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. 1993 Oct;53(4):908–915.

Two-locus models of disease: comparison of likelihood and nonparametric linkage methods.

L R Goldin 1, D E Weeks 1
PMCID: PMC1682376  PMID: 8213819

Abstract

The power to detect linkage for likelihood and nonparametric (Haseman-Elston, affected-sib-pair, and affected-pedigree-member) methods is compared for the case of a common, dichotomous trait resulting from the segregation of two loci. Pedigree data for several two-locus epistatic and heterogeneity models have been simulated, with one of the loci linked to a marker locus. Replicate samples of 20 three-generation pedigrees (16 individuals/pedigree) were simulated and then ascertained for having at least 6 affected individuals. The power of linkage detection calculated under the correct two-locus model is only slightly higher than that under a single locus model with reduced penetrance. As expected, the nonparametric linkage methods have somewhat lower power than does the lod-score method, the difference depending on the mode of transmission of the linked locus. Thus, for many pedigree linkage studies, the lod-score method will have the best power. However, this conclusion depends on how many times the lod score will be calculated for a given marker. The Haseman-Elston method would likely be preferable to calculating lod scores under a large number of genetic models (i.e., varying both the mode of transmission and the penetrances), since such an analysis requires an increase in the critical value of the lod criterion. The power of the affected-pedigree-member method is lower than the other methods, which can be shown to be largely due to the fact that marker genotypes for unaffected individuals are not used.

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Selected References

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  1. Amos C. I., Elston R. C. Robust methods for the detection of genetic linkage for quantitative data from pedigrees. Genet Epidemiol. 1989;6(2):349–360. doi: 10.1002/gepi.1370060205. [DOI] [PubMed] [Google Scholar]
  2. Blackwelder W. C., Elston R. C. A comparison of sib-pair linkage tests for disease susceptibility loci. Genet Epidemiol. 1985;2(1):85–97. doi: 10.1002/gepi.1370020109. [DOI] [PubMed] [Google Scholar]
  3. Chotai J. On the lod score method in linkage analysis. Ann Hum Genet. 1984 Oct;48(Pt 4):359–378. doi: 10.1111/j.1469-1809.1984.tb00849.x. [DOI] [PubMed] [Google Scholar]
  4. Clerget-Darpoux F., Babron M. C., Bonaïti-Pellié C. Assessing the effect of multiple linkage tests in complex diseases. Genet Epidemiol. 1990;7(4):245–253. doi: 10.1002/gepi.1370070403. [DOI] [PubMed] [Google Scholar]
  5. Clerget-Darpoux F., Bonaïti-Pellié C., Hochez J. Effects of misspecifying genetic parameters in lod score analysis. Biometrics. 1986 Jun;42(2):393–399. [PubMed] [Google Scholar]
  6. Gershon E. S., Hamovit J., Guroff J. J., Dibble E., Leckman J. F., Sceery W., Targum S. D., Nurnberger J. I., Jr, Goldin L. R., Bunney W. E., Jr A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry. 1982 Oct;39(10):1157–1167. doi: 10.1001/archpsyc.1982.04290100031006. [DOI] [PubMed] [Google Scholar]
  7. Goldin L. R. Detection of linkage under heterogeneity: comparison of the two-locus vs. admixture models. Genet Epidemiol. 1992;9(1):61–66. doi: 10.1002/gepi.1370090107. [DOI] [PubMed] [Google Scholar]
  8. Greenberg D. A. A simple method for testing two-locus models of inheritance. Am J Hum Genet. 1981 Jul;33(4):519–530. [PMC free article] [PubMed] [Google Scholar]
  9. Haseman J. K., Elston R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. doi: 10.1007/BF01066731. [DOI] [PubMed] [Google Scholar]
  10. MacLean C. J., Bishop D. T., Sherman S. L., Diehl S. R. Distribution of lod scores under uncertain mode of inheritance. Am J Hum Genet. 1993 Feb;52(2):354–361. [PMC free article] [PubMed] [Google Scholar]
  11. Martinez M., Goldin L. R. Power of the linkage test for a heterogeneous disorder due to two independent inherited causes: a simulation study. Genet Epidemiol. 1990;7(3):219–230. doi: 10.1002/gepi.1370070306. [DOI] [PubMed] [Google Scholar]
  12. Neuman R. J., Rice J. P. Two-locus models of disease. Genet Epidemiol. 1992;9(5):347–365. doi: 10.1002/gepi.1370090506. [DOI] [PubMed] [Google Scholar]
  13. Olson J. M., Wijsman E. M. Linkage between quantitative trait and marker loci: methods using all relative pairs. Genet Epidemiol. 1993;10(2):87–102. doi: 10.1002/gepi.1370100202. [DOI] [PubMed] [Google Scholar]
  14. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222–228. [PMC free article] [PubMed] [Google Scholar]
  15. Vieland V. J., Hodge S. E., Greenberg D. A. Adequacy of single-locus approximations for linkage analyses of oligogenic traits. Genet Epidemiol. 1992;9(1):45–59. doi: 10.1002/gepi.1370090106. [DOI] [PubMed] [Google Scholar]
  16. Weeks D. E., Lange K. The affected-pedigree-member method of linkage analysis. Am J Hum Genet. 1988 Feb;42(2):315–326. [PMC free article] [PubMed] [Google Scholar]
  17. Weeks D. E., Lehner T., Squires-Wheeler E., Kaufmann C., Ott J. Measuring the inflation of the lod score due to its maximization over model parameter values in human linkage analysis. Genet Epidemiol. 1990;7(4):237–243. doi: 10.1002/gepi.1370070402. [DOI] [PubMed] [Google Scholar]

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