Skip to main content
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2003 Aug;40(8):553–559. doi: 10.1136/jmg.40.8.553

New approaches to investigating heterogeneity in complex traits

R Bomprezzi 1, P Kovanen 1, R Martin 1
PMCID: PMC1735544  PMID: 12920061

Full Text

The Full Text of this article is available as a PDF (523.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abbadi N., Philippe C., Chery M., Gilgenkrantz H., Tome F., Collin H., Theau D., Recan D., Broux O., Fardeau M. Additional case of female monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy due to opposite X-chromosome inactivation. Am J Med Genet. 1994 Aug 15;52(2):198–206. doi: 10.1002/ajmg.1320520215. [DOI] [PubMed] [Google Scholar]
  2. Alizadeh A. A., Eisen M. B., Davis R. E., Ma C., Lossos I. S., Rosenwald A., Boldrick J. C., Sabet H., Tran T., Yu X. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3;403(6769):503–511. doi: 10.1038/35000501. [DOI] [PubMed] [Google Scholar]
  3. Allison D. B., Schork N. J. Selected methodological issues in meiotic mapping of obesity genes in humans: issues of power and efficiency. Behav Genet. 1997 Jul;27(4):401–421. doi: 10.1023/a:1025696232582. [DOI] [PubMed] [Google Scholar]
  4. Balomenos D., Martín-Caballero J., García M. I., Prieto I., Flores J. M., Serrano M., Martínez-A C. The cell cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development. Nat Med. 2000 Feb;6(2):171–176. doi: 10.1038/72272. [DOI] [PubMed] [Google Scholar]
  5. Balomenos D., Martínez-A C. Cell-cycle regulation in immunity, tolerance and autoimmunity. Immunol Today. 2000 Nov;21(11):551–555. doi: 10.1016/s0167-5699(00)01748-5. [DOI] [PubMed] [Google Scholar]
  6. Barcellos L. F., Caillier S., Dragone L., Elder M., Vittinghoff E., Bucher P., Lincoln R. R., Pericak-Vance M., Haines J. L., Weiss A. PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients. Nat Genet. 2001 Sep;29(1):23–24. doi: 10.1038/ng722. [DOI] [PubMed] [Google Scholar]
  7. Bittner M., Meltzer P., Chen Y., Jiang Y., Seftor E., Hendrix M., Radmacher M., Simon R., Yakhini Z., Ben-Dor A. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000 Aug 3;406(6795):536–540. doi: 10.1038/35020115. [DOI] [PubMed] [Google Scholar]
  8. Boomsma Dorret, Busjahn Andreas, Peltonen Leena. Classical twin studies and beyond. Nat Rev Genet. 2002 Nov;3(11):872–882. doi: 10.1038/nrg932. [DOI] [PubMed] [Google Scholar]
  9. Chataway J., Feakes R., Coraddu F., Gray J., Deans J., Fraser M., Robertson N., Broadley S., Jones H., Clayton D. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain. 1998 Oct;121(Pt 10):1869–1887. doi: 10.1093/brain/121.10.1869. [DOI] [PubMed] [Google Scholar]
  10. Check Erika. NIH ponders issues of scale in protein push. Nature. 2002 May 9;417(6885):107–107. doi: 10.1038/417107a. [DOI] [PubMed] [Google Scholar]
  11. Collins A., Lonjou C., Morton N. E. Genetic epidemiology of single-nucleotide polymorphisms. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15173–15177. doi: 10.1073/pnas.96.26.15173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Collins F. S., Brooks L. D., Chakravarti A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 1998 Dec;8(12):1229–1231. doi: 10.1101/gr.8.12.1229. [DOI] [PubMed] [Google Scholar]
  13. Compston A. The genetic epidemiology of multiple sclerosis. Philos Trans R Soc Lond B Biol Sci. 1999 Oct 29;354(1390):1623–1634. doi: 10.1098/rstb.1999.0507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Compston Alastair, Coles Alasdair. Multiple sclerosis. Lancet. 2002 Apr 6;359(9313):1221–1231. doi: 10.1016/S0140-6736(02)08220-X. [DOI] [PubMed] [Google Scholar]
  15. Compston Alastair, Sawcer Stephen. Genetic analysis of multiple sclerosis. Curr Neurol Neurosci Rep. 2002 May;2(3):259–266. doi: 10.1007/s11910-002-0085-3. [DOI] [PubMed] [Google Scholar]
  16. Coraddu F., Sawcer S., Feakes R., Chataway J., Broadley S., Jones H. B., Clayton D., Gray J., Smith S., Taylor C. HLA typing in the United Kingdom multiple sclerosis genome screen. Neurogenetics. 1998 Dec;2(1):24–33. doi: 10.1007/s100480050048. [DOI] [PubMed] [Google Scholar]
  17. Costa T., Greer W., Rysiecki G., Buncic J. R., Ray P. N. Monozygotic twins discordant for Aicardi syndrome. J Med Genet. 1997 Aug;34(8):688–691. doi: 10.1136/jmg.34.8.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Davis R. E., Brown K. D., Siebenlist U., Staudt L. M. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001 Dec 17;194(12):1861–1874. doi: 10.1084/jem.194.12.1861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Drappa J., Vaishnaw A. K., Sullivan K. E., Chu J. L., Elkon K. B. Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med. 1996 Nov 28;335(22):1643–1649. doi: 10.1056/NEJM199611283352204. [DOI] [PubMed] [Google Scholar]
  20. Dyment D. A., Sadovnick A. D., Ebers G. C., Sadnovich A. D. Genetics of multiple sclerosis. Hum Mol Genet. 1997;6(10):1693–1698. doi: 10.1093/hmg/6.10.1693. [DOI] [PubMed] [Google Scholar]
  21. Enzinger Christian, Ropele Stefan, Strasser-Fuchs Siegrid, Kapeller Peter, Schmidt Helena, Poltrum Birgit, Schmidt Reinhold, Hartung Hans-Peter, Fazekas Franz. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele. Arch Neurol. 2003 Jan;60(1):65–70. doi: 10.1001/archneur.60.1.65. [DOI] [PubMed] [Google Scholar]
  22. Ewens W. J., Spielman R. S. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995 Aug;57(2):455–464. [PMC free article] [PubMed] [Google Scholar]
  23. Fearon D. T., Locksley R. M. The instructive role of innate immunity in the acquired immune response. Science. 1996 Apr 5;272(5258):50–53. doi: 10.1126/science.272.5258.50. [DOI] [PubMed] [Google Scholar]
  24. Gould Douglas B., John Simon W. M. Anterior segment dysgenesis and the developmental glaucomas are complex traits. Hum Mol Genet. 2002 May 15;11(10):1185–1193. doi: 10.1093/hmg/11.10.1185. [DOI] [PubMed] [Google Scholar]
  25. Hedenfalk I., Duggan D., Chen Y., Radmacher M., Bittner M., Simon R., Meltzer P., Gusterson B., Esteller M., Kallioniemi O. P. Gene-expression profiles in hereditary breast cancer. N Engl J Med. 2001 Feb 22;344(8):539–548. doi: 10.1056/NEJM200102223440801. [DOI] [PubMed] [Google Scholar]
  26. Hemmer Bernhard, Archelos Juan J., Hartung Hans-Peter. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci. 2002 Apr;3(4):291–301. doi: 10.1038/nrn784. [DOI] [PubMed] [Google Scholar]
  27. Hensiek A. E., Sawcer S. J., Feakes R., Deans J., Mander A., Akesson E., Roxburgh R., Coraddu F., Smith S., Compston D. A. S. HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):184–187. doi: 10.1136/jnnp.72.2.184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hirschhorn Joel N., Lohmueller Kirk, Byrne Edward, Hirschhorn Kurt. A comprehensive review of genetic association studies. Genet Med. 2002 Mar-Apr;4(2):45–61. doi: 10.1097/00125817-200203000-00002. [DOI] [PubMed] [Google Scholar]
  29. Jacobsen M., Schweer D., Ziegler A., Gaber R., Schock S., Schwinzer R., Wonigeit K., Lindert R. B., Kantarci O., Schaefer-Klein J. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat Genet. 2000 Dec;26(4):495–499. doi: 10.1038/82659. [DOI] [PubMed] [Google Scholar]
  30. Jacobsen Marc, Hoffmann Steve, Cepok Sabine, Stei Susanne, Ziegler Andreas, Sommer Norbert, Hemmer Bernhard. A novel mutation in PTPRC interferes with splicing and alters the structure of the human CD45 molecule. Immunogenetics. 2002 Apr 27;54(3):158–163. doi: 10.1007/s00251-002-0455-7. [DOI] [PubMed] [Google Scholar]
  31. James W. H. Review of the contribution of twin studies in the search for non-genetic causes of multiple sclerosis. Neuroepidemiology. 1996;15(3):132–141. doi: 10.1159/000109900. [DOI] [PubMed] [Google Scholar]
  32. John Sally, Jenkins Suzanne. Third international meeting on the genetic epidemiology of complex traits, April 4-6, 2002, Cambridge, UK. Hum Mutat. 2002 Sep;20(3):227–229. doi: 10.1002/humu.10120. [DOI] [PubMed] [Google Scholar]
  33. Khan J., Wei J. S., Ringnér M., Saal L. H., Ladanyi M., Westermann F., Berthold F., Schwab M., Antonescu C. R., Peterson C. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med. 2001 Jun;7(6):673–679. doi: 10.1038/89044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Knight J. Cancer comes under scrutiny in fresh genomics initiative. Nature. 2001 Apr 19;410(6831):855–855. doi: 10.1038/35073772. [DOI] [PubMed] [Google Scholar]
  35. Kononen J., Bubendorf L., Kallioniemi A., Bärlund M., Schraml P., Leighton S., Torhorst J., Mihatsch M. J., Sauter G., Kallioniemi O. P. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998 Jul;4(7):844–847. doi: 10.1038/nm0798-844. [DOI] [PubMed] [Google Scholar]
  36. Lai Eric, Bowman Clive, Bansal Aruna, Hughes Arlene, Mosteller Michael, Roses Allen D. Medical applications of haplotype-based SNP maps: learning to walk before we run. Nat Genet. 2002 Nov;32(3):353–353. doi: 10.1038/ng1102-353. [DOI] [PubMed] [Google Scholar]
  37. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  38. Lassmann H., Brück W., Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med. 2001 Mar;7(3):115–121. doi: 10.1016/s1471-4914(00)01909-2. [DOI] [PubMed] [Google Scholar]
  39. Lenardo M., Chan K. M., Hornung F., McFarland H., Siegel R., Wang J., Zheng L. Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol. 1999;17:221–253. doi: 10.1146/annurev.immunol.17.1.221. [DOI] [PubMed] [Google Scholar]
  40. Lohmueller Kirk E., Pearce Celeste L., Pike Malcolm, Lander Eric S., Hirschhorn Joel N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003 Jan 13;33(2):177–182. doi: 10.1038/ng1071. [DOI] [PubMed] [Google Scholar]
  41. Lucchinetti C., Brück W., Parisi J., Scheithauer B., Rodriguez M., Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000 Jun;47(6):707–717. doi: 10.1002/1531-8249(200006)47:6<707::aid-ana3>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  42. Maas Kevin, Chan Sanny, Parker Joel, Slater Angela, Moore Jason, Olsen Nancy, Aune Thomas M. Cutting edge: molecular portrait of human autoimmune disease. J Immunol. 2002 Jul 1;169(1):5–9. doi: 10.4049/jimmunol.169.1.5. [DOI] [PubMed] [Google Scholar]
  43. MacBeath G., Schreiber S. L. Printing proteins as microarrays for high-throughput function determination. Science. 2000 Sep 8;289(5485):1760–1763. doi: 10.1126/science.289.5485.1760. [DOI] [PubMed] [Google Scholar]
  44. MacGregor Alex J., Lanchbury Jerry, Rigby Alan S., Kaprio Jaakko, Snieder Harold. Using twin studies to label disease as genetic or environmental is inappropriate. BMJ. 2002 May 4;324(7345):1100–1101. doi: 10.1136/bmj.324.7345.1100/b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Martin D. A., Zheng L., Siegel R. M., Huang B., Fisher G. H., Wang J., Jackson C. E., Puck J. M., Dale J., Straus S. E. Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4552–4557. doi: 10.1073/pnas.96.8.4552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Martin R., Stürzebecher C. S., McFarland H. F. Immunotherapy of multiple sclerosis: where are we? Where should we go? Nat Immunol. 2001 Sep;2(9):785–788. doi: 10.1038/ni0901-785. [DOI] [PubMed] [Google Scholar]
  47. Miller Lance D., Long Philip M., Wong Limsoon, Mukherjee Sayan, McShane Lisa M., Liu Edison T. Optimal gene expression analysis by microarrays. Cancer Cell. 2002 Nov;2(5):353–361. doi: 10.1016/s1535-6108(02)00181-2. [DOI] [PubMed] [Google Scholar]
  48. Mouse Genome Sequencing Consortium. Waterston Robert H., Lindblad-Toh Kerstin, Birney Ewan, Rogers Jane, Abril Josep F., Agarwal Pankaj, Agarwala Richa, Ainscough Rachel, Alexandersson Marina. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002 Dec 5;420(6915):520–562. doi: 10.1038/nature01262. [DOI] [PubMed] [Google Scholar]
  49. Mousses Spyro, Kallioniemi Anne, Kauraniemi Päivikki, Elkahloun Abdel, Kallioniemi Olli-P. Clinical and functional target validation using tissue and cell microarrays. Curr Opin Chem Biol. 2002 Feb;6(1):97–101. doi: 10.1016/s1367-5931(01)00283-6. [DOI] [PubMed] [Google Scholar]
  50. Mumford C. J., Wood N. W., Kellar-Wood H., Thorpe J. W., Miller D. H., Compston D. A. The British Isles survey of multiple sclerosis in twins. Neurology. 1994 Jan;44(1):11–15. doi: 10.1212/wnl.44.1.11. [DOI] [PubMed] [Google Scholar]
  51. Murphree A. L., Benedict W. F. Retinoblastoma: clues to human oncogenesis. Science. 1984 Mar 9;223(4640):1028–1033. doi: 10.1126/science.6320372. [DOI] [PubMed] [Google Scholar]
  52. Nguyen Linh T., Ramanathan Murali, Weinstock-Guttman Bianca, Baier Monika, Brownscheidle Carol, Jacobs Lawrence D. Sex differences in in vitro pro-inflammatory cytokine production from peripheral blood of multiple sclerosis patients. J Neurol Sci. 2003 May 15;209(1-2):93–99. doi: 10.1016/s0022-510x(03)00004-2. [DOI] [PubMed] [Google Scholar]
  53. Nijeholt G. J., van Walderveen M. A., Castelijns J. A., van Waesberghe J. H., Polman C., Scheltens P., Rosier P. F., Jongen P. J., Barkhof F. Brain and spinal cord abnormalities in multiple sclerosis. Correlation between MRI parameters, clinical subtypes and symptoms. Brain. 1998 Apr;121(Pt 4):687–697. doi: 10.1093/brain/121.4.687. [DOI] [PubMed] [Google Scholar]
  54. Nowotny P., Kwon J. M., Goate A. M. SNP analysis to dissect human traits. Curr Opin Neurobiol. 2001 Oct;11(5):637–641. doi: 10.1016/s0959-4388(00)00261-0. [DOI] [PubMed] [Google Scholar]
  55. Oksenberg J. R., Barcellos L. F. The complex genetic aetiology of multiple sclerosis. J Neurovirol. 2000 May;6 (Suppl 2):S10–S14. [PubMed] [Google Scholar]
  56. Passarge Eberhard. Dissecting Hirschsprung disease. Nat Genet. 2002 Apr 15;31(1):11–12. doi: 10.1038/ng878. [DOI] [PubMed] [Google Scholar]
  57. Polymeropoulos M. H., Lavedan C., Leroy E., Ide S. E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997 Jun 27;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  58. Ramanathan M., Weinstock-Guttman B., Nguyen L. T., Badgett D., Miller C., Patrick K., Brownscheidle C., Jacobs L. In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects. J Neuroimmunol. 2001 Jun 1;116(2):213–219. doi: 10.1016/s0165-5728(01)00308-3. [DOI] [PubMed] [Google Scholar]
  59. Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
  60. Ristori G., Buttinelli C., Pozzilli C., Fieschi C., Salvetti M. Microbe exposure, innate immunity and autoimmunity. Immunol Today. 1999 Jan;20(1):54–54. doi: 10.1016/s0167-5699(98)01384-x. [DOI] [PubMed] [Google Scholar]
  61. Roach Huw D., Davies Gareth J., Attanoos Richard, Crane Michael, Adams Haydn, Phillips Siân. Asbestos: when the dust settles an imaging review of asbestos-related disease. Radiographics. 2002 Oct;22(Spec No):S167–S184. doi: 10.1148/radiographics.22.suppl_1.g02oc10s167. [DOI] [PubMed] [Google Scholar]
  62. Rook G. A. Clean living increases more than just atopic disease. Immunol Today. 2000 May;21(5):249–250. doi: 10.1016/s0167-5699(00)01630-3. [DOI] [PubMed] [Google Scholar]
  63. Rook G. A., Stanford J. L. Give us this day our daily germs. Immunol Today. 1998 Mar;19(3):113–116. doi: 10.1016/s0167-5699(97)01204-8. [DOI] [PubMed] [Google Scholar]
  64. Sadovnick A. D., Armstrong H., Rice G. P., Bulman D., Hashimoto L., Paty D. W., Hashimoto S. A., Warren S., Hader W., Murray T. J. A population-based study of multiple sclerosis in twins: update. Ann Neurol. 1993 Mar;33(3):281–285. doi: 10.1002/ana.410330309. [DOI] [PubMed] [Google Scholar]
  65. Salvador Jesus M., Hollander M. Christine, Nguyen Anh Thu, Kopp Jeffrey B., Barisoni Laura, Moore Jodene K., Ashwell Jonathan D., Fornace Albert J., Jr Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Immunity. 2002 Apr;16(4):499–508. doi: 10.1016/s1074-7613(02)00302-3. [DOI] [PubMed] [Google Scholar]
  66. Salvetti M., Ristori G., Bomprezzi R., Pozzilli P., Leslie R. D. Twins: mirrors of the immune system. Immunol Today. 2000 Jul;21(7):342–347. doi: 10.1016/s0167-5699(00)01658-3. [DOI] [PubMed] [Google Scholar]
  67. Sawcer S., Goodfellow P. N., Compston A. The genetic analysis of multiple sclerosis. Trends Genet. 1997 Jun;13(6):234–239. doi: 10.1016/S0168-9525(97)01140-2. [DOI] [PubMed] [Google Scholar]
  68. Sawcer S., Jones H. B., Feakes R., Gray J., Smaldon N., Chataway J., Robertson N., Clayton D., Goodfellow P. N., Compston A. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet. 1996 Aug;13(4):464–468. doi: 10.1038/ng0896-464. [DOI] [PubMed] [Google Scholar]
  69. Sawcer Stephen, Maranian Mel, Setakis Efrosini, Curwen Val, Akesson Eva, Hensiek Anke, Coraddu Francesca, Roxburgh Richard, Sawcer David, Gray Julia. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain. 2002 Jun;125(Pt 6):1337–1347. doi: 10.1093/brain/awf143. [DOI] [PubMed] [Google Scholar]
  70. Schena M., Shalon D., Davis R. W., Brown P. O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science. 1995 Oct 20;270(5235):467–470. doi: 10.1126/science.270.5235.467. [DOI] [PubMed] [Google Scholar]
  71. Scott W. K., Staijich J. M., Yamaoka L. H., Speer M. C., Vance J. M., Roses A. D., Pericak-Vance M. A. Genetic complexity and Parkinson's disease. Deane Laboratory Parkinson Disease Research Group. Science. 1997 Jul 18;277(5324):387–389. doi: 10.1126/science.277.5324.387. [DOI] [PubMed] [Google Scholar]
  72. Shirakawa T., Enomoto T., Shimazu S., Hopkin J. M. The inverse association between tuberculin responses and atopic disorder. Science. 1997 Jan 3;275(5296):77–79. doi: 10.1126/science.275.5296.77. [DOI] [PubMed] [Google Scholar]
  73. Stephenson J. Human genome studies expected to revolutionize cancer classification. JAMA. 1999 Sep 8;282(10):927–928. doi: 10.1001/jama.282.10.927. [DOI] [PubMed] [Google Scholar]
  74. Straus S. E., Sneller M., Lenardo M. J., Puck J. M., Strober W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. 1999 Apr 6;130(7):591–601. doi: 10.7326/0003-4819-130-7-199904060-00020. [DOI] [PubMed] [Google Scholar]
  75. Tabor Holly K., Risch Neil J., Myers Richard M. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet. 2002 May;3(5):391–397. doi: 10.1038/nrg796. [DOI] [PubMed] [Google Scholar]
  76. Threadgill David W., Hunter Kent W., Williams Robert W. Genetic dissection of complex and quantitative traits: from fantasy to reality via a community effort. Mamm Genome. 2002 Apr;13(4):175–178. doi: 10.1007/s00335-001-4001-Y. [DOI] [PubMed] [Google Scholar]
  77. Tubridy N., Coles A. J., Molyneux P., Compston D. A., Barkhof F., Thompson A. J., McDonald W. I., Miller D. H. Secondary progressive multiple sclerosis: the relationship between short-term MRI activity and clinical features. Brain. 1998 Feb;121(Pt 2):225–231. doi: 10.1093/brain/121.2.225. [DOI] [PubMed] [Google Scholar]
  78. Vastag Brian. Gene chips inch toward the clinic. JAMA. 2003 Jan 8;289(2):155-6, 159. doi: 10.1001/jama.289.2.155. [DOI] [PubMed] [Google Scholar]
  79. Verhoef S., Bakker L., Tempelaars A. M., Hesseling-Janssen A. L., Mazurczak T., Jozwiak S., Fois A., Bartalini G., Zonnenberg B. A., van Essen A. J. High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet. 1999 Jun;64(6):1632–1637. doi: 10.1086/302412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Voorhoeve P. Mathijs, Agami Reuven. Knockdown stands up. Trends Biotechnol. 2003 Jan;21(1):2–4. doi: 10.1016/s0167-7799(02)00002-1. [DOI] [PubMed] [Google Scholar]
  81. Vorechovsky I., Kralovicova J., Tchilian E., Masterman T., Zhang Z., Ferry B., Misbah S., Chapel H., Webster D., Hellgren D. Does 77C-->G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nat Genet. 2001 Sep;29(1):22–23. doi: 10.1038/ng723. [DOI] [PubMed] [Google Scholar]
  82. Wang J., Zheng L., Lobito A., Chan F. K., Dale J., Sneller M., Yao X., Puck J. M., Straus S. E., Lenardo M. J. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell. 1999 Jul 9;98(1):47–58. doi: 10.1016/S0092-8674(00)80605-4. [DOI] [PubMed] [Google Scholar]
  83. Weiss Kenneth M., Clark Andrew G. Linkage disequilibrium and the mapping of complex human traits. Trends Genet. 2002 Jan;18(1):19–24. doi: 10.1016/s0168-9525(01)02550-1. [DOI] [PubMed] [Google Scholar]
  84. Whitney Adeline R., Diehn Maximilian, Popper Stephen J., Alizadeh Ash A., Boldrick Jennifer C., Relman David A., Brown Patrick O. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci U S A. 2003 Feb 10;100(4):1896–1901. doi: 10.1073/pnas.252784499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Yan Jun, Mamula Mark J. Autoreactive T cells revealed in the normal repertoire: escape from negative selection and peripheral tolerance. J Immunol. 2002 Apr 1;168(7):3188–3194. doi: 10.4049/jimmunol.168.7.3188. [DOI] [PubMed] [Google Scholar]
  86. Zhang J., Markovic-Plese S., Lacet B., Raus J., Weiner H. L., Hafler D. A. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med. 1994 Mar 1;179(3):973–984. doi: 10.1084/jem.179.3.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Ziauddin J., Sabatini D. M. Microarrays of cells expressing defined cDNAs. Nature. 2001 May 3;411(6833):107–110. doi: 10.1038/35075114. [DOI] [PubMed] [Google Scholar]
  88. van de Vijver Marc J., He Yudong D., van't Veer Laura J., Dai Hongyue, Hart Augustinus A. M., Voskuil Dorien W., Schreiber George J., Peterse Johannes L., Roberts Chris, Marton Matthew J. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002 Dec 19;347(25):1999–2009. doi: 10.1056/NEJMoa021967. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES