Abstract
The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (linkage disequilibrium). The test does not require parental data but requires discordant sibships with at least one affected and one unaffected sibling. The SDT has many desirable properties: it uses all the siblings in the sibship; it remains valid if there are misclassifications of the affectation status; it does not detect spurious associations due to population stratification; asymptotically it has a chi2 distribution under the null hypothesis; and exact P values can be easily computed for a biallelic marker. We show how to extend the SDT to markers with multiple alleles and how to combine families with parents and data from discordant sibships. We discuss the power of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficiency (which is approximately the ratio of sample sizes) between SDT and the transmission/disequilibrium test (TDT) for special family structures. For sib pairs, we compare the SDT to a test proposed both by Curtis and, independently, by Spielman and Ewens. We show that, for discordant sib pairs, the SDT has good power for testing linkage disequilibrium relative both to Curtis's tests and to the TDT using trios comprising an affected sib and its parents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalence >.3.
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Selected References
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- Boehnke M., Langefeld C. D. Genetic association mapping based on discordant sib pairs: the discordant-alleles test. Am J Hum Genet. 1998 Apr;62(4):950–961. doi: 10.1086/301787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cleves M. A., Olson J. M., Jacobs K. B. Exact transmission-disequilibrium tests with multiallelic markers. Genet Epidemiol. 1997;14(4):337–347. doi: 10.1002/(SICI)1098-2272(1997)14:4<337::AID-GEPI1>3.0.CO;2-0. [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]
- Curtis D. Use of siblings as controls in case-control association studies. Ann Hum Genet. 1997 Jul;61(Pt 4):319–333. doi: 10.1046/j.1469-1809.1998.6210089.x. [DOI] [PubMed] [Google Scholar]
- Laird N. M., Blacker D., Wilcox M. The sib transmission/disequilibrium test is a Mantel-Haenszel test. Am J Hum Genet. 1998 Dec;63(6):1915–1916. doi: 10.1086/302151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MANTEL N., HAENSZEL W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959 Apr;22(4):719–748. [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]
- Ott J. Statistical properties of the haplotype relative risk. Genet Epidemiol. 1989;6(1):127–130. doi: 10.1002/gepi.1370060124. [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]
- 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]
- Suarez B. K., Reich T., Trost J. Limits of the general two-allele single locus model with incomplete penetrance. Ann Hum Genet. 1976 Nov;40(2):231–243. doi: 10.1111/j.1469-1809.1976.tb00186.x. [DOI] [PubMed] [Google Scholar]
- Thomson G. Analysis of complex human genetic traits: an ordered-notation method and new tests for mode of inheritance. Am J Hum Genet. 1995 Aug;57(2):474–486. [PMC free article] [PubMed] [Google Scholar]