Advertisement

Family-Based Association Studies

  • Kui ZhangEmail author
  • Hongyu Zhao
Chapter
  • 1.7k Downloads

Abstract

Over the past decade, association studies based on linkage disequilibrium have become increasingly popular for detecting genetic variations underlying complex human diseases because association-based methods have been shown to have more power than traditional linkage-based methods in theoretical and empirical studies. There are two general designs in association studies: family-based designs that use pedigrees and population-based designs that use unrelated individuals. Although population-based designs are generally more powerful than family-based designs, and the recruitment of unrelated individuals is easier than the recruitment of families, they are subject to bias in the presence of population stratification. As a compromise between linkage studies and population-based association studies, family-based association designs can have similar power with population-based designs and are robust in the presence of population stratification. Therefore, family-based association designs have received great attention recently. In this chapter, we first review methods that can analyze the simplest family-based association design with one affected offspring with its two parents, all genotyped at a bi-allelic marker locus. We then discuss its various extensions that can increase power and utilize multi-allelic markers, families with multiple siblings, families with incomplete parental genotypes, quantitative traits, and multiple tightly linked markers. The association methods using family-based designs can be broadly classified into two groups: nonparametric methods based on the allele counting and parametric methods based on the likelihood function. Although these methods result in similar test statistics for the simplest family-based association design with one affected offspring with its two parents, their extensions on more complex situations vary greatly. Further developments of statistical methods to utilize general pedigrees and to detect gene–environment interactions are also discussed. Finally, we conclude this review by listing the available software packages that can carry out the analysis of family-based association designs and illustrating some of them based on a real data set.

Keywords

Parental Genotype Transmission Disequilibrium Test Affected Offspring General Pedigree Disease Susceptibility Locus 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

We are grateful to the authors of reference [24] for the use of the Oxford ACE data, which is available on request from Dr. Martin Farrall (mfarrall@well.ox.ac.uk). This work was supported in part by the grants NIH GM074913 (KZ) and GM59507 (HZ) from the National Institute of General Medical Sciences.

References

  1. 1.
    Ogden CL, Flegal KM, Carroll MD, Johnson CL (2002) Prevalence and trends in overweight among US Children and adolescents, 1999–2000. JAMA – J Am Med Assoc 288:1728–1732Google Scholar
  2. 2.
    Flegal KM, Carroll MD, Ogden CL, Johnson CL (2002) Prevalence and trends in obesity among US adults, 1999–2000. JAMA-J Am Medical Assoc 288:1723–1727CrossRefGoogle Scholar
  3. 3.
    Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer HM, Byrd-Holt DD (1998) Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults - The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 21:518–524PubMedCrossRefGoogle Scholar
  4. 4.
    Risch N (2000) Searching for genetic determinants in the new millennium. Nature 405: 847–856PubMedCrossRefGoogle Scholar
  5. 5.
    Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306:234–238PubMedCrossRefGoogle Scholar
  6. 6.
    Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073–1080PubMedCrossRefGoogle Scholar
  7. 7.
    Strathdee CA, Gavish H, Shannon WR, Buchwald M (1992) Cloning of cDNAs for Faconi’s anaemia by functional complementation. Nature 356:763–767PubMedCrossRefGoogle Scholar
  8. 8.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 253:66–71CrossRefGoogle Scholar
  9. 9.
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792PubMedCrossRefGoogle Scholar
  10. 10.
    Lewontin RC (1964) The interaction of selection and linkage I. general considerations. Genetics 49:49–67PubMedGoogle Scholar
  11. 11.
    Boehnke, M (1994) Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes. Am J Human Genet 55:379–390Google Scholar
  12. 12.
    Kruglyak L, Lander ES (1995) High-resolution genetic mapping of complex traits. Am J Human Genet 56:1212–1223Google Scholar
  13. 13.
    Jorde LB (1995) Linkage disequilibrium as a gene mapping tool. Am J Human Genet 56:11–14Google Scholar
  14. 14.
    Ardlie K, Kruglyak L, Seielstad M (2002) Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 3:299–309PubMedCrossRefGoogle Scholar
  15. 15.
    Carlson CS, Eberle MA, Kruglyyak L, Nickerson DA. 2004. Mapping complex disease loci in whole-genome association studies. Nature 429:446–452PubMedCrossRefGoogle Scholar
  16. 16.
    Clark AG (2003) Finding genes underlying risk of complex disease by linkage disequilibrium mapping. Curr Opin Genet Develop 13:296–302CrossRefGoogle Scholar
  17. 17.
    Laird NM, Lange C (2006) Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 7:385–394PubMedCrossRefGoogle Scholar
  18. 18.
    Nordborg M, Tavaré S (2002) Linkage disequilibrium: what history has to tell us. Trend Genet 18:83–90CrossRefGoogle Scholar
  19. 19.
    Gudmundsson G, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, Rafnar T, Bergthorsson JT, Agnarsson BA et al. (2007) Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39:631–637PubMedCrossRefGoogle Scholar
  20. 20.
    Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S, Penegar S, Chandler I, Gorman M et al. (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39:984–988PubMedCrossRefGoogle Scholar
  21. 21.
    Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z et al. (2007) Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39:645–649PubMedCrossRefGoogle Scholar
  22. 22.
    McGinnis R, Shifman S, Darvasi A (2002) Power and efficiency of the TDT and case-control design for association scans. Behav Genet 32:135–144PubMedCrossRefGoogle Scholar
  23. 23.
    Witte JS, Gauderman WJ, Thomas DC (1999) Asymptotic bias and efficiency in and case-control studies of candidate genes and gene-environment interactions: basic family designs. Am J Epiemiol 149:693–705Google Scholar
  24. 24.
    Keavney B, McKenzie CA, Connell JM, Julier C, Ratcliffe PJ, Sobel E, Lathrop M, Farrall M (1998) Measured haplotype analysis of the angiotensin-I converting enzyme gene. Human Molecular Genet 7:1745–1751CrossRefGoogle Scholar
  25. 25.
    Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Human Genet 52:506–516Google Scholar
  26. 26.
    Ewens WJ, Spielman RS (2005) What is the significance of a significant TDT? Human Heredity 60:206–210PubMedCrossRefGoogle Scholar
  27. 27.
    Bickeboller H, Clerget-Darpoux F (1995) Statistical properties of the allelic and genotypic transmission/disequilibrium test for multiallelic markers. Genet Epidemiol 12:865–870PubMedCrossRefGoogle Scholar
  28. 28.
    Lazzeroni LC, Lange K (1998) A conditional inference framework for extending the transmission/disequilibrium test. Human Heredity 48:67–81PubMedCrossRefGoogle Scholar
  29. 29.
    Sham PC, Curtis D (1995) An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Human Genet 59:323–336CrossRefGoogle Scholar
  30. 30.
    Spielman RS, Ewens WJ (1996) The TDT and other family based tests for linkage disequilibrium and association. Am J Human Genet 59:983–989Google Scholar
  31. 31.
    Sham PC (1997) The transmission/disequilibrium tests for multiallelic loci. Am J Human Genet 61:774–778CrossRefGoogle Scholar
  32. 32.
    Schaid DJ (1996) General score tests for associations of genetic markers with disease using cases and their parents. Genet Epidemiol 13:423–449PubMedCrossRefGoogle Scholar
  33. 33.
    Cleves MA, Olson JM, Jacobs KB (1997) Exact transmission-disequilibrium tests with multiallelic markers. Genet Epidemiol 14:337–347PubMedCrossRefGoogle Scholar
  34. 34.
    Morris AP, Whittaker JC, Curnow RN (1997) A likelihood ratio test for detecting patterns of disease-marker association. Ann Human Genet 61:335–350CrossRefGoogle Scholar
  35. 35.
    Whittaker JC, Thompson DJ (1999) Finite-sample properties of family-based association tests. Am J Human Genet 64:910–915CrossRefGoogle Scholar
  36. 36.
    Clayton DG (1999) A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Human Genet 65:1170–1177CrossRefGoogle Scholar
  37. 37.
    Cordell H J, Barratt BJ, Clayton DG (2004) Case/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet Epidemiol 26:167–185PubMedCrossRefGoogle Scholar
  38. 38.
    Harley JB, Moser KL, Neas BR (1995) Logistic transmission modeling of simulated data. Genet Epidemiol 12:607–612PubMedCrossRefGoogle Scholar
  39. 39.
    Rice JP, Neuman RJ, Hoshaw SL, Daw EW, Gu C (1995) TDT with covariates and genomic screens with mod scores: their behavior on simulated data. Genet Epidemiol 12:659–664PubMedCrossRefGoogle Scholar
  40. 40.
    Waldman ID, Robinson BF, Rowe DC (1999) A logistic regression based extension of the TDT for continuous and categorical traits. Ann Human Genet 63:329–340CrossRefGoogle Scholar
  41. 41.
    Sinsheimer JS, Blangero J, Lange K (2000) Gamete competition models. Am J Human Genet 66:1168–1172CrossRefGoogle Scholar
  42. 42.
    Weinberg CR, Wilcox AJ, Lie RT (1998) A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Human Genet 62:969–978CrossRefGoogle Scholar
  43. 43.
    Weinberg CR (1999b) Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Human Genet 65:229–235CrossRefGoogle Scholar
  44. 44.
    Baksh MF, Balding DJ, Vyse TJ, Whittaker JC (2005) A likelihood ratio approach to family-based association studies with covariates. Annal Human Genet 70:131–139CrossRefGoogle Scholar
  45. 45.
    Koeleman BPC, Dudbridge F, Cordell HJ, Todd JA (2000) Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test. Ann Human Genet 64:207–213CrossRefGoogle Scholar
  46. 46.
    Schaid DJ (1999) Likelihoods and TDT for the case-parents design. Genet Epidemiol 16: 250–260PubMedCrossRefGoogle Scholar
  47. 47.
    Clayton D, Jones H (1999) Transmission/disequilibrium tests for extended marker haplotypes. Am J Human Genet 65:1161–1169CrossRefGoogle Scholar
  48. 48.
    Lunetta KL, Faraone SV, Biederman J, Laird NM (2000) Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. Am J Human Genet 66:605–614CrossRefGoogle Scholar
  49. 49.
    Rabinowitz D, Laird NM (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Human Heredity 504:227–233Google Scholar
  50. 50.
    Sun FZ, Flanders WD, Yang QH, Khoury MJ (1999) The transmission disequilibrium test (TDT) when only one parent is available: The 1-TDT. Am J Epidemiol 150:97–104PubMedGoogle Scholar
  51. 51.
    Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: The pedigree disequilibrium test. Am J Human Genet 67:146–154CrossRefGoogle Scholar
  52. 52.
    Lake SL, Blacker D, Laird NM (2000) Family-based tests of association in the presence of linkage. Am J Human Genet 67:1515–1525CrossRefGoogle Scholar
  53. 53.
    Zhang S, Sha Q, Chen H, Dong J, Jiang R (2003) Transmission/disequilibrium test based on haplotype sharing for tightly linked markers. Am J Human Genet 73:566–579CrossRefGoogle Scholar
  54. 54.
    Martin ER, Kaplan NL, Weir BS (1997) Tests for linkage and association in nuclear families. Am J Human Genet 61:439–448CrossRefGoogle Scholar
  55. 55.
    Wicks J (2000) Exploiting excess sharing: A more powerful test of linkage for affected sib pairs than the transmission/disequilibrium test. Am J Human Genet 66:2005–2008CrossRefGoogle Scholar
  56. 56.
    Guo CY, Lunetta KL, DeStefano AL, Ordovas JM, Cupples LA (2007) Informative-transmission disequilibrium test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring. Genet Epidemiol 31:115–133PubMedCrossRefGoogle Scholar
  57. 57.
    Whittaker JC, Lewis CM (1998) The effect of family structure on linkage tests using allelic association. Am J Human Genet 63:889–897CrossRefGoogle Scholar
  58. 58.
    Siegmund KD, Gauderman WJ (2001) Association tests in nuclear families. Human Heredity 52:66–76PubMedCrossRefGoogle Scholar
  59. 59.
    Martin ER, Bass MP, Hauser ER, Kaplan NL (2003b) Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Human Genet 73:1016–1026CrossRefGoogle Scholar
  60. 60.
    Cordell HJ, Clayton DG (2002) A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Human Genet 70:124–141CrossRefGoogle Scholar
  61. 61.
    Cordell HJ (2004) Properties of Case/Pseudocontrol Analysis for genetic association studies: effects of recombination, ascertainment, and multiple affected offspring. Genet Epidemiol 26:186–205PubMedCrossRefGoogle Scholar
  62. 62.
    Siegmund KD, Langholz B, Kraft P, Thomas DC (2000) Testing linkage disequilibrium in sibships. Am J Human Genet 67:244–248CrossRefGoogle Scholar
  63. 63.
    White H (1982) Maximum likelihood estimation of misspecified models. Econometrica 50: 1–25CrossRefGoogle Scholar
  64. 64.
    Zou GY (2006) Statistical methods for the analysis of genetic association studies. Ann Human Genet 70:262–276CrossRefGoogle Scholar
  65. 65.
    Millstein J, Siegmund KD, Conti DV, Gauderman WJ (2005) Testing association and linkage using affected-sib-parent study designs. Genet Epidemiol 29:225–233PubMedCrossRefGoogle Scholar
  66. 66.
    Curtis D (1997) Use of siblings as controls in case-control association studies. Ann Human Genet 61:319–333CrossRefGoogle Scholar
  67. 67.
    Curtis D, Sham PC (1995) A note on the application of the transmission disequilibrium test when a parent is missing. Am J Human Genet 56:811–812Google Scholar
  68. 68.
    Spielman RS, Ewens WJ (1999) TDT clarification. Am J Human Genet 64:668–668CrossRefGoogle Scholar
  69. 69.
    Knapp M (1999a) The transmission/disequilibrium test and parental-genotype reconstruction: the reconstruction-combined transmission/disequilibrium test. Am J Human Genet 64:861–870CrossRefGoogle Scholar
  70. 70.
    Spielman RS, Ewens WJ (1998) A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Human Genet 62:450–458CrossRefGoogle Scholar
  71. 71.
    Knapp M (1999b) Using exact p-values to compare the power between the reconstruction-combined transmission/disequilibrium test and the sib transmission/disequilibrium test. Am J Human Genet 65:1208–1210CrossRefGoogle Scholar
  72. 72.
    Monks SA, Kaplan NL, Weir BS (1998) A comparative study of sibship tests of linkage and/or association. Am J Human Genet 63:1507–1516CrossRefGoogle Scholar
  73. 73.
    Boehnke M, Langefeld CD (1998) Genetic association mapping based on discordant sib pairs: the discordant-alleles test. Am J Human Genet 62:950–961CrossRefGoogle Scholar
  74. 74.
    Schaid DJ, Rowland C (1998) Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and disease. Am J Human Genet 63:1492–1506CrossRefGoogle Scholar
  75. 75.
    Laird NM, Blacker D, Wilcox M (1998) The sib transmission/disequilibrium test is a Mantel-Haenszel test. Am J Human Genet 63:1915–1916CrossRefGoogle Scholar
  76. 76.
    Horvath S, Laird NM (1998) A discordant-sibship test for disequilibrium and linkage: no need for parental data. Am J Human Genet 63:1886–1897CrossRefGoogle Scholar
  77. 77.
    Sun FZ, Flanders WD, Yang Q, Khoury MJ (1998) A new method for estimating the risk ratio in studies using case-parental control design. Am J Epidemiol 148:902–909PubMedGoogle Scholar
  78. 78.
    Wang D, Sun F (2000) Sample sizes for the transmission disequilibrium tests: TDT, S-TDT and 1-TDT. Commun Statistic – Theory Meth 29:1129–1142Google Scholar
  79. 79.
    Sun FZ, Yang QH, Zhao HY, Flanders WD (2000) Transmission/disequilibrium tests for quantitative traits. Ann Human Genet 64:555–565CrossRefGoogle Scholar
  80. 80.
    Schaid DJ, Li H (1997) Genotype relative-risks and association tests for nuclear families with missing parental data. Genet Epidemiol 14:1113–1118PubMedCrossRefGoogle Scholar
  81. 81.
    Martin RB, Alda M, MacLean CJ (1998) Parental genotype reconstruction: applications of haplotype relative risk to incomplete parental data. Genet Epidemiol 15:471–490PubMedCrossRefGoogle Scholar
  82. 82.
    Weinberg CR (1999a) Allowing for missing parents in genetic studies of case-parent triads. Am J Human Genet 64:1186–1193CrossRefGoogle Scholar
  83. 83.
    Whittemore AS, Tu IP (2000) Detection of disease genes by use of family data. I. Likelihood based theory. Am J Human Genet 66:1328–1340CrossRefGoogle Scholar
  84. 84.
    Shih MC, Whittemore AS (2002) Tests for genetic association using family data. Genet Epidemiol 22:128–145PubMedCrossRefGoogle Scholar
  85. 85.
    Jonasdottir G, Humphreys K, Palmgren J (2007) Testing association in the presence of linkage - a powerful score for binary traits. Genet Epidemiol 31:528–540PubMedCrossRefGoogle Scholar
  86. 86.
    Croiseau P, Genin E, Cordell HJ (2007) Dealing with missing data in family-based association studies: a multiple imputation approach. Human Heredity 63:229–238PubMedGoogle Scholar
  87. 87.
    Allen AS, Rathouz PJ, Glen A, Satten GA (2003) Informative missingness in genetic association studies: case-parent designs. Am J Human Genet 72:671–680CrossRefGoogle Scholar
  88. 88.
    Chen Y (2004) New approach to association testing in case-parent designs under informative parental missingness. Genet Epidemiol 27:131–140PubMedCrossRefGoogle Scholar
  89. 89.
    Schaid DJ, Sommer SS (1993) Genotype risk ratio: methods for design and analysis of candidate-gene association studies. Am J Human Genet 53:127–130Google Scholar
  90. 90.
    Sebastiani P, Abad MM, Alpargu G, Ramoni MF (2004) Robust transmission/disequilibrium test for incomplete family genotypes. Genetics 168:2329–2337PubMedCrossRefGoogle Scholar
  91. 91.
    Allison DB (1997) Transmission disequilibrium tests for quantitative traits. Am J Human Genet 60:676–690Google Scholar
  92. 92.
    Allison D B, Neale MC (2001) Joint tests of linkage & association for quantitative traits. Theoretical Population Biol 60:239–251CrossRefGoogle Scholar
  93. 93.
    Allison DB, Heo M, Kaplan N, Martin ER (1999) Sibling based tests of linkage and association for quantitative traits. Am J Human Genet 64:1754–1764CrossRefGoogle Scholar
  94. 94.
    George V, Tiwari HK, Zhu X, Elston RC (1999) A test of Transmission/Disequilibrium for quantitative traits in pedigree data using multiple regression. Am J Human Genet 65:236–245CrossRefGoogle Scholar
  95. 95.
    Zhu X, Elston RC (2001) Transmission/disequilibrium test for quantitative traits. Genet Epidemiol 20:57–74PubMedCrossRefGoogle Scholar
  96. 96.
    Zhu X, Elston RC (2000) Power comparison of regression methods to test quantitative traits for association and linkage. Genet Epidemiol 18:322–330PubMedCrossRefGoogle Scholar
  97. 97.
    Zhu X, Elston RC, Cooper RS (2001) Testing quantitative traits for association and linkage in the presence or absence of parental data. Human Heredity 51:183–191PubMedCrossRefGoogle Scholar
  98. 98.
    Yang Q, Rabinowitz D, Isasi C, Shea S (2000) Adjusting for confounding due to population admixture when estimating the effect of candidate genes on quantitative traits. Human Heredity 50:227–233PubMedCrossRefGoogle Scholar
  99. 99.
    Liu Y, Tritchler D, Bull SB (2002) A unified framework for transmission-disequilibrium test analysis of discrete and continuous traits. Genet Epidemiol 22:26–40PubMedCrossRefGoogle Scholar
  100. 100.
    Kistner EO, Weinberg CR (2004) Method for using complete and incomplete trios to identify genes related to a quantitative trait. Genet Epidemiol 27:33–42PubMedCrossRefGoogle Scholar
  101. 101.
    Kistner EO, Weinberg CR (2005) A method for identifying genes related to a quantitative trait, incorporating multiple siblings and missing parents. Genet Epidemiol 29:155–165PubMedCrossRefGoogle Scholar
  102. 102.
    Fulker DW, Cherny SS, Sham PC, Hewitt JK (1999) Combined linkage and association sib-pair analysis for quantitative traits. Am J Human Genet 64:259–267CrossRefGoogle Scholar
  103. 103.
    Cardon LR (2000) A sib-pair regression model of linkage disequilibrium for quantitative traits. Human Heredity 50:350–358PubMedCrossRefGoogle Scholar
  104. 104.
    Abecasis GR, Cardon LR, Cookson WO (2000a) A general test of association for quantitative traits in nuclear families. Am J Human Genet 66:279–292CrossRefGoogle Scholar
  105. 105.
    Abecasis GR, Cookson WOC, Cardon LR (2000b) Pedigree tests of transmission disequilibrium. Euro J Human Genet 8:545–551CrossRefGoogle Scholar
  106. 106.
    Chen W, Abecasis GR (2007) Family-based association tests for genome wide association scans. Am J Human Genet 81:913–926CrossRefGoogle Scholar
  107. 107.
    Purcell S, Sham P, Daly MJ (2005) Parental phenotypes in family-based association analysis. Am J Human Genet 76:249–259CrossRefGoogle Scholar
  108. 108.
    Diao G, Lin DY (2006) Improving the power of association tests for quantitative traits in family studies. Genet Epidemiol 30:301–313PubMedCrossRefGoogle Scholar
  109. 109.
    Box GEP, Cox DR. 1964. An analysis of transformations. J Roy Stat Soc, Series B 26: 211–246Google Scholar
  110. 110.
    Xiong MM, Krushkal J, Boerwinkle E. 1998. TDT statistics for mapping quantitative trait loci. Ann Human Genet 62:431–452CrossRefGoogle Scholar
  111. 111.
    Fan RZ, Floros J, Xiong MM (2002) Models and tests of linkage and association studies of quantitative trait locus for multi-allele marker loci. Human Heredity 53:130–145PubMedCrossRefGoogle Scholar
  112. 112.
    Rabinowitz D (1997) A transmission disequilibrium test for quantitative trait loci. Human Heredity 47:342–350PubMedCrossRefGoogle Scholar
  113. 113.
    Monks SA, Kaplan NL (2000) Removing the sampling restrictions from family-based test of association for a quantitative trait locus. Am J Human Genet 66:576–592CrossRefGoogle Scholar
  114. 114.
    Akey J, Jin L, Xiong M (2001) Haplotypes vs single marker linkage disequilibrium tests: what do we gain? Euro J Human Genet 9:291–300CrossRefGoogle Scholar
  115. 115.
    Chapman JM, Copper JD, Todd JA, Clayton DG (2003) Detecting disease association due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Human Heredity 56:18–31PubMedCrossRefGoogle Scholar
  116. 116.
    Roeder K, Bacanu S, Sonpar V, Zhang X, Devlin B (2005) Analysis of single-locus tests to detect gene/disease associations. Genet Epidemiol 28:207–219PubMedCrossRefGoogle Scholar
  117. 117.
    Xiong M, Zhao J, Boerwinkle E (2002) Generalized T 2 test for genome association studies. Am J Human Genet 70:1257–1268CrossRefGoogle Scholar
  118. 118.
    Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Human Heredity 53:79–91PubMedCrossRefGoogle Scholar
  119. 119.
    Zhao H, Zhang S, Merikangas KR, Trixler M, Widenauer DB, Sun FZ, Kidd KK. 2000. Transmission/disequilibrium tests using multiple tightly linked markers. Am J Human Genet 67:936–946CrossRefGoogle Scholar
  120. 120.
    Morris RW, Kaplan NL (2002) On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles. Genet Epidemiol 23:221–233PubMedCrossRefGoogle Scholar
  121. 121.
    Liang KY, Hsu FC, Beaty TH, Barnes KC (2001) Multipoint linkage-disequilibrium-mapping approach based on the case-parent trio design. Am J Human Genet 68:937–950CrossRefGoogle Scholar
  122. 122.
    Liang KY, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73:13–22CrossRefGoogle Scholar
  123. 123.
    Hsu FC, Liang KY, Beaty TH, Barnes KC (2002) Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traits. Genet Epidemiol 22: 298–312PubMedCrossRefGoogle Scholar
  124. 124.
    Fan R, Xiong M (2002) Combined high resolution linkage and association mapping of quantitative trait loci. Euro J Human Genet 11:125–137CrossRefGoogle Scholar
  125. 125.
    Fan RZ, Jung JS (2003) High-resolution joint linkage disequilibrium and linkage mapping of quantitative trait loci based on sibship data. Human Heredity 56:166–187PubMedCrossRefGoogle Scholar
  126. 126.
    Fan RZ, Spinka C, Jin L, Jung JS (2005b) Pedigree linkage disequilibrium mapping of quantitative trait loci. Euro J Human Genet 13:216–231CrossRefGoogle Scholar
  127. 127.
    Fan RZ, Knapp M, Wjst M, Zhao CX, Xiong MM (2005a) High resolution T2 association tests of complex diseases based on family data. Ann Human Genet 69:187–208CrossRefGoogle Scholar
  128. 128.
    Xu X, Tian L, Wei LJ (2003) Combining dependent tests for linkage or association across multiple phenotypic traits. Biostatistics 4:223–229PubMedCrossRefGoogle Scholar
  129. 129.
    Xu X, Rakovski C, Xu X, Larid N (2006) An efficient family-based association test using multiple markers. Genet Epidemiol 30:620–626PubMedCrossRefGoogle Scholar
  130. 130.
    Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2003a) Using the noninformative families in family-based association tests: a powerful new testing strategy. Am J Human Genet 73:801–811CrossRefGoogle Scholar
  131. 131.
    Van Steen K, McQueen MB, Herbert A, Raby B, Lyon H, Demeo DL, Murphy A, Su J, Datta S, Rosenow C, Christman M, Silverman EK, Laird NM, Weiss ST, Lange C (2005) Genomic screening and replication using the same data set in family-based association testing. Nat Genet 37:683–691PubMedCrossRefGoogle Scholar
  132. 132.
    Rakovski CS, Xu X, Lazarus R, Blacker D, Laird NM (2007) A New multimarker test for family-Based association studies. Genet Epidemiol 31:9–17PubMedCrossRefGoogle Scholar
  133. 133.
    Van der Meulen MA, te Meerman GJ (1997) Haplotype sharing analysis in affected individuals from nuclear families withy at least one affected offspring. Genet Epidemiol 14:915–919Google Scholar
  134. 134.
    Bourgain C, Genin E, Quesneville H, Clerget-Darproux F (2000) Search multifactorial disease susceptibility genes in founder populations. Ann Human Genet 64:255–265CrossRefGoogle Scholar
  135. 135.
    Bourgain C, Genin E, Holopainen P, Mustalahti K, Maki M, Partanen J, Clerget-Darproux F (2001) Use of closely related affected individuals for the genetic study of complex disease in founder populations. Am J Human Genet 68:154–159CrossRefGoogle Scholar
  136. 136.
    Bourgain C, Genin E, Ober C, Clerget-Darproux F (2002) Missing data in haplotype analysis: a study on the MILC method. Ann Human Genet 66:99–108CrossRefGoogle Scholar
  137. 137.
    Lange EM, Boehnke M (2004) The haplotype runs test: the parent-parent-affected offspring trio design. Genet Epidemiol 27:118–130PubMedCrossRefGoogle Scholar
  138. 138.
    Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121PubMedCrossRefGoogle Scholar
  139. 139.
    Seltman H, Roeder K, Devlin B (2001) Transmission/Disequilibrium test meets measured haplotype analysis: Family-based association analysis guided by evolution of haplotypes. Am J Human Genet 68:1250–1263CrossRefGoogle Scholar
  140. 140.
    Knapp M, Becker T (2003) Family-based association analysis with tightly linked markers. Human Heredity 56:2–9PubMedCrossRefGoogle Scholar
  141. 141.
    Lin S, Chakravarti A, Cutler DJ (2004) Exhaustive allelic transmission disequilibrium tests as a new approach to genome-wide association studies. Nature Genet 36:1181–1188PubMedCrossRefGoogle Scholar
  142. 142.
    Knapp M, Becker T (2004) Impact of genotyping errors on type I error rate of the haplotype-sharing transmission/disequilibrium test (HS-TDT). Am J Human Genet 74:589–591CrossRefGoogle Scholar
  143. 143.
    Sha QY, Dong JP, Jiang RF, Chen HS, Zhang SL (2005) Haplotype sharing transmission/disequilibrium tests that allow for genotyping errors. Genet Epidemiol 28:341–351PubMedCrossRefGoogle Scholar
  144. 144.
    Toivonen HTT, Onkamo P, Vasko K, Ollikainen V, Sevon P, Mannila H, Herr M, Kere J (2000) Data mining applied to linkage disequilibrium mapping. Am J Human Genet 67:133–145CrossRefGoogle Scholar
  145. 145.
    Zhang S, Sha Q, Chen H, Dong J, Jiang R (2004) Impact of genotyping errors on type I error rate of the haplotype-sharing transmission/disequilibrium test (HS-TDT) - Reply. Am J Human Genet 74:591–593CrossRefGoogle Scholar
  146. 146.
    Epstein MP, Kwee LC (2008) Haplotype Association Analysis. In: Shili Lin, Hongyu Zhao (eds). Handbook on analyzing human genetic data: computational approaches and software. In press.Google Scholar
  147. 147.
    Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM (2004) Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26:61–69PubMedCrossRefGoogle Scholar
  148. 148.
    Allen AS, Satten GA (2007) Inference on haplotype/disease association using parent affected-child data: the projection conditional on parental haplotypes method. Genetic Epidemiol 31:211–223CrossRefGoogle Scholar
  149. 149.
    Allen-Brady K, Wong J, Camp NJ (2006) PedGenie: an analysis approach for genetic association testing in extended pedigrees and genealogies of arbitrary size. BMC Bioinformatics 7:209PubMedCrossRefGoogle Scholar
  150. 150.
    Dudbridge F, Koeleman BP, Todd JA, Clayton DG (2000) Unbiased application of the transmission/disequilibrium test to multilocus haplotypes. Am J Human Genet 66:2009–2012CrossRefGoogle Scholar
  151. 151.
    Li C, Boehnke M (2006) Haplotype association analysis for late onset diseases using nuclear family data. Genet Epidemiol 30:220–230PubMedCrossRefGoogle Scholar
  152. 152.
    Lo S, Zheng T (2002) Backward haplotype transmission association (BHTA) algorithm - a fast multiple-marker screening method. Human Heredity 53:197–215PubMedCrossRefGoogle Scholar
  153. 153.
    Yu K, Gu CC, Province M, Xiong CJ, Rao DC (2004) Genetic association mapping under founder heterogeneity via weighted haplotype similarity analysis in candidate genes. Genet Epidemiol 27:182–191PubMedCrossRefGoogle Scholar
  154. 154.
    Yu K, Xu J, Rao DC, Province M (2005a) Using tree-based recursive partitioning methods to group haplotypes for increased power in association studies. Ann Human Genet 69:577–589CrossRefGoogle Scholar
  155. 155.
    Yu K, Zhang SL, Borecki I, Kraja A, Xiong CJ, Myers R, Province M (2005b) A haplotype similarity based transmission/disequilibrium test under founder heterogeneity. Ann Human Genet 69:455–467CrossRefGoogle Scholar
  156. 156.
    Zhang S, Zhang K, Li J, Zhao H (2002) On a family-based haplotype pattern mining method for linkage disequilibrium mapping. Proc Pacific Symp Biocomputing 7:100–111Google Scholar
  157. 157.
    Martin ER, Bass MP,Gilbert JR, Pericak-Vance MA, Hauser ER (2003a) Genotype-based association test for general pedigrees: The genotype-PDT. Genet Epidemiol 25:203–213PubMedCrossRefGoogle Scholar
  158. 158.
    Martin ER, Bass MP, Kaplan NL (2001) Correcting for a potential bias in the pedigree disequilibrium test. Am J Human Genet 68:1065–1067CrossRefGoogle Scholar
  159. 159.
    Liu X, Gordon D (2003) A general class of association tests for family-based data using weight functions. Genet Epidemiol 24:208–219PubMedCrossRefGoogle Scholar
  160. 160.
    Cantor RM, Chen GK, Pajukanta P, Lange K (2005) Association testing in a linked region using large pedigrees. Am J Human Genet 76:538–542CrossRefGoogle Scholar
  161. 161.
    Xiong M, Jin L (2000) Combined linkage and linkage disequilibrium mapping for genome screens. Genetic Epidemiol 19:211–234CrossRefGoogle Scholar
  162. 162.
    Umbach DM, Weinberg CR (2000) The use of case-parent triads to study joint effects of genotype and exposure. Am J Human Genet 66:251–261CrossRefGoogle Scholar
  163. 163.
    Hsu FC, Liang KY, Beaty TH (2003) Multipoint linkage disequilibrium mapping approach: incorporating evidence of linkage and linkage disequilibrium from unlinked region. Genet Epidemiol 25:1–13PubMedCrossRefGoogle Scholar
  164. 164.
    Lake SL, Laird NM (2004) Tests of gene-environment interaction for case-parent triads with general environmental exposures. Ann Human Genet 68:55–64CrossRefGoogle Scholar
  165. 165.
    Martin ER, Ritchie MD, Hahn L, Kang S, Moore JH (2006) A novel method to identify gene–gene effects in nuclear families: the MDR-PDT. Genet Epidemiol 30:111–123PubMedCrossRefGoogle Scholar
  166. 166.
    Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Human Genet 69:138–147CrossRefGoogle Scholar
  167. 167.
    Lange C, Blacker D, Laird NM (2004a) Family-based association tests for survival and times-to-onset analysis. Stat Med 23:179–189PubMedCrossRefGoogle Scholar
  168. 168.
    Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2004b) PBAT: tools for family-based association studies Am J Human Genet 74:367–369Google Scholar
  169. 169.
    Sham PC, Cherny SS, Purcell S, Hewitt JK (2000) Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. Am J Human Genet 66:1616–1630CrossRefGoogle Scholar
  170. 170.
    Purcell S, Cherny SS, Sham PC (2003). Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150PubMedCrossRefGoogle Scholar
  171. 171.
    Hoffmann T, Lange C (2006) P2BAT: a massive parallel implementation of PBAT for genome-wide association studies in R. Bioinformatics 15:3103–3105CrossRefGoogle Scholar
  172. 172.
    Lange C, Laird NM (2002a) Analytical sample size and power calculations for a general class of family-based association tests: dichotomous traits. Am J Human Genet 71:575–584CrossRefGoogle Scholar
  173. 173.
    Lange C, Laird NM (2002b) On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations. Genet Epidemiol 23:165–180PubMedCrossRefGoogle Scholar
  174. 174.
    Van Steen K, Lange C (2005) PBAT: a comprehensive software package for genome-wide association analysis of complex family-based studies. Human Genom 2:67–69Google Scholar
  175. 175.
    Gauderman WJ (2002a) Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 21:35–50PubMedCrossRefGoogle Scholar
  176. 176.
    Gauderman WJ (2002b) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484PubMedCrossRefGoogle Scholar
  177. 177.
    Gauderman WJ (2003) Candidate gene association studies for a quantitative trait, using parent-offspring trios. Genet Epidemiol 25:327–338PubMedCrossRefGoogle Scholar
  178. 178.
    Brown BW (2004) Power calculations for the transmission/disequilibrium and affected sib pair tests using elementary probability methods. Genet Res 83:133–141PubMedCrossRefGoogle Scholar
  179. 179.
    Gordon D, Heath SC, Liu X, Ott J (2001) A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data Am J Human Genet 69:371–380Google Scholar
  180. 180.
    Gordon G, Haynes C, Johnnidis C, Patel SB, Bowcock AM, Ott J (2004) A transmission disequilibrium test for general pedigrees that is robust to the presence of random genotyping errors and any number of untyped parents. Euro J Human Genet 12:752–761CrossRefGoogle Scholar
  181. 181.
    Zhang K, Sun F, Zhao H (2005) HAPLORE: A Program for Haplotype Reconstruction in General Pedigrees without Recombination. Bioinformatics 21:90–103PubMedCrossRefGoogle Scholar
  182. 182.
    Falls JG, Pulford DJ, Wylie AA, Jirtle RL (1999) Genomic imprinting: implications for human disease. Am J Pathol 154:635–647PubMedGoogle Scholar
  183. 183.
    Morison IM, Paton CJ, Cleverley SD (2001) The imprinted gene and parent-of-origin effect database. Nucleic Acids Res 29:275–276PubMedCrossRefGoogle Scholar
  184. 184.
    Whittaker JC, Gharani N, Hindmarsh P, McCarthy MI (2003) Estimation and testing of parent-of-origin effects for quantitative traits. Am J Human Genet 72:1035–1039CrossRefGoogle Scholar
  185. 185.
    Hu YQ, Zhou JY, Sun F, Fung WK (2007) The Transmission Disequilibrium Test and imprinting effects test based on Case-Parent Pairs. Genet Epidemiol 31:273–287PubMedCrossRefGoogle Scholar
  186. 186.
    Thomas D, Xie R, Gebregziabher M (2004) Two-stage sampling designs for gene association studies. Genet Epidemiol 27:401–414PubMedCrossRefGoogle Scholar
  187. 187.
    Feng T, Zhang S, Sha Q (2007) Two-stage association tests for genome-wide association studies based on family data with arbitrary family structure. Euro J Human Genet 15:1169–1175CrossRefGoogle Scholar
  188. 188.
    Van Steen K, Laird NM, Markel P, Molenberghs G (2007) Approaches to handling incomplete data in family-based association testing. Ann Human Genet 71:141–151CrossRefGoogle Scholar
  189. 189.
    Whittaker JC, Morris AP (2001) Family-based tests of association and/or linkage. Annal Human Genet 65:407–419CrossRefGoogle Scholar
  190. 190.
    Zhao H (2000) Family based association studies. Stat Meth Medical Res 9:563–587CrossRefGoogle Scholar
  191. 191.
    Ho GY, Bailey-Wilson JE (2000) The transmission/disequilibrium test for linkage on the X chromosome. Am J Human Genet 66:1158–1160CrossRefGoogle Scholar
  192. 192.
    Horvath S, Laird NM, Knapp M (2000) The transmission/disequilibrium test and parental-genotype reconstruction for X-chromosomal markers. Am J Human Genet 66:1161–1167CrossRefGoogle Scholar
  193. 193.
    Ghosh S, Reich T (2004). The Sib TDT adjusted for age of disease onset. Ann Human Genet 68:249–256CrossRefGoogle Scholar
  194. 194.
    Jiang HY, Harrington D, Raby BA, Bertram L, Blacker D, Weiss ST, Lange C (2006) Family-based association test for time-to-onset data with time-dependent differences between the hazard functions. Genet Epidemiol 30:124–132PubMedCrossRefGoogle Scholar
  195. 195.
    Mokliatchouk O, Blacker D, Rabinowitz D (2001) Association tests for traits with variable age at onset. Human Heredity 51:46–53PubMedCrossRefGoogle Scholar
  196. 196.
    Epstein MP, Veal CD, Trembath RC, Barker JNWN, Li C, Satten GA (2005) Genetic association analysis using data from triads and unrelated subjects. Am J Human Genet 76:592–608CrossRefGoogle Scholar
  197. 197.
    Kazeem GR, Farrall M (2005) Integrating case-control and TDT studies. Ann Human Genet 69:329–335CrossRefGoogle Scholar
  198. 198.
    Nagelkerke NJD, Hoebee B, Teunis P, Kimman TG (2004) Combining the transmission disequilibrium test and case-control methodology using generalized logistic regression Euro J Human Genet 12:964–970Google Scholar
  199. 199.
    Lange C, Silverman EK, Xu X, Weiss ST, Laird NM (2003c) A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 4:195–206PubMedCrossRefGoogle Scholar
  200. 200.
    Lange C, Lyon H, DeMeo D, Raby B, Silverman EK, Weiss ST (2003b) A new powerful non-parametric two-Stage approach for testing multiple phenotypes in family-based association studies. Human Heredity 56:10–17PubMedCrossRefGoogle Scholar
  201. 201.
    Cervino ACL, Hill AVS (2000) Comparison of tests for association and linkage in incomplete families. Am J Human Genet 67:120–132CrossRefGoogle Scholar
  202. 202.
    Kaplan NL, Martin ER, Weir BS (1997) Power studies for the transmission/disequilibrium tests with multiple alleles. Am J Human Genet 60:691–702Google Scholar
  203. 203.
    Li Z, Gastwirth JL, Gail MH (2005) Power and related statistical properties of conditional likelihood score tests for association studies in nuclear families with parental genotypes. Ann Human Genet 69:296–314CrossRefGoogle Scholar
  204. 204.
    Nicodemus KK, Luna A, Shugart YY (2007) An evaluation of power and type I error of single-nucleotide polymorphism transmission/disequilibrium-based statistical methods under different family structures, missing parental data, and population stratification. Am J Human Genet 80:178–185CrossRefGoogle Scholar
  205. 205.
    Pritchard JK, Rosenberg NA (1999) Use of unlinked genetic markers to detect population stratification in association studies. Am J Human Genet 65:220–228CrossRefGoogle Scholar
  206. 206.
    Pritchard JK, Stephens M, Rosenberg NA, Donnelly P (2000) Association mapping in structured populations. Am J Human Genet 67:170–181CrossRefGoogle Scholar
  207. 207.
    Yu J, Pressoir G, Briggs WH, Vroh Bi I, Yamasaki M, Doebley JF, McMullen MD, Gaut BS, Nielsen DM, Holland JB, Kresovich S, Buckler ES (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nat Genet 38:203–208PubMedCrossRefGoogle Scholar
  208. 208.
    Abecasis GR, Cherny SS, Cardon LR (2001) The impact of genotyping error on family-based analysis of quantitative traits. Euro J Human Genet 9:130–134CrossRefGoogle Scholar
  209. 209.
    Mitchell AA, Cutler DJ, Chakravarti A (2003) Undetected genotyping errors cause apparent over transmission of common alleles in the transmission/disequilibrium test. Am J Human Genet 72:598–610CrossRefGoogle Scholar
  210. 210.
    Botstein D, Risch N (2003) Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nat Genet 33:228–237PubMedCrossRefGoogle Scholar
  211. 211.
    Curtis (1999) Combining the sibling disequilibrium test and Transmission/Disequilibrium test for multiallelic markers. Am J Human Genet 64:1785–1786Google Scholar
  212. 212.
    Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004PubMedCrossRefGoogle Scholar
  213. 213.
    Lange C, DeMeo DL, Laird NM (2002) Power and design considerations for a general class of family based association tests: quantitative traits. Am J Human Genet 71:1330–1341CrossRefGoogle Scholar
  214. 214.
    O’Connell JR (2000) Zero-recombinant haplotyping: applications to fine mapping using SNPs. Genet Epidemiol 19:S64–S70PubMedCrossRefGoogle Scholar
  215. 215.
    Onkamo P, Ollikainen V, Sevon P, Toivonen HT, Mannila H, Kere J (2002) Association analysis for quantitative traits by data mining: QHPM. Ann Human Genet 66:419–429CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Section on Statistical GeneticsDepartment of Biostatistics University of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Epidemiology and Public HealthYale University School of MedicineNew HavenUSA

Personalised recommendations