Skip to main content
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Apr;64(4):1194–1205. doi: 10.1086/302331

Comparison of linkage-disequilibrium methods for localization of genes influencing quantitative traits in humans.

G P Page 1, C I Amos 1
PMCID: PMC1377844  PMID: 10090905

Abstract

Linkage disequilibrium has been used to help in the identification of genes predisposing to certain qualitative diseases. Although several linkage-disequilibrium tests have been developed for localization of genes influencing quantitative traits, these tests have not been thoroughly compared with one another. In this report we compare, under a variety of conditions, several different linkage-disequilibrium tests for identification of loci affecting quantitative traits. These tests use either single individuals or parent-child trios. When we compared tests with equal samples, we found that the truncated measured allele (TMA) test was the most powerful. The trait allele frequencies, the stringency of sample ascertainment, the number of marker alleles, and the linked genetic variance affected the power, but the presence of polygenes did not. When there were more than two trait alleles at a locus in the population, power to detect disequilibrium was greatly diminished. The presence of unlinked disequilibrium (D'*) increased the false-positive error rates of disequilibrium tests involving single individuals but did not affect the error rates of tests using family trios. The increase in error rates was affected by the stringency of selection, the trait allele frequency, and the linked genetic variance but not by polygenic factors. In an equilibrium population, the TMA test is most powerful, but, when adjusted for the presence of admixture, Allison test 3 becomes the most powerful whenever D'*>.15.

Full Text

The Full Text of this article is available as a PDF (288.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abel L., Müller-Myhsok B. Maximum-likelihood expression of the transmission/disequilibrium test and power considerations. Am J Hum Genet. 1998 Aug;63(2):664–667. doi: 10.1086/301975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allison D. B., Heo M., Schork N. J., Wong S. L., Elston R. C. Extreme selection strategies in gene mapping studies of oligogenic quantitative traits do not always increase power. Hum Hered. 1998 Mar-Apr;48(2):97–107. doi: 10.1159/000022788. [DOI] [PubMed] [Google Scholar]
  3. Allison D. B. Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet. 1997 Mar;60(3):676–690. [PMC free article] [PubMed] [Google Scholar]
  4. Amos C. I. Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet. 1994 Mar;54(3):535–543. [PMC free article] [PubMed] [Google Scholar]
  5. Boerwinkle E., Chakraborty R., Sing C. F. The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods. Ann Hum Genet. 1986 May;50(Pt 2):181–194. doi: 10.1111/j.1469-1809.1986.tb01037.x. [DOI] [PubMed] [Google Scholar]
  6. Boerwinkle E., Menzel H. J., Kraft H. G., Utermann G. Genetics of the quantitative Lp(a) lipoprotein trait. III. Contribution of Lp(a) glycoprotein phenotypes to normal lipid variation. Hum Genet. 1989 Apr;82(1):73–78. doi: 10.1007/BF00288277. [DOI] [PubMed] [Google Scholar]
  7. Boerwinkle E., Visvikis S., Welsh D., Steinmetz J., Hanash S. M., Sing C. F. The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals. Am J Med Genet. 1987 Jul;27(3):567–582. doi: 10.1002/ajmg.1320270310. [DOI] [PubMed] [Google Scholar]
  8. Dean M., Stephens J. C., Winkler C., Lomb D. A., Ramsburg M., Boaze R., Stewart C., Charbonneau L., Goldman D., Albaugh B. J. Polymorphic admixture typing in human ethnic populations. Am J Hum Genet. 1994 Oct;55(4):788–808. [PMC free article] [PubMed] [Google Scholar]
  9. Funke H., Rust S., Assmann G. Detection of apolipoprotein E variants by an oligonucleotide "melting" procedure. Clin Chem. 1986 Jul;32(7):1285–1289. [PubMed] [Google Scholar]
  10. Hästbacka J., de la Chapelle A., Mahtani M. M., Clines G., Reeve-Daly M. P., Daly M., Hamilton B. A., Kusumi K., Trivedi B., Weaver A. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 1994 Sep 23;78(6):1073–1087. doi: 10.1016/0092-8674(94)90281-x. [DOI] [PubMed] [Google Scholar]
  11. Kaplan N. L., Martin E. R., Weir B. S. Power studies for the transmission/disequilibrium tests with multiple alleles. Am J Hum Genet. 1997 Mar;60(3):691–702. [PMC free article] [PubMed] [Google Scholar]
  12. Lander E. S., Botstein D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics. 1989 Jan;121(1):185–199. doi: 10.1093/genetics/121.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  14. Nickerson D. A., Taylor S. L., Weiss K. M., Clark A. G., Hutchinson R. G., Stengård J., Salomaa V., Vartiainen E., Boerwinkle E., Sing C. F. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet. 1998 Jul;19(3):233–240. doi: 10.1038/907. [DOI] [PubMed] [Google Scholar]
  15. Ott J., Rabinowitz D. The effect of marker heterozygosity on the power to detect linkage disequilibrium. Genetics. 1997 Oct;147(2):927–930. doi: 10.1093/genetics/147.2.927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Page G. P., Amos C. I., Boerwinkle E. The quantitative LOD score: test statistic and sample size for exclusion and linkage of quantitative traits in human sibships. Am J Hum Genet. 1998 Apr;62(4):962–968. doi: 10.1086/301783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rabinowitz D. A transmission disequilibrium test for quantitative trait loci. Hum Hered. 1997 Nov-Dec;47(6):342–350. doi: 10.1159/000154433. [DOI] [PubMed] [Google Scholar]
  18. Risch N., Zhang H. Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science. 1995 Jun 16;268(5217):1584–1589. doi: 10.1126/science.7777857. [DOI] [PubMed] [Google Scholar]
  19. Spielman R. S., Ewens W. J. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet. 1996 Nov;59(5):983–989. [PMC free article] [PubMed] [Google Scholar]
  20. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  21. Surguchov A. P., Page G. P., Smith L., Patsch W., Boerwinkle E. Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):941–947. doi: 10.1161/01.atv.16.8.941. [DOI] [PubMed] [Google Scholar]
  22. Traeger-Synodinos J., Mavroidis N., Kanavakis E., Drogari E., Humphries S. E., Day I. N., Kattamis C., Matsaniotis N. Analysis of low density lipoprotein receptor gene mutations and microsatellite haplotypes in Greek FH heterozygous children: six independent ancestors account for 60% of probands. Hum Genet. 1998 Mar;102(3):343–347. doi: 10.1007/s004390050703. [DOI] [PubMed] [Google Scholar]
  23. Wang J., Freeman D. J., Grundy S. M., Levine D. M., Guerra R., Cohen J. C. Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J Clin Invest. 1998 Mar 15;101(6):1283–1291. doi: 10.1172/JCI1343. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES