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Am J Hum Genet. May 1998; 62(5): 1198–1211.
PMCID: PMC1377101

Multipoint quantitative-trait linkage analysis in general pedigrees.

Abstract

Multipoint linkage analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component linkage analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.

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Selected References

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  • Almasy L, Dyer TD, Blangero J. Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet Epidemiol. 1997;14(6):953–958. [PubMed]
  • Amos CI. Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet. 1994 Mar;54(3):535–543. [PMC free article] [PubMed]
  • Amos CI, Dawson DV, Elston RC. The probabilistic determination of identity-by-descent sharing for pairs of relatives from pedigrees. Am J Hum Genet. 1990 Nov;47(5):842–853. [PMC free article] [PubMed]
  • Amos CI, Zhu DK, Boerwinkle E. Assessing genetic linkage and association with robust components of variance approaches. Ann Hum Genet. 1996 Mar;60(Pt 2):143–160. [PubMed]
  • Beaty TH, Self SG, Liang KY, Connolly MA, Chase GA, Kwiterovich PO. Use of robust variance components models to analyse triglyceride data in families. Ann Hum Genet. 1985 Oct;49(Pt 4):315–328. [PubMed]
  • Blangero J. Statistical genetic approaches to human adaptability. Hum Biol. 1993 Dec;65(6):941–966. [PubMed]
  • Blangero J, Almasy L. Multipoint oligogenic linkage analysis of quantitative traits. Genet Epidemiol. 1997;14(6):959–964. [PubMed]
  • Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet. 1997 Mar;15(3):273–276. [PubMed]
  • Davis S, Schroeder M, Goldin LR, Weeks DE. Nonparametric simulation-based statistics for detecting linkage in general pedigrees. Am J Hum Genet. 1996 Apr;58(4):867–880. [PMC free article] [PubMed]
  • Duggirala R, Williams JT, Williams-Blangero S, Blangero J. A variance component approach to dichotomous trait linkage analysis using a threshold model. Genet Epidemiol. 1997;14(6):987–992. [PubMed]
  • Elston RC, Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21(6):523–542. [PubMed]
  • Feingold E, Brown PO, Siegmund D. Gaussian models for genetic linkage analysis using complete high-resolution maps of identity by descent. Am J Hum Genet. 1993 Jul;53(1):234–251. [PMC free article] [PubMed]
  • Fulker DW, Cherny SS. An improved multipoint sib-pair analysis of quantitative traits. Behav Genet. 1996 Sep;26(5):527–532. [PubMed]
  • Fulker DW, Cherny SS, Cardon LR. Multipoint interval mapping of quantitative trait loci, using sib pairs. Am J Hum Genet. 1995 May;56(5):1224–1233. [PMC free article] [PubMed]
  • Goldgar DE. Multipoint analysis of human quantitative genetic variation. Am J Hum Genet. 1990 Dec;47(6):957–967. [PMC free article] [PubMed]
  • Haseman JK, Elston RC. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. [PubMed]
  • Heath SC. Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am J Hum Genet. 1997 Sep;61(3):748–760. [PMC free article] [PubMed]
  • Heath SC, Snow GL, Thompson EA, Tseng C, Wijsman EM. MCMC segregation and linkage analysis. Genet Epidemiol. 1997;14(6):1011–1016. [PubMed]
  • Hopper JL, Mathews JD. Extensions to multivariate normal models for pedigree analysis. Ann Hum Genet. 1982 Oct;46(Pt 4):373–383. [PubMed]
  • Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed]
  • Kruglyak L, Lander ES. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995 Aug;57(2):439–454. [PMC free article] [PubMed]
  • Lander ES, Green P. Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2363–2367. [PMC free article] [PubMed]
  • Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. [PubMed]
  • Lange K, Weeks D, Boehnke M. Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol. 1988;5(6):471–472. [PubMed]
  • Lange K, Westlake J, Spence MA. Extensions to pedigree analysis. III. Variance components by the scoring method. Ann Hum Genet. 1976 May;39(4):485–491. [PubMed]
  • Schork NJ. Extended multipoint identity-by-descent analysis of human quantitative traits: efficiency, power, and modeling considerations. Am J Hum Genet. 1993 Dec;53(6):1306–1319. [PMC free article] [PubMed]
  • Sobel E, Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet. 1996 Jun;58(6):1323–1337. [PMC free article] [PubMed]
  • Stern MP, Duggirala R, Mitchell BD, Reinhart LJ, Shivakumar S, Shipman PA, Uresandi OC, Benavides E, Blangero J, O'Connell P. Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans. Genome Res. 1996 Aug;6(8):724–734. [PubMed]
  • Terwilliger JD, Speer M, Ott J. Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol. 1993;10(4):217–224. [PubMed]
  • Todorov AA, Siegmund KD, Gu C, Borecki IB, Elston RC. Probabilities of identity-by-descent patterns in sibships when the parents are not genotyped. Genet Epidemiol. 1997;14(6):909–913. [PubMed]
  • Towne B, Siervogel RM, Blangero J. Effects of genotype-by-sex interaction on quantitative trait linkage analysis. Genet Epidemiol. 1997;14(6):1053–1058. [PubMed]
  • Whittemore AS, Halpern J. Probability of gene identity by descent: computation and applications. Biometrics. 1994 Mar;50(1):109–117. [PubMed]
  • Wijsman EM, Amos CI. Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions. Genet Epidemiol. 1997;14(6):719–735. [PubMed]
  • Williams JT, Duggirala R, Blangero J. Statistical properties of a variance components method for quantitative trait linkage analysis in nuclear families and extended pedigrees. Genet Epidemiol. 1997;14(6):1065–1070. [PubMed]

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