullivan M, Bell R, D'Souza R, Jeffery S, Bamford JM, Markus HS. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127:212-219.
180. Lee SJ, Lee DH, Yoo HW, Koo SK, Park ES, Park JW, Lim HG, Jung SC. Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria. J Hum Genet. 2005;50:648-54.
181. Kraus JP, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo MP, Sebastio G, de Franchis R, Andria G, Kluijtmans LA, Blom H, Boers GH, Gordon RB, Kamoun P, Tsai MY, Kruger WD, Koch HG, Ohura T, Gaustadnes M. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat. 1999;13:362-75.
182. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. AnnNeurol. 1984;16:481-8.
183. Martinez-Fernandez E, Gil-Peralta A, Garcia-Lozano R, Chinchon I, Aguilera I, Fernandez-Lopez O, Arenas J, Campos Y, Bautista J. Mitochondrial disease and stroke. Stroke. 2001;32:2507-10.
184. Yoneda M, Maeda M, Kimura H, Fujii A, Katayama K, Kuriyama M. Vasogenic edema on MELAS: a serial study with diffusion-weighted MR imaging. Neurology. 1999;53:2182-4.
185. Clark JM, Marks MP, Adalsteinsson E, Spielman DM, Shuster D, Horoupian D, Albers GW. MELAS: Clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy. Neurology. 1996;46:223-7.
186. Judge DP, Dietz HC. Marfan's syndrome. Lancet. 2005;366:1965-76.
187. Nollen GJ, Mulder BJM. What is new in the Marfan syndrome? International Journal of Cardiology. 2004;97:103-108.
188. Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407-11.
189. Wityk RJ, Zanferrari C, Oppenheimer S. Neurovascular complications of marfan syndrome: a retrospective, hospital-based study. Stroke. 2002;33:680-4.
190. Spittell PC, Spittell JA, Jr., Joyce JW, Tajik AJ, Edwards WD, Schaff HV, Stanson AW. Clinical features and differential diagnosis of aortic dissection: experience with 236 cases (1980 through 1990). Mayo Clin Proc. 1993;68:642-51.
191. Schievink WI, Michels VV, Piepgras DG. Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke. 1994;25:889-903.
192. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673-80.
193. North KN, Whiteman DA, Pepin MG, Byers PH. Cerebrovascular complications in Ehlers-Danlos syndrome type IV. Ann Neurol. 1995;38:960-4.
194. van den Berg JS, Hennekam RC, Cruysberg JR, Steijlen PM, Swart J, Tijmes N, Limburg M. Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum. Cerebrovasc Dis. 2000;10:315-9.
195. Ikezaki K, Han DH, Kawano T, Kinukawa N, Fukui M. A clinical comparison of definite moyamoya disease between South Korea and Japan. Stroke. 1997;28:2513-7.
196. Hallemeier CL, Rich KM, Grubb RL, Jr., Chicoine MR, Moran CJ, Cross DT, 3rd, Zipfel GJ, Dacey RG, Jr., Derdeyn CP. Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke. 2006;37:1490-6.
197. Fukui M. Current state of study on moyamoya disease in Japan. Surg Neurol. 1997;47:138-43.
198. Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet. 1999;64:533-7.
199. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, Inoue T, Ikezaki K, Matsushima T, Fukui M. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke. 2000;31:930-5.
200. Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, Arinami T. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet. 2004;49:278-81.
201. Celentano A, Mancini FP, Crivaro M, Palmieri V, Ferrara LA, De Stefano V, Di Minno G, de Simone G. Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension. Am J Cardiol. 1999;83:1196-200.
202. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Bmj. 2002;325:1202.
203. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005;365:224-32.
204. Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004;61:1652-61.
205. Humphries SE, Morgan L. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol. 2004;3:227-35.
206. Slooter AJ, Rosendaal FR, Tanis BC, Kemmeren JM, van der Graaf Y, Algra A. Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. J Thromb Haemost. 2005;3:1213-7.
207. Dikmen M, Ozbabalik D, Gunes HV, Degirmenci I, Bal C, Ozdemir G, Basaran A. Acute stroke in relation to homocysteine and methylenetetrahydrofolate reductase gene polymorphisms. Acta Neurol Scand. 2006;113:307-14.
208. Grossmann R, Geisen U, Merati G, Mullges W, Schambeck CM, Walter U, Schwender S. Genetic risk factors in young adults with 'cryptogenic' ischemic cerebrovascular disease. Blood Coagul Fibrinolysis. 2002;13:583-90.
209. Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke. 2005;36:1581-7.
210. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J, Jr. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-77.
211. Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006;98:1123-33.
212. Brenner D, Labreuche J, Poirier O, Cambien F, Amarenco P. Renin-angiotensin-aldosterone system in brain infarction and vascular death. Ann Neurol. 2005;58:131-8.
213. Rubattu S, Di Angelantonio E, Stanzione R, Zanda B, Evangelista A, Pirisi A, De Paolis P, Cota L, Brunetti E, Volpe M. Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant. J Hypertens. 2004;22:2129-34.
214. Tuncer N, Tuglular S, Kilic G, Sazci A, Us O, Kara I. Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. J Clin Neurosci. 2006;13:224-7.
215. Hassan A, Markus HS. Genetics and ischaemic stroke. Brain. 2000;123 ( Pt 9):1784-812.
216. Sethi AA, Tybjaerg-Hansen A, Gronholdt ML, Steffensen R, Schnohr P, Nordestgaard BG. Angiotensinogen mutations and risk for ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. Six case-control studies from the Copenhagen City Heart Study. Ann Intern Med. 2001;134:941-54.
217. Schmidt H, Fazekas F, Kostner GM, van Duijn CM, Schmidt R. Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study. Stroke. 2001;32:405-12.
218. Lalouschek W, Schillinger M, Hsieh K, Endler G, Tentschert S, Lang W, Cheng S, Mannhalter C. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke.2005;36:1405-9.
219. Rubattu S, Speranza R, Ferrari M, Evangelista A, Beccia M, Stanzione R, Assenza GE, Volpe M, Rasura M. A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study. Eur J Neurol. 2005;12:989-93.
220. Santamaria A, Oliver A, Borrell M, Mateo J, Belvis R, Marti-Fabregas J, Ortin R, Tirado I, Souto JC, Fontcuberta J. Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels. Stroke. 2003;34:2387-91.
221. Aznar J, Mira Y, Vaya A, Corella D, Ferrando F, Villa P, Estelles A. Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke. Thromb Haemost. 2004;91:1031-4.
222. Jood K, Ladenvall P, Tjarnlund-Wolf A, Ladenvall C, Andersson M, Nilsson S, Blomstrand C, Jern C. Fibrinolytic gene polymorphism and ischemic stroke. Stroke. 2005;36:2077-81.
223. Wiklund PG, Nilsson L, Ardnor SN, Eriksson P, Johansson L, Stegmayr B, Hamsten A, Holmberg D, Asplund K. Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts. Stroke. 2005;36:1661-5.
224. van Goor ML, Garcia EG, Leebeek F, Brouwers GJ, Koudstaal P, Dippel D. The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke. A case-control study. Thromb Haemost. 2005;93:92-6.
225. Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood. 2002;100:3-10.
226. Lai J, Zhou D, Xia S, Shang Y, Zhu J, Pan J, Hua B, Zhu Y, Cui L. Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population. Neurol India. 2006;54:366-9.
227. Seripa D, Dobrina A, Margaglione M, Matera MG, Gravina C, Vecile E, Fazio VM. Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke. Cerebrovasc Dis. 2003;15:276-81.
228. Couderc R, Mahieux F, Bailleul S, Fenelon G, Mary R, Fermanian J. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study. Stroke. 1993;24:661-4.
229. de Andrade M, Thandi I, Brown S, Gotto A, Jr., Patsch W, Boerwinkle E. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet. 1995;56:1379-90.
230. Schmidt R, Schmidt H, Fazekas F, Schumacher M, Niederkorn K, Kapeller P, Weinrauch V, Kostner GM. Apolipoprotein E polymorphism and silent microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study. Stroke. 1997;28:951-6.
231. Pedro-Botet J, Senti M, Nogues X, Rubies-Prat J, Roquer J, D'Olhaberriague L, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992;23:1556-62.
232. Kessler C, Spitzer C, Stauske D, Mende S, Stadlmuller J, Walther R, Rettig R. The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol. 1997;17:2880-4.
233. Margaglione M, Seripa D, Gravina C, Grandone E, Vecchione G, Cappucci G, Merla G, Papa S, Postiglione A, Di Minno G, Fazio VM. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian Case-Control Study. Stroke. 1998;29:399-403.
234. MO MC, Muir KW, Weir CJ, Dyker AG, Bone I, Nicoll JA, Lees KR. The apolipoprotein E epsilon4 allele and outcome in cerebrovascular disease. Stroke. 1998;29:1882-7.
235. Alberts MJ, Graffagnino C, McClenny C, DeLong D, Strittmatter W, Saunders AM, Roses AD. ApoE genotype and survival from intracerebral haemorrhage. Lancet. 1995;346:575.
236. Teasdale GM, Nicoll JA, Murray G, Fiddes M. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet. 1997;350:1069-71.
237. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D. Cerebrovascular disease, the apolipoprotein e4 allele, and cognitive decline in a community-based study of elderly men. Stroke. 1996;27:2230-5.
238. White RP, Deane C, Vallance P, Markus HS. Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia. Stroke. 1998;29:467-72.
239. Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA. Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab. 1994;14:175-92.
240. White RP, Vallance P, Markus HS. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci (Lond). 2000;99:555-60.
241. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774-7.
242. Hassan A, Gormley K, O'Sullivan M, Knight J, Sham P, Vallance P, Bamford J, Markus H. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke. 2004;35:654-659.
243. Hou L, Osei-Hyiaman D, Yu H, Ren Z, Zhang Z, Wang B, Harada S. Association of a 27-bp repeat polymorphism in ecNOS gene with ischemic stroke in Chinese patients. Neurology. 2001;56:490-496.
244. Yahashi Y, Kario K, Shimada K, Matsuo M. The 27-bp repeat polymorphism in intron 4 of the endothelial cell nitric oxide synthase gene and ischemic stroke in a Japanese population. Blood Coagul Fibrinolysis. 1998;9:405-9.
245. Elbaz A, Poirier O, Moulin T, Chedru F, Cambien F, Amarenco P. Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. Stroke. 2000;31:1634-1639.
246. Markus HS, Ruigrok Y, Ali N, Powell JF. Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke. 1998;29:1908-1911.
247. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003;35:131-8.
248. Song Q, Cole JW, O'Connell JR, Stine OC, Gallagher M, Giles WH, Mitchell BD, Wozniak MA, Stern BJ, Sorkin JD, McArdle PF, Naj AC, Xu Q, Gibbons GH, Kittner SJ. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study. Hum Mol Genet. 2006;15:2468-78.
249. Bevan S, Porteous L, Sitzer M, Markus HS. Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis. Stroke. 2005;36:949-53.
250. Lohmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, Meitinger T, Dichgans M. ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients. Stroke. 2005;36:731-736.
251. Nilsson-Ardnor S, Wiklund PG, Lindgren P, Nilsson AK, Janunger T, Escher SA, Hallbeck B, Stegmayr B, Asplund K, Holmberg D. Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population. Stroke. 2005;36:1666-71.
252. Meschia JF, Brott TG, Brown RD, Jr., Crook R, Worrall BB, Kissela B, Brown WM, Rich SS, Case LD, Evans EW, Hague S, Singleton A, Hardy J. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol. 2005;58:351-61.
253. van Rijn MJ, Slooter AJ, Schut AF, Isaacs A, Aulchenko YS, Snijders PJ, Kappelle LJ, van Swieten JC, Oostra BA, van Duijn CM. Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population. Neurology. 2005;65:1203-9.
254. Saleheen D, Bukhari S, Haider SR, Nazir A, Khanum S, Shafqat S, Anis MK, Frossard P. Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Stroke. 2005;36:2275-7.
255. Nakayama T, Asai S, Sato N, Soma M. Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese: a case-control study. Stroke. 2006;37:69-76.
256. Woo D, Kaushal R, Kissela B, Sekar P, Wolujewicz M, Pal P, Alwell K, Haverbusch M, Ewing I, Miller R, Kleindorfer D, Flaherty M, Chakraborty R, Deka R, Broderick J. Association of Phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Stroke. 2006;37:371-6.
257. Kuhlenbaumer G, Berger K, Huge A, Lange E, Kessler C, John U, Funke H, Nabavi DG, Stogbauer F, Ringelstein EB, Stoll M. Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort. J Neurol Neurosurg Psychiatry. 2006;77:521-4.
258. Brophy VH, Ro SK, Rhees BK, Lui LY, Lee JM, Umblas N, Bentley LG, Li J, Cheng S, Browner WS, Erlich HA. Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status. Stroke. 2006;37:1385-90.
259. Zee RYL, Cheng S, Hegener HH, Erlich HA, Ridker PM. Genetic Variants of Arachidonate 5-Lipoxygenase-Activating Protein, and Risk of Incident Myocardial Infarction and Ischemic Stroke: A Nested Case-Control Approach. Stroke. 2006;37:2007-2011.
260. Rosand J, Bayley N, Rost N, de Bakker PIW. Many hypotheses but no replication for the association between PDE4D and stroke. 2006;38:1091-1092.
261. Helgadottir A, Gretarsdottir S, St Clair D, Manolescu A, Cheung J, Thorleifsson G, Pasdar A, Grant SF, Whalley LJ, Hakonarson H, Thorsteinsdottir U, Kong A, Gulcher J, Stefansson K, MacLeod MJ. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet. 2005;76:505-9.
262. Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggstrom JZ. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006;103:8161-6.
263. Helgadottir A, Manolescu A, Helgason A, Thorleifsson G, Thorsteinsdottir U, Gudbjartsson DF, Gretarsdottir S, Magnusson KP, Gudmundsson G, Hicks A, Jonsson T, Grant SF, Sainz J, O'Brien SJ, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Levey AI, Abramson JL, Reilly MP,Vaccarino V, Wolfe ML, Gudnason V, Quyyumi AA, Topol EJ, Rader DJ, Thorgeirsson G, Gulcher JR, Hakonarson H, Kong A, Stefansson K. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet. 2006;38:68-74.
264. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet. 1996;13:429-34.
265. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gauguier D, Reid JL, Macrae IM, Dominiczak AF. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet. 1997;16:364-7.
266. Hassan A, Ali N, Dong Y, Carter ND, Markus HS. Atrial natriuretic peptide gene G664A polymorphism and the risk of ischemic cerebrovascular disease. Neurology. 2001;57:1726-8.
267. Rubattu S, Stanzione R, Di Angelantonio E, Zanda B, Evangelista A, Tarasi D, Gigante B, Pirisi A, Brunetti E, Volpe M. Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans. Stroke. 2004;35:814-8.
268. Zuo Q, Zhang Z, Lei Z. Adaptive scale of infant and children: Medical University of China, Beijing, China; 1988.
269. Gong Y, Dai X. Chinese-Wechsler young children scale of intelligence (C-WYCSI): Map Press, Hunan, China; 1992.
270. Gong Y, Cai T. Wechsler intelligence scale for children, Chinese revision (C-WISC): Map Press, Hunan, China; 1993.
271. Psychiatry CAo. Chinese classification of mental disorders,2nd revision. In. Nanking: Southeast University Press; 1995.
272. Organization TWH. The ICD-10 classification of mental and behavioral disorders: clinical descriptions and diagnostic guidelines. Geneva, Switzerland: WHO; 1992.
273. Wang HY, Zhang FC, Gao JJ, Fan JB, Liu P, Zheng ZJ, Xi H, Sun Y, Gao XC, Huang TZ, Ke ZJ, deficiency disorder in China. Molecular Psychiatry. 2000;5:363-368.
274. Li F, Yan F, Han z, Yang W, Li X, Li Y. A study of the relationship between health care during labour and children's mental retardation in QinBa mountain area, Shaanxi province. J Xi'an Med Univ. 1999;20:100-102.
275. Oppenheimer JH, Schwartz HL. Molecular Basis of Thyroid Hormone-Dependent Brain Development. Endocr Rev. 1997;18:462-475.
276. Anderson GW. Thyroid hormones and the brain. Front Neuroendocrinol. 2001;22:1-17.
277. Winter WE, Signorino MR. Review: molecular thyroidology. Ann Clin Lab Sci. 2001;31:221-44.
278. Cushman LJ, Showalter AD, Rhodes SJ. Genetic defects in the development and function of the anterior pituitary gland. Ann Med. 2002;34:179-91.
279. De Felice M, Postiglione MP, Di Lauro R. Minireview: thyrotropin receptor signaling in development and differentiation of the thyroid gland: insights from mouse models and human diseases. Endocrinology. 2004;145:4062-7.
280. Li S, Crenshaw EB, 3rd, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature. 1990;347:528-33.
281. Rhodes SJ, DiMattia GE, Rosenfeld MG. Transcriptional mechanisms in anterior pituitary cell differentiation. Curr Opin Genet Dev. 1994;4:709-17.
282. Noguchi T, Sugisaki T, Tsukada Y. Postnatal action of growth and thyroid hormones on theretarded cerebral myelinogenesis of Snell dwarf mice (dw). J Neurochem. 1982;38:257-63.
283. Sekiguchi M, Abe H, Moriya M, Tanaka O, Nowakowski RS. Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse. J Comp Neurol. 1998;400:363-74.
284. Lin S, Li S, Drolet D, Rosenfeld M. Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development. 1994;120:515-522.
285. Cohen LE, Radovick S. Molecular Basis of Combined Pituitary Hormone Deficiencies. Endocr Rev. 2002;23:431-442.
286. Blankenstein O, Muhlenberg R, Kim C, Wuller S, Pfaffle R, Heimann G. A new C-terminal located mutation (V272ter) in the PIT-1 gene manifesting with severe congenital hypothyroidism. Possible functionality of the PIT-1 C-terminus. Horm Res. 2001;56:81-6.
287. de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van den Berghe G, Martial JA. The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab. 1995;80:3127-30.
288. Guo TW, Zhang FC, Gao JJ, Bian L, Gao XC, Ma J, Yang M, Ji Q, Duan SW, Zheng ZJ, Li RL, 14q31 are not associated with mental retardation in the iodine-deficient areas of China. Neurosci Lett. 2005;382:179-84.
289. Sham PC, Curtis D. Monte-Carlo tests for associations between disease and alleles at highly polymorphic loci. Annals of Human Genetics. 1995;59:97-105.
290. Zapata C, Carollo C, Rodriguez S. Sampling variance and distribution of the D ' measure of overall gametic disequilibrium between multiallelic loci. Ann Hum Genet. 2001;65:395-406.
291. Xie X, Ott J. Testing linkage disequilibrium between a disease gene and marker loci. Am J Hum Genet. 1993;53:1107-1107.
292. Zhao JH, Curtis D, Sham PC. Model-free analysis and permutation tests for allelic associations. Hum Hered. 2000;50:133-139.
293. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15:97-8.
294. Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol. 2003;25:115-21.
295. Erdfelder E, Faul F, Buchner A. G*Power: a general power analysis program. Behav Res Methods Instrum Comput. 1996;28:1-11.
296. Zhang Z, Wang Z, Zhang R, Gong F, Wang Z. The iodine nutritive status of the pregnant women and wet nurses in Qin-Ba mountain areas. Chin J Endemiol. 2001;20:201-203.
297. Rajas F, Delhase M, De La Hoya M, Verdood P, Castrillo JL, Hooghe-Peters EL. Nuclear factor 1 regulates the distal silencer of the human PIT1/GHF1 gene. Biochem J. 1998;333 ( Pt 1):77-84.
298. Lew D, Brady H, Klausing K, Yaginuma K, Theill LE, Stauber C, Karin M, Mellon PL. GHF-1-promoter-targeted immortalization of a somatotropic progenitor cell results in dwarfism in transgenic mice. Genes Dev. 1993;7:683-93.
299. Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin SC, Yu VC, Rosenfeld MG. A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene. Genes Dev. 1993;7:913-32.
300. Delhase M, Vila V, Hooghe-Peters EL, Castrillo J. A novel pituitary transcription factor is produced by alternative splicing of the human GHF-1/PIT-1 gene. Gene. 1995;155:273-275.
301. Collins A, Morton NE. Mapping a disease locus by allelic association. Proc Natl Acad Sci U S A.1998;95:1741-5.
302. Kuiper GG, Shughrue PJ, Merchenthaler I, Gustafsson JA. The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol. 1998;19:253-86.
303. Mitchner NA, Garlick C, Ben-Jonathan N. Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland. Endocrinology. 1998;139:3976-83.
304. Zhu YS, Pfaff DW. Differential regulation of AP-1 DNA binding activity in rat hypothalamus and pituitary by estrogen. Brain Res Mol Brain Res. 1998;55:115-25.
305. Delhase M, Castrillo JL, de la Hoya M, Rajas F, Hooghe-Peters EL. AP-1 and Oct-1 transcription factors down-regulate the expression of the human PIT1/GHF1 gene. J Biol Chem. 1996;271:32349-58.
306. Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler GB, Jr. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J Clin Invest. 1994;94:2475-80.
307. Lorey FW, Cunningham GC. Birth prevalence of primary congenital hypothyroidism by sex and ethnicity. Hum Biol. 1992;64:531-8.
308. Devos H, Rodd C, Gagne N, Laframboise R, Van Vliet G. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab. 1999;84:2502-6.
309. Pomeroy SL, Kim JY. Biology and pathobiology of neuronal development. Ment Retard Dev Disabil Res Rev. 2000;6:41-6.
310. Schaller RH. Membrane trafficking in the presynaptic nerve terminal. Neuron. 1995;14:893-897.
311. Renieri A, Pescucci C, Longo I, Ariani F, Mari F, Meloni I. Non-syndromic X-linked mental retardation: from a molecular to a clinical point of view. J Cell Physiol. 2005;204:8-20.
312. Stenmark H, Olkkonen VM. The Rab GTPase family. Genome Biol. 2001;2:reviews3007.
313. Thakker-Varia S, Alder J, Crozier RA, Plummer MR, Black IB. Rab3A is required for brain-derived neurotrophic factor-induced synaptic plasticity: Transcriptional analysis at the population and single-cell levels. Journal of Neuroscience. 2001;21:6782-6790.
314. Geppert M, Bolshakov VY, Siegelbaum SA, Takei K, De Camilli P, Hammer RE, Sudhof TC. The role of Rab3A in neurotransmitter release. Nature. 1994;369:493-497.
315. Geppert M, Goda Y, Stevens CF, Sudhof TC. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature. 1997;387:810-4.
316. Castillo PE, Janz R, Sdhof TC, Tzounopoulos T, Malenka RC, Nicoll RA. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature. 1997;388:590-593.
317. Leenders AGM, da Silva FHL, Ghijsen WEJM, Verhage M. Rab3A is involved in transport of synaptic vesicles to the active zone in mouse brain nerve terminals. Mol. Biol. Cell. 2001;12:3095-3102.
318. Basel-Vanagaite L, Alkelai A, Straussberg R, Magal N, Inbar D, Mahajna M, Shohat M. Mapping of a new locus for autosomal recessive non-syndromic mental retardation in the chromosomal region 19p13.12-p13.2: further genetic heterogeneity. Journal of Medical Genetics. 2003;40:729-732.
319. Sullivan M, Olsen AS, Houslay MD. Genomic organisation of the human cyclic AMP-specific phosphodiesterase PDE4C gene and its chromosomal localisation to 19p13.1, between RAB3A and JUND. Cellular Signalling. 1999;11:735-742.
320. Milatovich A, Bolger G, Michaeli T, Francke U. Chromosome localizations of genes for fivecAMP-specific phosphodiesterases in man and mouse. Somat Cell Mol Genet. 1994;20:75-86.
321. Bienvenu T, des Portes V, Saint Martin A, McDonell N, Billuart P, Carrie A, Vinet M, Couvert P, Toniolo D, Ropers H, Moraine C, van Bokhoven H, Fryns J, Kahn A, Beldjord C, Chelly J. Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. Hum. Mol. Genet. 1998;7:1311-1315.
322. D'Adamo P, Menegon A, Lo Nigro C, Grasso M, Gulisano M, Tamanini F, Bienvenu T, Gedeon AK, Oostra B, Wu SK, Tandon A, Valtorta F, Balch WE, Chelly J, Toniolo D. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet. 1998;19:134-9.
323. Nokelainen P, Flint J. Genetic effects on human cognition: lessons from the study of mental retardation syndromes. J Neurol Neurosurg Psychiatry. 2002;72:287-96.
324. Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, Hoffmann K, Maina EN, Morgan NV, Tee L, Morton J, Ainsworth JR, Horn D, Rosser E, Cole TRP, Stolte-Dijkstra I, Fieggen K, Clayton-Smith J, Megarbane A, Shield JP, Newbury-Ecob R, Dobyns WB, Graham JM, Kjaer KW, Warburg M, Bond J, Trembath RC, Harris LW, Takai Y, Mundlos S, Tannahill D, Woods CG, Maher ER. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet. 2005;37:221-224.
325. Chelly J, Mandel J-L. Monogenic causes of X-linked mental retardation. Nat Rev Genet. 2001;2:669-680.
326. Dichgans M. Genetics of ischaemic stroke. Lancet Neurol. 2007;6:149-61.
327. Zee RY, Brophy VH, Cheng S, Hegener HH, Erlich HA, Ridker PM. Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke. 2006;37:2012-7.
328. The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. WHO MONICA Project Principal Investigators. J Clin Epidemiol. 1988;41:105-14.
329. Germer S, Holland MJ, Higuchi R. High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res. 2000;10:258-66.
330. Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, Kelsoe JR. Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet. 2001;105:145-51.
331. Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001;29:E88-8.
332. Storey JD, Tibshirani R. Statistical significance for genomewide studies. PNAS. 2003;100:9440-9445.
333. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1-18.
334. Liu H, Maurice DH. Phosphorylation-mediated activation and translocation of the cyclic AMP-specific phosphodiesterase PDE4D3 by cyclic AMP-dependent protein kinase and mitogen-activated protein kinases. A potential mechanism allowing for the coordinated regulation of PDE4D activity and targeting. J Biol Chem. 1999;274:10557-65.
335. Miro X, Casacuberta JM, Gutierrez-Lopez MD, de Landazuri MO, Puigdomenech P. Phosphodiesterases 4D and 7A splice variants in the response of HUVEC cells to TNF-alpha(1). Biochem Biophys Res Commun. 2000;274:415-21.
336. Shepherd MC, Baillie GS, Stirling DI, Houslay MD. Remodelling of the PDE4 cAMPphosphodiesterase isoform profile upon monocyte-macrophage differentiation of human U937 cells. Br J Pharmacol. 2004;142:339-51.
337. Ariga M, Neitzert B, Nakae S, Mottin G, Bertrand C, Pruniaux MP, Jin SL, Conti M. Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation. J Immunol. 2004;173:7531-8.
338. Lorenowicz MJ, Fernandez-Borja M, Hordijk PL. cAMP Signaling in Leukocyte Transendothelial Migration. Arterioscler Thromb Vasc Biol. 2007.
339.Ichiki T. Role of cAMP response element binding protein in cardiovascular remodeling: good, bad, or both? Arterioscler Thromb Vasc Biol. 2006;26:449-55.
340. Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M, O'Donnell JM. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology. 2002;27:587-95.
341. Kato H, Araki T, Itoyama Y, Kogure K. Rolipram, a cyclic AMP-selective phosphodiesterase inhibitor, reduces neuronal damage following cerebral ischemia in the gerbil. Eur J Pharmacol. 1995;272:107-10.
342. Block F, Tondar A, Schmidt W, Schwarz M. Delayed treatment with rolipram protects against neuronal damage following global ischemia in rats. Neuroreport. 1997;8:3829-32.
343. Bok J, Zha XM, Cho YS, Green SH. An extranuclear locus of cAMP-dependent protein kinase action is necessary and sufficient for promotion of spiral ganglion neuronal survival by cAMP. J Neurosci. 2003;23:777-87.
344. Wang X, Tang X, Li M, Marshall J, Mao Z. Regulation of neuroprotective activity of myocyte-enhancer factor 2 by cAMP-protein kinase A signaling pathway in neuronal survival. J Biol Chem. 2005;280:16705-13.
345. Nakagawa S, Kim JE, Lee R, Malberg JE, Chen J, Steffen C, Zhang YJ, Nestler EJ, Duman RS. Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci. 2002;22:3673-82.
346. Sasaki T, Kitagawa K, Omura-Matsuoka E, Todo K, Terasaki Y, Sugiura S, Hatazawa J, Yagita Y, Hori M. The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia. Stroke. 2007;38:1597-1605.
347. De Caterina R, Zampolli A. From asthma to atherosclerosis--5-lipoxygenase, leukotrienes, and inflammation. N Engl J Med. 2004;350:4-7.
348. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237:1171-6.
349. Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature. 1990;343:282-4.
350. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983;220:568-75.
351. Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z, Funk CD, Lusis AJ. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002;91:120-6.
352. Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ. Expanding expression of the 5-lipoxygenase pathway within thearterial wall during human atherogenesis. Proc Natl Acad Sci U S A. 2003;100:1238-43.
353. Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350:29-37.
354. Aiello RJ, Bourassa PA, Lindsey S, Weng W, Freeman A, Showell HJ. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol. 2002;22:443-9.
355. Ghazalpour A, Wang X, Lusis AJ, Mehrabian M. Complex inheritance of the 5-lipoxygenase locus influencing atherosclerosis in mice. Genetics. 2006;173:943-51.
356.Kajimoto K, Shioji K, Ishida C, Iwanaga Y, Kokubo Y, Tomoike H, Miyazaki S, Nonogi H, Goto Y, Iwai N. Validation of the association between the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a Japanese population. Circ J. 2005;69:1029-34.
357. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263-5.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |