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Model‐Free Tests for Genetic Linkage

Christopher I. Amos¹

¹University of Texas, Houston, Texas

Publication Name:

Current Protocols in Human Genetics

Unit Number:

Unit 1.8

DOI:

10.1002/0471142905.hg0108s28

Online Posting Date:

May, 2001

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Abstract

This unit covers statistical methods of linkage analysis that do not require assuming a detailed genetic model as is required for standard lod score analysis. The unit has been updated to include the latest methods in sib-pair analysis as well as relative- pair analysis, including the NPL method used in GENEHUNTER and GENEHUNTER PLUS.

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Unit Introduction
Key Concepts
Strategic Approach
Commentary
Literature Cited
Figures
Tables

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Figures

Figure 1.8.1

Decision tree for model-free linkage analysis. Abbreviations: ACT, Analysis of Complex Traits; APM, affected pedigree member method; ASP, affected sib-pair method; H-E, Haseman-Elston regression method; SOLAR, Sequential Oligogenic Linkage Analysis Routines.

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Figure 1.8.2

Sample pedigree for illustrating identity by descent and identity by state calculations. The box with the slash represents a deceased individual.

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Figure 1.8.3

Data file representing pedigree shown in Figure 1.7.3, modified for use with SIBPAL.

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Figure 1.8.4

Parameter file for an FSP run, corresponding to data in Figure 1.8.3.

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Figure 1.8.5

SIBPAL parameter file for an affected-sib-pair analysis.

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Figure 1.8.6

Locus description file for SIBPAL analysis.

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Figure 1.8.7

Output from analysis by SimIBD of M2 data from Example 3, assuming a 1/p^1/2 weight function. Note that only the beginning and end of the output file are displayed.

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Figure 1.8.8

Pedigree data needed for GENEHUNTER PLUS analysis.

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Literature Cited

Literature Cited
	Abel, L. and Muller-Myhsok, B. 1998. Robustness and power of the maximum-likelihood-binomial and maximum-likelihood-score methods, in multipoint linkage analysis of affected-sibship data. Am. J. Hum. Genet. 63:638-647.
	Allison, D.B. and Beasley, M. 1998. A method and computer program for controlling the family-wise alpha rate in gene association studies involving multiple phenotypes. Genet. Epidemiol. 15:87-101.
	Almasy, L. and Blangero, J. 1998. Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62:1198-1211.
	Amos, C.I. 1994. Robust detection of genetic linkage by variance components analysis. Am. J. Hum. Genet. 54:535-543.
	Amos, C.I. and Elston, R.C. 1989. Robust methods for the detection of genetic linkage for quantitative data from pedigrees. Genet. Epidemiol. 6:349-361.
	Amos, C.I., Elston, R.C., Wilson, A.F., and Bailey-Wilson, J.E. 1989. A more powerful robust sib-pair test of linkage for quantitative traits. Genet. Epidemiol. 6:435-451.
	Amos, C.I., Dawson, D.V., and Elston, R.C. 1990. The probabilistic determination of identity-by-descent sharing for pairs of relatives from pedigrees. Am. J. Hum. Genet. 47:842-853.
	Amos, C.I., Zhu, D., and Boerwinkle, E. 1996. Assessing genetic linkage and association with robust components of variance approaches. Ann. Hum. Genet. 60:143-166.
	Blackwelder, W.C. and Elston, R.C. 1982. Power and robustness of sib-pair linkage tests and extension to larger sibships. Commun. Stat. Theor. Methods 11:449-484.
	Blackwelder, W.C. and Elston, R.C. 1985. A comparison of sib pair linkage tests for disease susceptibility loci. Genet. Epidemiol. 2:5-97.
	Boehnke, M. 1991. Estimating allele frequencies. Am. J. Hum. Genet. 48:22-25.
	Cardon, L.R. and Fulker, D.W. 1994. The power of interval mapping of quantitative trait loci, using selected sib pairs. Am. J. Hum. Genet. 55:825-833.
	Carey, G. and Williamson, J.A. 1991. Linkage analysis of quantitative traits: Increased power by using selected samples. Am. J. Hum. Genet. 49:786-796.
	Chotai, J. 1984. On the lod score method in linkage analysis. Ann. Hum. Genet. 48:359-378.
	Commenges, D. 1994. Robust genetic linkage analysis based on a score test of homogeneity: The weighted pairwise correlation statistic. Genet. Epidemiol. 11:189-200.
	Commenges, D., Olson, J., and Wijsman, E. 1994. The weighted rank pairwise correlation statistic for linkage analysis: Simulation study and application to Alzheimer's disease. Genet. Epidemiol. 11:201-212.
	Cox, N.J. and Spielman, R.S. 1989. The insulin gene and susceptibility to IDDM. Genet. Epidemiol. 6:65-69.
	Curtis, D. and Sham, P.C. 1994. Using risk calculation to implement an extended relative pair analysis. Ann. Hum. Genet. 58:151-162.
	Davis, S. and Weeks, D.E. 1997. Comparison of nonparametric statistics for detection of linkage in nuclear families: Single-marker evaluation. Am. J. Hum. Genet. 61:1431-1444.
	Davis, S., Schroeder, M., Goldin, L.R., and Weeks, D.E. 1996. Nonparametric simulation-based statistics for detecting linkage in general pedigrees. Am. J. Hum. Genet. 58:867-880.
	Dawson, D.V., Kaplan, E.B., and Elston, R.C. 1990. Extensions to sib-pair linkage tests applicable to disorders characterized by late onset. Genet. Epidemiol. 7:153-166.
	de Andrade, M. and Amos, C.I. 2000. Ascertainment issues in variance components models. Genet. Epidemiol. 19:333-344.
	Dernenois, F.M. and Amos, C.I. 1989. Power of the sib-pair and lodscore methods for linkage analysis of quantitative traits. Prog. Clin. Biol. Res. 329:201-206.
	Feingold, E., Brown, P.O., and Siegmund, D. 1993. Gaussian models for genetic linkage analysis using complete high-resolution maps of identity by descent. Am. J. Hum. Genet. 53:234-251.
	Fulker, D.W. and Cardon, L.R. 1994. A sib-pair approach to interval mapping of quantitative trait loci. Am. J. Hum. Genet. 54:1092-1103.
	Fulker, D.W., Cherny, S.S., and Cardon, L.R. 1995. Multipoint interval mapping of quantitative trait loci, using sib pairs. Am. J. Hum. Genet. 56:1224-1233.
	Goldgar, D.E. and Oniki, R.O. 1992. Comparison of a multipoint identity by descent method with parametric multipoint linkage analysis for mapping quantitative traits. Am. J. Hum. Genet. 50:598-606.
	Hall, P. 1992. The bootstrap and Edgeworth expansion. In Springer Series in Statistics. Springer-Verlag, New York.
	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.
	Hodge, S.E. 1984. The information contained in multiple sibling pairs. Genet. Epidemiol. 1:109-122.
	Hodge, S.E. and Elston, R.C. 1994. Lods, wrods, and mods: The interpretation of lod scores calculated under different models. Genet. Epidemiol. 11:329-342.
	Karigl, G. 1982. A mathematical approach to multiple genetic relationships. Theor. Popul. Biol. 21:379-393.
	Knapp, M., Seuchter, S.A., and Baur, M.P. 1994. Linkage analysis in nuclear families. II. Relationship between ASP and lod score tests. Hum. Hered. 44:44-51.
	Kong, A. and Cox, N.J. 1997. Allele-sharing models: LOD scores and accurate linkage tests. Am. J. Hum. Genet. 61:1179-1188.
	Kruglyak, L. and Lander, E.S. 1995. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57:439-454.
	Kruglyak, L., Daly, M.J., and Lander, E.S. 1995. Rapid multipoint linkage analysis of recessive traits in nuclear families including homozygosity mapping. Am. J. Hum. Genet. 56:519-527.
	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.
	Lander, E.S. and Botstein, D. 1989. Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185-199.
	Lander, E.S. and Kruglyak, L. 1995. Genetic dissection of complex traits:Guidelines for interpreting and reporting linkage results. Nat. Genet. 11:241-247.
	Lange, K., Weeks, D., and Boehnke, M. 1988. Programs for pedigree analysis: MENDEL, FISHER, and dGENE. Genet. Epidemiol. 5:471-472.
	Morton, N.E. 1998. Significance levels in complex inheritance. Am. J. Hum. Genet. 62:690-697.
	Olson, J.M. 1995. Robust multipoint linkage analysis: An extension of the Haseman-Elston method. Genet. Epidemiol. 12:163-176.
	Olson, J.M. and Wijsman, E. 1993. Linkage between quantitative trait and marker locus: Methods using relative pairs. Genet. Epidemiol. 10:87-102.
	Ott, J. 1992. Strategies for characterizing highly polymorphic markers in human gene mapping. Am. J. Hum. Genet. 51:283-290.
	Ott, J. 1999. Analysis of Human Genetic Linkage, 3rd ed. Johns Hopkins University Press, Baltimore.
	Risch, N. 1990a. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 16:222-228.
	Risch, N. 1990b. Linkage strategies for genetically complex traits. III. The effect of marker polymorphism on analysis of affected relative pairs. Am. J. Hum. Genet. 16:242-253.
	Risch, N. and Zhang, H. 1995. Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science 268:1584-1589.
	Risch, N., Claus, E., and Giuffra, L. 1989. Linkage and mode of inheritancein complex traits. Prog. Clin. Biol. Res. 329:183-188.
	Rosner, B. 1982. Fundamentals of Biostatistics pp. 317- 323. Duxbury Press, Boston.
	SAGE. 1997. Statistical Analysis for Genetic Epidemiology, Release 3.1. Computer program available from the Department of Epidemiology and Biostatistics, MetroHealth Campus, Case Western Reserve University, Cleveland.
	Sawcer, S., Jones, H.B., Judge, D., Visser, F., Compston, A., Goodfellow, P.N., and Clayton, D. 1997. Empirical genomewide significance levels established by wholegenome simulators. Genet. Epidemiol. 14:223-229.
	Schaid, D.J. and Nick, T.G. 1990. Sib-pair linkage tests for disease susceptibility loci: Common tests vs. the asymptotically most powerful tests. Genet. Epidemiol. 7:359-370.
	Suarez, B.K. and Van Eerdewegh, P. 1984. A comparison of three affected-sib-pair scoring methods to detect HLA-linked disease susceptibility genes. Am. J. Med. Genet. 18:135-146.
	Suarez, B.K., Rice, J., and Reich, T. 1978. The generalized sib pair IBD distribution: Its use in the detection of linkage. Ann. Hum. Genet. Lond. 42:87-94.
	Terwilliger, J.D. and Ott, J. 1994. Handbook of Human Genetic Linkage. Johns Hopkins University Press, Baltimore.
	Weeks, D.E. and Lange, K. 1988. The affected-pedigree-member method of linkage analysis. Am. J. Hum. Genet. 42:315-326.
	Weeks, D.E. and Lange, K. 1992. A multilocus extension of the affected-pedigree-member method of linkage analysis. Am. J. Hum. Genet. 50:859-868.
	Weeks, D.E., Lehner, T., Squires-Wheeler, E., Kaufman, C., Ott, J. 1990. Measuring the inflation of the lod score due to its maximization over model parameters in human linkage analysis. Genet. Epidemiol. 7:237-243.
	Weeks, D.E., Valappil, T.I., Schroeder, M., and Brown, D.L. 1995. An X-linked version of the affected-pedigree-member method of linkage analysis. Hum. Hered. 46:25-33.
	Whittemore, A.S. 1996. Genome scanning for linkage: An overview. Am. J. Hum. Genet. 59:704-716.
	Wijsman, E.M. and Amos, C.I. 1997. Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: Summary of GAW10 contributions. Genet. Epidemiol. 14:719-735.
	Zinn-Justin, A. and Abel, L. 1999. Introduction of the IBD information into the weighted pairwise correlation method for linkage analysis. Genet. Epidemiol. 17:35-50.