Abstract
Linkage analysis with genetic markers has been successful in the localization of genes for many monogenic human diseases. In studies of complex diseases, however, tests that rely on linkage disequilibrium (the simultaneous presence of linkage and association) are often more powerful than those that rely on linkage alone. This advantage is illustrated by the transmission/disequilibrium test (TDT). The TDT requires data (marker genotypes) for affected individuals and their parents; for some diseases, however, data from parents may be difficult or impossible to obtain. In this article, we describe a method, called the "sib TDT" (or "S-TDT"), that overcomes this problem by use of marker data from unaffected sibs instead of from parents, thus allowing application of the principle of the TDT to sibships without parental data. In a single collection of families, there might be some that can be analyzed only by the TDT and others that are suitable for analysis by the S-TDT. We show how all the data may be used jointly in one overall TDT-type procedure that tests for linkage in the presence of association. These extensions of the TDT will be valuable for the study of diseases of late onset, such as non-insulin-dependent diabetes, cardiovascular diseases, and other diseases associated with aging.
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Selected References
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- Bell G. I., Horita S., Karam J. H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984 Feb;33(2):176–183. doi: 10.2337/diab.33.2.176. [DOI] [PubMed] [Google Scholar]
- Cox N. J., Spielman R. S. The insulin gene and susceptibility to IDDM. Genet Epidemiol. 1989;6(1):65–69. doi: 10.1002/gepi.1370060113. [DOI] [PubMed] [Google Scholar]
- Curtis D., Sham P. C. A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet. 1995 Mar;56(3):811–812. [PMC free article] [PubMed] [Google Scholar]
- Duffy D. L. Screening a 2 cM genetic map for allelic association: a simulated oligogenic trait. Genet Epidemiol. 1995;12(6):595–600. doi: 10.1002/gepi.1370120612. [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]
- Harley J. B., Moser K. L., Neas B. R. Logistic transmission modeling of simulated data. Genet Epidemiol. 1995;12(6):607–612. doi: 10.1002/gepi.1370120614. [DOI] [PubMed] [Google Scholar]
- Hodge S. E. An oliogenic disease displaying weak marker associations: a summary of contributions to problem 1 of GAW9. Genet Epidemiol. 1995;12(6):545–554. doi: 10.1002/gepi.1370120604. [DOI] [PubMed] [Google Scholar]
- Julier C., Hyer R. N., Davies J., Merlin F., Soularue P., Briant L., Cathelineau G., Deschamps I., Rotter J. I., Froguel P. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature. 1991 Nov 14;354(6349):155–159. doi: 10.1038/354155a0. [DOI] [PubMed] [Google Scholar]
- Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
- McGinnis R. E., Ewens W. J., Spielman R. S. The TDT reveals linkage and linkage disequilibrium in a rare disease. Genet Epidemiol. 1995;12(6):637–640. doi: 10.1002/gepi.1370120619. [DOI] [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]
- Schaid D. J. General score tests for associations of genetic markers with disease using cases and their parents. Genet Epidemiol. 1996;13(5):423–449. doi: 10.1002/(SICI)1098-2272(1996)13:5<423::AID-GEPI1>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
- Sham P. C., Curtis D. An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet. 1995 Jul;59(Pt 3):323–336. doi: 10.1111/j.1469-1809.1995.tb00751.x. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]