Abstract
Molecular geneticists are developing the third-generation human genome map with single-nucleotide polymorphisms (SNPs), which can be assayed via chip-based microarrays. One use of these SNP markers is the ability to locate loci that may be responsible for complex traits, via linkage/linkage-disequilibrium analysis. In this communication, we describe a semiparametric method for combined linkage/linkage-disequilibrium analysis using SNP markers. Asymptotic results are obtained for the estimated parameters, and the finite-sample properties are evaluated via a simulation study. We also applied this technique to a simulated genome-scan experiment for mapping a complex trait with two major genes. This experiment shows that separate linkage and linkage-disequilibrium analyses correctly detected the signals of both major genes; but the rates of false-positive signals seem high. When linkage and linkage-disequilibrium signals were combined, the analysis yielded much stronger and clearer signals for the presence of two major genes than did two separate analyses.
Full Text
The Full Text of this article is available as a PDF (758.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Chee M., Yang R., Hubbell E., Berno A., Huang X. C., Stern D., Winkler J., Lockhart D. J., Morris M. S., Fodor S. P. Accessing genetic information with high-density DNA arrays. Science. 1996 Oct 25;274(5287):610–614. doi: 10.1126/science.274.5287.610. [DOI] [PubMed] [Google Scholar]
- Devlin B., Risch N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics. 1995 Sep 20;29(2):311–322. doi: 10.1006/geno.1995.9003. [DOI] [PubMed] [Google Scholar]
- Donis-Keller H., Green P., Helms C., Cartinhour S., Weiffenbach B., Stephens K., Keith T. P., Bowden D. W., Smith D. R., Lander E. S. A genetic linkage map of the human genome. Cell. 1987 Oct 23;51(2):319–337. doi: 10.1016/0092-8674(87)90158-9. [DOI] [PubMed] [Google Scholar]
- Ewens W. J., Spielman R. S. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995 Aug;57(2):455–464. [PMC free article] [PubMed] [Google Scholar]
- Guo S. W. Linkage disequilibrium measures for fine-scale mapping: a comparison. Hum Hered. 1997 Nov-Dec;47(6):301–314. doi: 10.1159/000154430. [DOI] [PubMed] [Google Scholar]
- Kruglyak L., Daly M. J., Lander E. S. Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping. Am J Hum Genet. 1995 Feb;56(2):519–527. [PMC free article] [PubMed] [Google Scholar]
- Kruglyak L., Lander E. S. High-resolution genetic mapping of complex traits. Am J Hum Genet. 1995 May;56(5):1212–1223. [PMC free article] [PubMed] [Google Scholar]
- Kruglyak L. The use of a genetic map of biallelic markers in linkage studies. Nat Genet. 1997 Sep;17(1):21–24. doi: 10.1038/ng0997-21. [DOI] [PubMed] [Google Scholar]
- Martin E. R., Kaplan N. L., Weir B. S. Tests for linkage and association in nuclear families. Am J Hum Genet. 1997 Aug;61(2):439–448. doi: 10.1086/514860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray J. C., Buetow K. H., Weber J. L., Ludwigsen S., Scherpbier-Heddema T., Manion F., Quillen J., Sheffield V. C., Sunden S., Duyk G. M. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science. 1994 Sep 30;265(5181):2049–2054. doi: 10.1126/science.8091227. [DOI] [PubMed] [Google Scholar]
- Ott E. Contemporary mechanics: hamiltonian systems. Science. 1989 Sep 29;245(4925):1516–1516. doi: 10.1126/science.245.4925.1516. [DOI] [PubMed] [Google Scholar]
- Schaid D. J., Sommer S. S. Comparison of statistics for candidate-gene association studies using cases and parents. Am J Hum Genet. 1994 Aug;55(2):402–409. [PMC free article] [PubMed] [Google Scholar]
- Self S. G., Longton G., Kopecky K. J., Liang K. Y. On estimating HLA/disease association with application to a study of aplastic anemia. Biometrics. 1991 Mar;47(1):53–61. [PubMed] [Google Scholar]
- Spielman R. S., McGinnis R. E., Ewens W. J. The transmission/disequilibrium test detects cosegregation and linkage. Am J Hum Genet. 1994 Mar;54(3):559–563. [PMC free article] [PubMed] [Google Scholar]
- Terwilliger J. D., Shannon W. D., Lathrop G. M., Nolan J. P., Goldin L. R., Chase G. A., Weeks D. E. True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage mapping. Am J Hum Genet. 1997 Aug;61(2):430–438. doi: 10.1086/514855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang D. G., Fan J. B., Siao C. J., Berno A., Young P., Sapolsky R., Ghandour G., Perkins N., Winchester E., Spencer J. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science. 1998 May 15;280(5366):1077–1082. doi: 10.1126/science.280.5366.1077. [DOI] [PubMed] [Google Scholar]
- Whittemore A. S. Genome scanning for linkage: an overview. Am J Hum Genet. 1996 Sep;59(3):704–716. [PMC free article] [PubMed] [Google Scholar]
- Xiong M., Guo S. W. Fine-scale genetic mapping based on linkage disequilibrium: theory and applications. Am J Hum Genet. 1997 Jun;60(6):1513–1531. doi: 10.1086/515475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhao L. P., Grove J., Quiaoit F. A method for assessing patterns of familial resemblance in complex human pedigrees, with an application to the nevus-count data in Utah kindreds. Am J Hum Genet. 1992 Jul;51(1):178–190. [PMC free article] [PubMed] [Google Scholar]
- Zhao L. P., Quiaoit F., Hsu L., Aragaki C. Efficient, robust, and unified method for mapping complex traits (I): two-point linkage analysis. Am J Med Genet. 1998 Jun 5;77(5):366–383. [PubMed] [Google Scholar]