Abstract
Optimal design of quantitative-trait loci (QTL) mapping studies requires a precise understanding of the power of QTL linkage versus QTL association analysis, under a range of different conditions. In this article, we investigate the power of QTL linkage and association analyses for simple random sibship samples, under the variance-components model proposed by Fulker et al. After a brief description of an extension of this variance-components model, we show that the powers of both linkage and association analyses are crucially dependent on the proportion of phenotypic variance attributable to the QTL. The main difference between the two tests is that, whereas the power of association is directly related to the QTL heritability, the power of linkage is related more closely to the square of the QTL heritability. We also describe both how the power of linkage is attenuated by incomplete linkage and incomplete marker information and how the power of association is attenuated by incomplete linkage disequilibrium.
Full Text
The Full Text of this article is available as a PDF (243.3 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allison D. B., Neale M. C., Zannolli R., Schork N. J., Amos C. I., Blangero J. Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. Am J Hum Genet. 1999 Aug;65(2):531–544. doi: 10.1086/302487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Allison D. B., Thiel B., St Jean P., Elston R. C., Infante M. C., Schork N. J. Multiple phenotype modeling in gene-mapping studies of quantitative traits: power advantages. Am J Hum Genet. 1998 Oct;63(4):1190–1201. doi: 10.1086/302038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Almasy L., Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998 May;62(5):1198–1211. doi: 10.1086/301844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Botstein D., White R. L., Skolnick M., Davis R. W. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet. 1980 May;32(3):314–331. [PMC free article] [PubMed] [Google Scholar]
- Chapman N. H., Wijsman E. M. Genome screens using linkage disequilibrium tests: optimal marker characteristics and feasibility. Am J Hum Genet. 1998 Dec;63(6):1872–1885. doi: 10.1086/302139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Comuzzie A. G., Mahaney M. C., Almasy L., Dyer T. D., Blangero J. Exploiting pleiotropy to map genes for oligogenic phenotypes using extended pedigree data. Genet Epidemiol. 1997;14(6):975–980. doi: 10.1002/(SICI)1098-2272(1997)14:6<975::AID-GEPI69>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
- Dolan C. V., Boomsma D. I. Optimal selection of sib pairs from random samples for linkage analysis of a QTL using the EDAC test. Behav Genet. 1998 May;28(3):197–206. doi: 10.1023/a:1021423214032. [DOI] [PubMed] [Google Scholar]
- Eaves L. J., Neale M. C., Maes H. Multivariate multipoint linkage analysis of quantitative trait loci. Behav Genet. 1996 Sep;26(5):519–525. doi: 10.1007/BF02359757. [DOI] [PubMed] [Google Scholar]
- Eaves L., Meyer J. Locating human quantitative trait loci: guidelines for the selection of sibling pairs for genotyping. Behav Genet. 1994 Sep;24(5):443–455. doi: 10.1007/BF01076180. [DOI] [PubMed] [Google Scholar]
- Fulker D. W., Cherny S. S. An improved multipoint sib-pair analysis of quantitative traits. Behav Genet. 1996 Sep;26(5):527–532. doi: 10.1007/BF02359758. [DOI] [PubMed] [Google Scholar]
- Fulker D. W., Cherny S. S., Cardon L. R. Multipoint interval mapping of quantitative trait loci, using sib pairs. Am J Hum Genet. 1995 May;56(5):1224–1233. [PMC free article] [PubMed] [Google Scholar]
- Fulker D. W., Cherny S. S., Sham P. C., Hewitt J. K. Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet. 1999 Jan;64(1):259–267. doi: 10.1086/302193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Halushka M. K., Fan J. B., Bentley K., Hsie L., Shen N., Weder A., Cooper R., Lipshutz R., Chakravarti A. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet. 1999 Jul;22(3):239–247. doi: 10.1038/10297. [DOI] [PubMed] [Google Scholar]
- Harpending H. C., Batzer M. A., Gurven M., Jorde L. B., Rogers A. R., Sherry S. T. Genetic traces of ancient demography. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1961–1967. doi: 10.1073/pnas.95.4.1961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Jorde L. B., Watkins W. S., Carlson M., Groden J., Albertsen H., Thliveris A., Leppert M. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am J Hum Genet. 1994 May;54(5):884–898. [PMC free article] [PubMed] [Google Scholar]
- Kruglyak L., Lander E. S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995 Aug;57(2):439–454. [PMC free article] [PubMed] [Google Scholar]
- Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999 Jun;22(2):139–144. doi: 10.1038/9642. [DOI] [PubMed] [Google Scholar]
- MORTON N. E. Sequential tests for the detection of linkage. Am J Hum Genet. 1955 Sep;7(3):277–318. [PMC free article] [PubMed] [Google Scholar]
- Martin N., Boomsma D., Machin G. A twin-pronged attack on complex traits. Nat Genet. 1997 Dec;17(4):387–392. doi: 10.1038/ng1297-387. [DOI] [PubMed] [Google Scholar]
- Morton N. E., Wu D. Alternative bioassays of kinship between loci. Am J Hum Genet. 1988 Jan;42(1):173–177. [PMC free article] [PubMed] [Google Scholar]
- Ohta T., Kimura M. Linkage disequilibrium at steady state determined by random genetic drift and recurrent mutation. Genetics. 1969 Sep;63(1):229–238. doi: 10.1093/genetics/63.1.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Risch N. J., Zhang H. Mapping quantitative trait loci with extreme discordant sib pairs: sampling considerations. Am J Hum Genet. 1996 Apr;58(4):836–843. [PMC free article] [PubMed] [Google Scholar]
- Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
- 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]
- Schork N. J. 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] [Google Scholar]
- Sved J. A. Linkage disequilibrium and homozygosity of chromosome segments in finite populations. Theor Popul Biol. 1971 Jun;2(2):125–141. doi: 10.1016/0040-5809(71)90011-6. [DOI] [PubMed] [Google Scholar]
- Todorov A. A., Vogler G. P., Gu C., Province M. A., Li Z., Heath A. C., Rao D. C. Testing causal hypotheses in multivariate linkage analysis of quantitative traits: general formulation and application to sibpair data. Genet Epidemiol. 1998;15(3):263–278. doi: 10.1002/(SICI)1098-2272(1998)15:3<263::AID-GEPI5>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
- Vogler G. P., Tang W., Nelson T. L., Hofer S. M., Grant J. D., Tarantino L. M., Fernandez J. R. A multivariate model for the analysis of sibship covariance structure using marker information and multiple quantitative traits. Genet Epidemiol. 1997;14(6):921–926. doi: 10.1002/(SICI)1098-2272(1997)14:6<921::AID-GEPI60>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]