Analytical Methods Applied to Psychiatric Genetics

  • Elena L. Grigorenko
  • David L. Pauls
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 77)


The development of gene-mapping methodology has not been a linear process. Instead, this development has been multidimensional, culminating in the creation of a powerful and heterogeneous collection of tools. A description of the history of the development of this would include words such as “opportunistic” (i.e., capitalizing on the newest developments in computer technology and genomics) and “problem-solving oriented” (i.e., constantly addressing issues (such as the spotted nature of linkage disequilibrium) that arose during the development of the methodology). Therefore, the following presentation is method-oriented rather than problemoriented. In describing the modern methodology of gene mapping, attempts will be made to describe the origin of a given methodology, the problems it was designed to address, and its known strengths and weaknesses.


Linkage Disequilibrium Disease Gene Population Stratification Recombination Fraction Transmission Disequilibrium Test 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Morton N.E. (1955) Sequential tests for the detection of linkage. Am. J. Hum. Genet. 7, 277–318.PubMedGoogle Scholar
  2. 2.
    Elston R.C. and Steward J. (1971) A general model for the analysis of pedigree data. Hum. Hered. 21, 523–542.PubMedCrossRefGoogle Scholar
  3. 3.
    Ott J. (1974) Estimation of the recombination fraction in human pedigrees: Efficient computation of the likelihood for human linkage studies. Am. J. Hum. Genet. 26, 588–597.PubMedGoogle Scholar
  4. 4.
    Lathrop G.M., Lalouel J.M., Julier C., and Ott J. (1984) Strategies for multilocus linkage analysis in humans. PNAS 81, 3443–3446.PubMedCrossRefGoogle Scholar
  5. 5.
    Wijsman E.M. and Amos C. (1997) Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions. Genet. Epidemiol. 14, 719–735.PubMedCrossRefGoogle Scholar
  6. 6.
    Yuan B., Vaske D., Weber J.L., Beck J., and Sheffield V.C. (1997) Improved set of short-tandem-repeat polymorphisms for screening the human genome. Am. J. Hum. Genet. 60, 459–460.PubMedGoogle Scholar
  7. 7.
    Kruglyak L., Daly M.J., Reeve-Daly M.P., and Lander E.S. (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363.PubMedGoogle Scholar
  8. 8.
    Daw E.W., Health S.C., and Wijsman E.M. (1999) Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer’s disease pedigrees. Am. J. Hum. Genet. 64, 839–851.PubMedCrossRefGoogle Scholar
  9. 9.
    Heath S.C. (1997) Markov chain Monte Carlo segregatin and linkage analysis for oligogenic models. Am. J. Hum. Genet. 61, 748–760.PubMedCrossRefGoogle Scholar
  10. 10.
    Health S.C., Snow G.L., Thompson E.A., Tseng C., and Wijsman E.M. (1997) MCMC segregation and linkage analysis. Genet. Epidemiol. 14, 1011–1016.CrossRefGoogle Scholar
  11. 11.
    Almasy L. and Blangero J. (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62, 1198–1121.PubMedCrossRefGoogle Scholar
  12. 12.
    Martinez M., Khlat M., Leboyer M., and Clerget-Darpoux F.(1989) Performance of linkage analysis under misclassification error when the genetic model is unknown. Genet. Epidemiol. 6, 253–258.PubMedCrossRefGoogle Scholar
  13. 13.
    Risch N. and Giuffra L. (1992) Model misspecification and multipoint linkage analysis. Hum. Hered. 42, 77–92.PubMedCrossRefGoogle Scholar
  14. 14.
    Schork N.J., Boehnke M., Terwilliger J.D., and Ott J. (1993) Twotrait-locus linkage analysis: a powerful strategy for mapping complex genetic traits. Am. J. Hum. Genet. 53, 1127–1136.PubMedGoogle Scholar
  15. 15.
    Abreu P.C., Greenberg D.A., and Hodge S.E. (1999) Direct power comparisons between simple lod scores and NPL scores for linkage analysis in complex diseases. Am. J. Hum. Genet. 65, 847–857.PubMedCrossRefGoogle Scholar
  16. 16.
    Göring H.H.H. and Terwilliger J.D. (2000) Linkage analysis in the presence of errors III: marker loci and their map as nuisance parameters. Am. J. Hum. Genet. 66, 1298–1309.PubMedCrossRefGoogle Scholar
  17. 17.
    Göring H.H.H. and Terwilliger J.D. (2000) Linkage analysis in the presence of errors. IV. Joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. Am. J. Hum. Genet. 66, 1310–1327.PubMedCrossRefGoogle Scholar
  18. 18.
    Whittemore A.S. (1996) Genome scanning for linkage: an overview. Am. J. Hum. Genet. 59, 704–716.PubMedGoogle Scholar
  19. 19.
    Fimmers R., Seuchter S.A., Neugebauer M., Knapp M., and Baur M.P. (1989) Identity-by-descent analysis using all genotype solutions, in Multipoint mapping and linkage based on affected pedigree members: Genetic Analysis Workshop 6, (Elston R.C., Spence M.A., Hodge S.E., and MacCluer J. W., eds.), Alan R. Liss, New York, NY, pp. 123–128.Google Scholar
  20. 20.
    Kruglyak L. and Lander E.S. (1995) Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454.PubMedGoogle Scholar
  21. 21.
    Whittemore A.S. and Halpern J. (1994) A class of tests for linkage using affected pedigree members. Biometrics 50, 117–127.Google Scholar
  22. 22.
    Irwin M., Cox N., and Kong A. (1994) Sequential imputation for multilocus linkage analysis. Proc. Natl. Acad. Sci. USA 91, 11,684–11,688.PubMedCrossRefGoogle Scholar
  23. 23.
    O’Connell J.R. and Weeks D.E. (1995) The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nat. Genet. 11, 402–408.PubMedCrossRefGoogle Scholar
  24. 24.
    Schwab S.G., Albus M., Hallmayer J., Honig S., Borrmann M., Lichtermann D., et al. (1995) Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nat. Genet. 11, 325–327.PubMedCrossRefGoogle Scholar
  25. 25.
    Friddle C., Koskela R., Ranade K., Hebert J., Cargill M., Clark C.D., et al. (2000) Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype. Am. J. Hum. Genet. 66, 205–215.PubMedCrossRefGoogle Scholar
  26. 26.
    Gudbjartsoon D.F., Jonasson K., Frigge M.L., and Kong C.A. (2000) Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13.CrossRefGoogle Scholar
  27. 27.
    Hyer R.N., Julier C., Buckley J.D., Trucco M., Rotter J., Spielman R., et al. (1991) High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q. Am. J. Hum. Genet. 48, 243–257.PubMedGoogle Scholar
  28. 28.
    Knapp M., Seuchter S.A., and Baur M.P. (1994) Two-locus disease models with two marker loci: the power of affected-sib-pair tests. Am. J. Hum. Genet. 55, 1030–1041.PubMedGoogle Scholar
  29. 29.
    Lander E.S. and Green P. (1987) Construction of multilocus genetic maps in humans. Proc. Natl. Acad. Sci. USA 84, 2363–2367.PubMedCrossRefGoogle Scholar
  30. 30.
    Guo S.W. and Thompson E.A. (1992) A Monte Carlo method for combined segregation and linkage analysis. Am. J. Hum. Genet. 51, 1111–1126.PubMedGoogle Scholar
  31. 31.
    Borewinkle E., Chakraborty R., and Sing C. (1986) The use of measured genotype information in the analysis of quantitative phenotypes in man. Ann. Hum. Genet. 50, 181–194.CrossRefGoogle Scholar
  32. 32.
    Boerwinkle E.R.C. and Sing C.F. (1986) Bias of the contribution of single-locus effects to the variance of a quantitative trait. Am. J. Hum. Genet. 39, 663–676.Google Scholar
  33. 33.
    Wijsman E.M. and Nur N. (2000) On estimating the proportion of variance in a phenotypic trait attributable to a measured locus. Hum. Hered. 51, 145–149.CrossRefGoogle Scholar
  34. 34.
    Haseman J.K. and Elston R.C. (1972) The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19.PubMedCrossRefGoogle Scholar
  35. 35.
    Lange K., Westlake J., and Spence M.A. (1976) Extensions to pedigree analysis. III. Variance components by the scoring method. Ann. Hum. Genet. 39, 485–491.PubMedCrossRefGoogle Scholar
  36. 36.
    Hopper J.L. and Matthews J.D. (1982) Extensions to multivariate normal models for pedigree analysis. Ann. Hum. Genet. 46, 373–383.PubMedCrossRefGoogle Scholar
  37. 37.
    Amos C.I. (1994) Robust variance-components approach for assessing genetic linkage in pedigrees. Am. J. Hum. Genet. 54, 535–543.PubMedGoogle Scholar
  38. 38.
    Goldgar D.E. (1990) Multipoint analysis of human quantitative genetic variation. Am. J. Hum. Genet. 47, 957–967.PubMedGoogle Scholar
  39. 39.
    Schork N.J. (1993) Extended multipoint identity-by-descent analysis of human quantitative traits: efficiency, power, and modeling considerations. Am. J. Hum. Genet. 53, 1306–1319.PubMedGoogle Scholar
  40. 40.
    Pratt S.C., Daly M.J., and Kruglyak L. (2000) Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components. Am. J. Hum. Genet. 66, 1153–1157.PubMedCrossRefGoogle Scholar
  41. 41.
    Amos C.I., Zhu D.K., and Boerwinkle E. (1996) Assessing genetic linkage and association with robust components of variance approaches. Ann. Hum. Genet. 60, 143–160.PubMedCrossRefGoogle Scholar
  42. 42.
    Amos C.I., Krushkal J., Thiel T.J., Young A., Zhu D.K., Boerwinkle E., et al. (1997) Comparison of model-free linkage mapping strategies for the study of a complex trait. Genet. Epidemiol. 14, 743–748.PubMedCrossRefGoogle Scholar
  43. 43.
    Pugh E.W., Jaquish C.E., Sorant A.J.M., Doetsch J.P., Bailey-Wilson J.E., and Wilson A.F. (1997) Comparison of sib-pair and variance components methods for genomic screening. Genet. Epidemiol. 14, 867–872.PubMedCrossRefGoogle Scholar
  44. 44.
    Williams J.T., Duggirala R., and Blangero J. (1997) Statistical properties of a variance components method for quantitative trait linkage analysis in nuclear families and extended pedigrees. Genet. Epidemiol. 14, 1065–1070.PubMedCrossRefGoogle Scholar
  45. 45.
    Boehnke M. (1994) Limits of resolution of genetic linkage studies: implications for the positional cloning of human genetic disease. Am. J. Hum. Genet. 55, 379–390.PubMedGoogle Scholar
  46. 46.
    Hästbacka J., de la Chapelle A., Kaitila I., Sistonen P., Weaver A., and Lander E. (1992) Linkage disequilibrium mapping in isolated founder populations: diastrophis dysphasia in Finland. Nat. Genet. 2, 204–211.PubMedCrossRefGoogle Scholar
  47. 47.
    Hästbacka J.K., de la Chapelle A., Mahanti M. M., Clines G., Reeve-Daly M.P., Daly M., et al. (1994) The diastrophic dysphasia gene encodes a novel sulfate transporter: positional cloning by finestructure linkage disequilibrium mapping. Cell 78, 1073–1087.PubMedCrossRefGoogle Scholar
  48. 48.
    Kerem B., Rommens J.M., Buchanan J.A., Markiewicz D., Cox T.K., Chakravarti A., et al. (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080.PubMedCrossRefGoogle Scholar
  49. 49.
    Altshuler D., Pollara V.J., Cowles C.R., Van Etten W.J., Baldwin J., Linton L., et al. (2000a) An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407, 513–516.PubMedCrossRefGoogle Scholar
  50. 50.
    Mullikin J.C., Hunt S.E., Cole C.G., Mortimore B.J., Rice C.M., Burton J., et al. (2000) An SNP map of human chromosome 22. Nature 407, 516–520.PubMedCrossRefGoogle Scholar
  51. 51.
    Devlin B. and Risch N. (1995) A comparison of linkage disequilibrium measures for fine scale mapping. Genomics 29, 311–322.PubMedCrossRefGoogle Scholar
  52. 52.
    Feder J.N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D.A., Basava A., et al. (1996) A novel MHC class I-like gene is mutation in patients with hereditary haemochromatosis. Nat. Genet. 13, 399–408.PubMedCrossRefGoogle Scholar
  53. 53.
    Kaplan N., Hill W.G., and Weir B.S. (1995) Likelihood methods for locating disease genes in nonequilibrium populations. Am. J. Hum. Genet. 56, 18–32.PubMedGoogle Scholar
  54. 54.
    Devlin B., Risch N., and Roeder K. (1996) Disequilibrium mapping: composite likelihood for pairwise disequilibrium. Genomics 36, 1–16.PubMedCrossRefGoogle Scholar
  55. 55.
    Lam J.C., Roeder K., and Devlin B. (2000) Haplotype fine mapping by evolutionary trees. Am. J. Hum. Genet. 66, 659–673.PubMedCrossRefGoogle Scholar
  56. 56.
    Riordan J.R., Rommens J.M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., et al. (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066–1073.PubMedCrossRefGoogle Scholar
  57. 57.
    Rommens J.M., Iannuzzi M.C., Kerem B., Drumm M.L., Melmer G., Dean M., et al. (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059–1065.PubMedCrossRefGoogle Scholar
  58. 58.
    Abecasis G.R., Nogushi E., Heinzmann A., Traherne J.A., Bhattacharyya S., Leaves N.I., et al. (2001) Extent and distortion of linkage disequilibrium in three genomic regions. Am. J. Hum. Genet. 68, 191–197.PubMedCrossRefGoogle Scholar
  59. 59.
    Cardon L.R. and Bell J.I. (2001) Association study designs for complexd iseases. Nature Reviews, Genetics 2, 91–99.CrossRefGoogle Scholar
  60. 60.
    Devlin B. and Roeder K. (1999) Genomic control for association studies. Biometrics 55, 997–1004.PubMedCrossRefGoogle Scholar
  61. 61.
    Cambien F., Poirier O., Lecerf L., Eans A., Cambou J.P., Arveiler D., et al. (1992) Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359, 641–644.PubMedCrossRefGoogle Scholar
  62. 62.
    Jeron A., Hengstenberg C., Engel S., Lowel H., Riegger G.A., Schunkert H., et al. (2001) The D-allele of the ACE polymorphism is related to increased QT dispersion in 609 patients after myocardial infarction. Eur. Heart J. 22, 663–668.PubMedCrossRefGoogle Scholar
  63. 63.
    Keavney B., McKenzie C., Parish S., Palmer A., Clark S., Youngman L., et al. (2000) Large-scale test of hypothesized associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet 355, 434–442.PubMedGoogle Scholar
  64. 64.
    Altshuler D., Hirschhorn J.N., Klannemark M., Lindgren C.M., Vohl M.C., Nemesh J., et al. (2000b) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80.PubMedCrossRefGoogle Scholar
  65. 65.
    Barcellos L.F., Klitz W., Field L.L., Tobias R., Bowcock A.M., Wilson R., et al. (1997) Associating mapping of disease loci by use of a pooled DNA genomic screen. Am. J. Hum. Genet. 61, 734–747.PubMedCrossRefGoogle Scholar
  66. 66.
    Daniels J., Holmans P., Williams N., Turic D., McGuffin P., Plomin R., et al. (1998) A simple method for analyzing microsatellite allele image patterns generated from DNA pools and its application to allelic association studies. Am. J. Hum. Genet. 62, 1189–1197.PubMedCrossRefGoogle Scholar
  67. 67.
    Shaw S.H., Carrasquillo M.M., Kashuk C., Puffenberger E.G., and Chakravarti A. (1998) Allele frequency distributions in poled DNA samples: applications to mapping complex disease gene. Genome Res. 8, 111–123.PubMedGoogle Scholar
  68. 68.
    Emahazion T., Feuk L., Jobs M., Sawyer S.L., Fredman D., St. Clair D., et al. (2001) SNP association studies in Alzheimer’s disease highlight problems for complex disease analysis. Trends Genet. 17, 401–407.CrossRefGoogle Scholar
  69. 69.
    Jorde L.B., Watkins W.S., Carlson M., Groden J., Albertson H., Thliveris A., et al. (1994) Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am. J. Hum. Genet. 54, 884–898.PubMedGoogle Scholar
  70. 70.
    Hill W.G. and Weis B.S. (1994) Maximum-likelihood estimation of gene location by linkage disequilibrium. Am. J. Hum. Genet. 54, 705–714.PubMedGoogle Scholar
  71. 71.
    Rubinstein P., Walker M., Carpenter C., Carrier C., Krassner J., Falk C., et al. (1981) Genetics of HLA disease association: the use of the haplotype relative risk (HRR) and the “Haplo-Delta” (Dh) estimates in juvenile diabetes from three racial groups. Hum. Immunol. 3, 384.CrossRefGoogle Scholar
  72. 72.
    Field L.L., Fothrgill-Payne C., Bertrams J., and Baur M.P. (1986) HLD-DR effects in a large German IDDM data set. Genet. Epidemiol. (suppl.) 1, 323–328.CrossRefGoogle Scholar
  73. 73.
    Falk C.T. and Rubinstein P. (1987) Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233.PubMedCrossRefGoogle Scholar
  74. 74.
    Khoury M.J. (1994) Case-parental control method in the search for disease-susceptibility genes. Am. J. Hum. Genet. 55, 414–415.PubMedGoogle Scholar
  75. 75.
    Schaid D.J. and Sommer S.S. (1994) Comparison of statistics for candidate-gene association studies using cases and parents. Am. J. Hum. Genet. 55, 402–409.PubMedGoogle Scholar
  76. 76.
    Thomson G. (1995) Mapping disease genes: family-based association studies. Am. J. Hum. Genet. 57, 487–498.PubMedGoogle Scholar
  77. 77.
    Knapp M., Seuchter S.A., and Baur M.P. (1993) The haplotyperelative risk (HRR) method for analysis of association in nuclear families. Am. J. Hum. Genet. 52, 1085–1093.PubMedGoogle Scholar
  78. 78.
    Ott J. (1989) Statistical properties of the haplotype relative risk. Genet. Epidemiol. 6, 127–130.PubMedCrossRefGoogle Scholar
  79. 79.
    Terwilliger J.D. and Ott J. (1992) A haplotype based ‘haplotype relative risk’ approach to detecting allelic associations. Hum. Hered. 42, 337–346.PubMedCrossRefGoogle Scholar
  80. 80.
    Schaid D.J. and Sommer S.S. (1993) Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am. J. Hum. Genet. 53, 1114–1126.PubMedGoogle Scholar
  81. 81.
    Spielman R.S. and Ewens W.J. (1993) Transmission/disequilibrium test (TDT) for linkage and linkage disequilibrium between disease and marker. Am. J. Hum. Genet. (suppl.) 53, 863.Google Scholar
  82. 82.
    Spielman R.S., McGinnis R.E., and Ewens W.J. (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516.PubMedGoogle Scholar
  83. 83.
    Tiret L., Nicaud V., Ehnholm C., Havekes L., Menzel H.J., Ducimetiere P., et al. (1993) Inference of the strength of genotypedisease association from studies comparing off-spring with and without parental history of disease. Ann. Hum. Genet. 57, 141–149.PubMedCrossRefGoogle Scholar
  84. 84.
    Hodge S.E. (1993) Linkage analysis versus association analysis: distinguishing between two models that explain disease-marker associations. Am. J. Hum. Genet. 53, 367–384.PubMedGoogle Scholar
  85. 85.
    Hodge S.E. (1994) Reply to Suarez and Hampe and Spielman et al.: cosegregation, association, and linkage. Am. J. Hum. Genet. 54, 560–563.Google Scholar
  86. 86.
    Suarez B.K. and Hampe C.L. (1994) Linkage and association. Am. J. Hum. Genet. 54, 554–559.PubMedGoogle Scholar
  87. 87.
    Klitz W., Thomson G., Borot N., and Cambon-Thomsen A. (1992) Evolutionary and population perspective of the human HLA complex, in Evolutionary Biology (vol. 26), (Hecht M. K., ed.), Plenum, New York, NY, pp., 35–72.Google Scholar
  88. 88.
    Field L.L. (1989) Genes predisposing to IDDM in multiplex families. Genet. Epidemiol. 6, 101–106.PubMedCrossRefGoogle Scholar
  89. 89.
    Thomson G., Robinson W.P., Kuhner M.K., Joe S., and Klitz W. (1989) HLA and insulin gene associations with IDDM. Genet. Epidemiol. 6, 155–160.PubMedCrossRefGoogle Scholar
  90. 90.
    Spielman R.S., Baur M.P., and Clerget-Darpoux F. (1989) Genetic analysis of IDDM: summary of GAW 5 IDDM results. Genet. Epidemiol. 6, 43–58.PubMedCrossRefGoogle Scholar
  91. 91.
    Bennet S.T., Lucassen A.M., Gough S. C., Powell E.E., Undlien D.E., Pritchard L.E., et al. (1995) Susceptibility to human type diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat. Genet. 9, 284–292.CrossRefGoogle Scholar
  92. 92.
    Merriman T., Twells R., Merriman M., Eaves I., Cox R., Cucca F., et al. (1997) Evidence by allelic association-dependent methods for a type I diabetes polygene (IDDM6) on chromosome 18q21. Hum. Mol. Genet. 6, 1003–1010.PubMedCrossRefGoogle Scholar
  93. 93.
    Boehnke M. and Langefeld C.D. (1998) Genetic association mapping based on discordant sib pairs: the discordant-alleles test. Am. J. Hum. Genet. 61, 319–333.Google Scholar
  94. 94.
    Curtis D. (1997) Use of siblings as controls in case-control association studies. Ann. Hum. Genet. 61, 319–333.PubMedCrossRefGoogle Scholar
  95. 95.
    Martin E.R., Kaplan N.I., and Weir B.S. (1997) Tests for linkage and association in nuclear families. Am. J. Hum. Genet. 61, 439–448.PubMedCrossRefGoogle Scholar
  96. 96.
    Sham P.C. and Curtis D. (1995) An extended transmission/disequilibrium test (TDT) for multiallelic marker loci. Ann. Hum. Genet. 59, 323–336.PubMedCrossRefGoogle Scholar
  97. 97.
    Spielman R.S. and Ewens W.J. (1996) The TDT and other familybased tests for linkage disequilibirum and association (Editorial). Am. J. Hum. Genet. 59, 983–989.PubMedGoogle Scholar
  98. 98.
    Spielman R.S. and Ewens W.J. (1998) A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am. J. Hum. Genet. 62, 450–458.PubMedCrossRefGoogle Scholar
  99. 99.
    Seltman H., Roeder K., and Devlin B. (2001) Transmission/Disequilibrium Test meets measured haplotype analysis: family-based association analysis guided by evolution of haplotypes. Am. J. Hum. Genet. 68, 1250–1263.PubMedCrossRefGoogle Scholar
  100. 100.
    Templeton A.R. (1995) A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping of DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer’s disease and the apoprotein E locus. Genetics 140, 403–409.PubMedGoogle Scholar
  101. 101.
    Gordon D., Heath S.C., Liu X., and Ott J. (2001) A transmission/ disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. Am. J. Hum. Genet. 69, 371–780.PubMedCrossRefGoogle Scholar
  102. 102.
    Bacanu S.-A., Devlin B., and Roeder K. (2000) The power of genomic control. Am. J. Hum. Genet. 66, 1933–1944.PubMedCrossRefGoogle Scholar
  103. 103.
    Clayton D.G. and Jones H. (1999) Transmission/disequilibrium tests for extended marker haplotypes. Am. J. Hum. Genet. 65, 1161–1169.PubMedCrossRefGoogle Scholar
  104. 104.
    Clayton D.G. (1999) A generalization of the transmission/disequilibrium tests for uncertain-haplotype transmission. Am. J. Hum. Genet. 65, 1170–1177.PubMedCrossRefGoogle Scholar
  105. 105.
    Lazzeroni L.C. and Lange K. (1998) A conditional inference framework for extending the transmission/disequilibrium test. Hum. Hered. 48, 67–81.PubMedCrossRefGoogle Scholar
  106. 106.
    Merriman T.R., Eaves I.A., Twells R.C., Merriman M.E., Danoy P.A., Muxworthy C.E., et al. (1998) Transmission of haplotypes of miscrosatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6). Hum. Mol. Genet. 7, 517–524.PubMedCrossRefGoogle Scholar
  107. 107.
    Rabinowitz D. and Laird N. (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum. Hered. 50, 211–223.PubMedCrossRefGoogle Scholar
  108. 108.
    Zhao H., Zhang S., Merikangas K.R., Trixter M., Wildenauer D.B., Sun F., et al. (2000) Transmission/disequilibrium tests using multiple tightly linked markers. Am. J. Hum. Genet. 67, 936–946.PubMedCrossRefGoogle Scholar
  109. 109.
    Jin K., Speed T., Klitz W., and Thomson G. (1994) A statistical test of segregation distortion. Biometrics 50, 1189–1198.PubMedCrossRefGoogle Scholar
  110. 110.
    Maxwell A.E. (1970) Comparing the classification of subjects by two independent judges. Br. J. Psychiatry 116, 651–655.PubMedCrossRefGoogle Scholar
  111. 111.
    Rothman K.J. (1986) Modern Epidemiology, Little & Brown, Boston, MA.Google Scholar
  112. 112.
    Trembath R.C., Clough R.L., Rosbotham J.L., Jones A.B., Camp R.D.R., Frodsham A., et al. (1997) Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum. Mol. Genet. 6, 813–820.PubMedCrossRefGoogle Scholar
  113. 113.
    George V.T. and Elston R.C. (1987) Testing the association between polymorphic markers and quantitative traits in pedigrees. Genet. Epidemiol. 4, 193–201.PubMedCrossRefGoogle Scholar
  114. 114.
    Allison D.D. (1997) Transmission-disequilibrium tests for quantitative traits. Am. J. Hum. Genet. 60, 676–690.PubMedGoogle Scholar
  115. 115.
    Rabinowitz D. (1997) A transmission disequilibrium test for quantitative trait loci. Hum. Hered. 47, 342–350.PubMedCrossRefGoogle Scholar
  116. 116.
    Fulker D.W., Cherny S.S., Sham P.C., and Hewitt J.K. (1999) Combined linkage and association sib-pair analysis for quantitative traits. Am. J. Hum. Genet. 64, 259–267.PubMedCrossRefGoogle Scholar
  117. 117.
    Cardon L.R. (2000) A sib-pair regression model of linkage disequilibrium for quantitative traits. Hum. Hered. 50, 350–358.PubMedCrossRefGoogle Scholar
  118. 118.
    Abecasis G.R., Cardon L.R., and Cookson W.O.C. (2000) A general test of association for quantitative traits in nuclear families. Am. J. Hum. Genet. 66, 279–292.PubMedCrossRefGoogle Scholar
  119. 119.
    Brookes A.J. (1999) The essence of SNPs. Gene 234, 177–186.PubMedCrossRefGoogle Scholar
  120. 120.
    Kwok P.Y., Deng Q., Zakeri H., Taylor S.L., and Nickerson D.A. (1996) Increasing the information content of STS-based genome maps: identifying polymorphisms in mapped STSs. Genomics 31, 123–126.PubMedCrossRefGoogle Scholar
  121. 121.
    Wang D.G., Fan J.B., Siao C.J., Berno A., Young P., Sapolsky R., et al. (1988) Related articles, nucleotide large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280(5366), 1077–1082.CrossRefGoogle Scholar
  122. 122.
    Lander E.S. (1996) The new genomics: global views of biology. Science 274, 536–539.PubMedCrossRefGoogle Scholar
  123. 123.
    Jorde L.B. (2000) Linkage disequilibrium and the search for complex disease genes. Genome Res. 10, 1435–1444.PubMedCrossRefGoogle Scholar
  124. 124.
    Kruglyak L. (1999) Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat. Genet. 22, 139–144.PubMedCrossRefGoogle Scholar
  125. 125.
    Risch N. and Merikangas K. (1996) Related Articles. The future of genetic studies of complex human diseases. Science 273(5281), 1516–1517.PubMedCrossRefGoogle Scholar
  126. 126.
    Terwilliger J.D. and Weiss K.M. (1998) Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr. Opin. Biotechnol. 8, 578–594.CrossRefGoogle Scholar
  127. 127.
    Weiss K.M. and Tewilliger J.D. (2000) How many diseases does it take to map a gene with SNPs? Nat. Genet. 26, 151–157.PubMedCrossRefGoogle Scholar
  128. 128.
    Bodmer W.F. (1986) Human genetics: the molecular challenge. Cold Spring Harbor Symp. Quant. Biol. 51, 1–13.PubMedGoogle Scholar
  129. 129.
    Collins A., Lonjou C., and Morton N.E. (1999) Genetic epidemiology of single-nucleotide polymorphisms. PNAS 95, 15,173–15,177.CrossRefGoogle Scholar
  130. 130.
    Laan M. and Pääbo S. (1997) Demographic history and linkage disequilibrium in human populations. Nat. Genet. 17, 435–438.PubMedCrossRefGoogle Scholar
  131. 131.
    Peltonen L. (2000) Positional cloning of disease genes: advantages of genetic isolates. Hum. Hered. 50, 66–75.PubMedCrossRefGoogle Scholar
  132. 132.
    Jorde L.B., Watkins W.S., Kere J., Nyman D., and Eriksson A.W. (2000) Gene mapping in isolated populations: new roles for old friends? Hum. Hered. 50, 57–65.PubMedCrossRefGoogle Scholar
  133. 133.
    Lonjou C., Collins A., and Morton N.E. (1999) Allelic association between marker loci. PNAS 96, 1621–1626.PubMedCrossRefGoogle Scholar
  134. 134.
    Ott J. (2000) Predicting the range of linkage disequilibrium. PNAS 97, 2–3.PubMedCrossRefGoogle Scholar
  135. 135.
    Brzustowicz L.M., Mérette C., Xie X., Townsend L., Gilliam T.C., and Ott J. (1993) Molecular and statistical approaches to the detection and correction of errors in genotype databases. Am. J. Hum. Genet. 53, 1137–1145.PubMedGoogle Scholar
  136. 136.
    Ehm M.G., Kimmel M., and Cottingham R.W., Jr. (1996) Error detection for genetic data, using likelihood methods. Am. J. Hum. Genet. 58, 225–234.PubMedGoogle Scholar
  137. 137.
    Lathrop G.M., Hooper A.B., Huntsman J.W., and Ward R.H. (1983) Evaluating pedigree data. 1. The estimation of pedigree error in the presence of marker mistyping. Am. J. Hum. Genet. 35, 241–262.PubMedGoogle Scholar
  138. 138.
    Lincoln S.E. and Lander E.S. (1992) Systematic detection of errors in genetic linkage data. Genomics 14, 604–610.PubMedCrossRefGoogle Scholar
  139. 139.
    Sasse G., Müller H., Chakraborty R., and Ott J. (1994) Estimating the frequency of nonpaternity in Switzerland. Hum. Hered. 44, 337–343.PubMedCrossRefGoogle Scholar
  140. 140.
    Stringham H.M. and Boehnke M. (1996) Identifying marker typing incompatibilities in linkage analysis. Am. J. Hum. Genet. 59, 946–950.PubMedGoogle Scholar
  141. 141.
    Gordon D., Heath S., and Ott J. (1999) True pedigree errors more frequent than apparent errors for single nucleotide polymorphisms. Hum. Hered. 49, 65–70.PubMedCrossRefGoogle Scholar
  142. 142.
    Gordon D., Leal S.M., Heath S.C., and Ott J. (2000) An analytic solution to single nucleotide polymorphism error-detection rates in nuclear families: implications for study design. Pacific Symposium on Biocomputing 1, 663–674.Google Scholar
  143. 143.
    Ott J. (2001) Major strengths and weaknesses of the lod score method. Adv. Genet. 42, 125–132.PubMedCrossRefGoogle Scholar
  144. 144.
    Keats B.J., Sherman S.L., and Ott J. (1990) Human gene mapping 10.5—report of the Committee on Linkage and Gene Order. Cytogenet. Cell Genet. 55, 387–394.PubMedCrossRefGoogle Scholar
  145. 145.
    Broman K.W., Murray J.C., Sheffield V.C., White R.L., and Weber R.L. (1998) Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–869.PubMedCrossRefGoogle Scholar
  146. 146.
    Li W., Fann C., and Ott J. (1998) Low-order polynomial trends of female-to-male map distance ratios along human chromosomes. Hum. Hered. 48, 266–270.PubMedCrossRefGoogle Scholar
  147. 147.
    Cleves M.A. and Elston R.C. (1997) Alternative test for linkage between two loci. Genet. Epidemiol. 14, 117–131.PubMedCrossRefGoogle Scholar
  148. 148.
    Halpern J. and Whittemore A.S. (1999) Multipoint linkage analysis. A cautionary note. Hum. Hered. 49, 194–196.PubMedCrossRefGoogle Scholar
  149. 149.
    Ott J., Lehner T., and Sandkuyl L.A. (1988) Fallacies of the technique of “ahplotyping” two apparently linked loci in multipoint linkage analysis. Am. J. Hum. Genet. 43, A154.Google Scholar
  150. 150.
    Daw E.W., Thompson E.A., and Wijsman E.M. (2000) Bias in multipoint linkage analysis arising from map misspecification. Genet. Epidemiol. 19, 336–380.CrossRefGoogle Scholar
  151. 151.
    Friemer N., Sandkuijl L., and Blower S. (1993) Incorrect specification of marker allele frequencies: effects on linkage analysis. Am. J. Hum. Genet. 52, 1102–1110.Google Scholar
  152. 152.
    Ott J. (1992) Strategies for characterizing highly polymorphic markers in human gene mapping. Am. J. Hum. Genet. 51, 293–290.Google Scholar
  153. 153.
    Devlin B., Risch N., and Roeder K. (1991) Estimation of allele frequencies for VNTR loci. Am. J. Hum. Genet. 48, 662–676.PubMedGoogle Scholar
  154. 154.
    Lange K. (1995) Applications of the Dirichlet distribution to forensic match probabilities. Genetica 96, 107–117.PubMedCrossRefGoogle Scholar
  155. 155.
    Lockwood J.R., Roder K., and Devlin B. (2001) A Bayesian hierarchical model for allele frequencies. Genet. Epidemiol. 20, 17–33.PubMedCrossRefGoogle Scholar
  156. 156.
    Chapman N.H. and Wijsman E.M. (1998) Genome screen using linkage disequilibrium tests: optimal marker characteristics and feasibility. Am. J. Hum. Genet. 63, 1872–1885.PubMedCrossRefGoogle Scholar
  157. 157.
    Rothman K. (1990) No adjustment are needed for multiple comparisons. Epidemiology 1, 43–46.PubMedCrossRefGoogle Scholar
  158. 158.
    Lander E. and Kruglyak L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247.PubMedCrossRefGoogle Scholar
  159. 159.
    Witte J.S., Elston R.C., and Schork N.S. (1996) Genetic dissection of complex traits (correspondence). Nat. Genet. 12, 355–356.PubMedCrossRefGoogle Scholar
  160. 160.
    Witte J.S., Elston R.C., and Cardon L.R. (2000) On the relative sample size required for multiple comparisons. Stat. Med. 19, 369–372.PubMedCrossRefGoogle Scholar
  161. 161.
    Lucek P., Hanke J., Reich J., Solla S., and Ott J. (1998) Multilocus nonparametric linkage analysis of complex trait loci with neural network. Hum. Hered. 48, 275–284.PubMedCrossRefGoogle Scholar
  162. 162.
    Hoh J. and Ott J. (2000) Scan statistics to scan markers for susceptibility genes. PNAS 17, 9615–9617.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Elena L. Grigorenko
    • 1
  • David L. Pauls
    • 2
  1. 1.Center for the Psychology of Abilities, Competencies, and Expertise (PACE), Department of PsychologyYale UniversityNew HavenUSA
  2. 2.Department of Psychiatry, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations