Removing the sampling restrictions from family-based tests of association for a quantitative-trait locus.

One strategy for localization of a quantitative-trait locus (QTL) is to test whether the distribution of a quantitative trait depends on the number of copies of a specific genetic-marker allele that an individual possesses. This approach tests for association between alleles at the marker and the QTL, and it assumes that association is a consequence of the marker being physically close to the QTL. However, problems can occur when data are not from a homogeneous population, since associations can arise irrespective of a genetic marker being in physical proximity to the QTL-that is, no information is gained regarding localization. Methods to address this problem have recently been proposed. These proposed methods use family data for indirect stratification of a population, thereby removing the effect of associations that are due to unknown population substructure. They are, however, restricted in terms of the number of children per family that can be used in the analysis. Here we introduce tests that can be used on family data with parent and child genotypes, with child genotypes only, or with a combination of these types of families, without size restrictions. Furthermore, equations that allow one to determine the sample size needed to achieve desired power are derived. By means of simulation, we demonstrate that the existing tests have an elevated false-positive rate when the size restrictions are not followed and that a good deal of information is lost as a result of adherence to the size restrictions. Finally, we introduce permutation procedures that are recommended for small samples but that can also be used for extensions of the tests to multiallelic markers and to the simultaneous use of more than one marker.

[1]  D. Schaid General score tests for associations of genetic markers with disease using cases and their parents , 1996, Genetic epidemiology.

[2]  W. Ewens,et al.  The transmission/disequilibrium test: history, subdivision, and admixture. , 1995, American journal of human genetics.

[3]  N M Laird,et al.  A discordant-sibship test for disequilibrium and linkage: no need for parental data. , 1998, American journal of human genetics.

[4]  W. Ewens,et al.  A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. , 1998, American journal of human genetics.

[5]  D Rabinowitz,et al.  A transmission disequilibrium test for quantitative trait loci. , 1997, Human heredity.

[6]  B. Weir Genetic Data Analysis II. , 1997 .

[7]  D. Falconer,et al.  Introduction to Quantitative Genetics. , 1962 .

[8]  W J Ewens,et al.  The TDT and other family-based tests for linkage disequilibrium and association. , 1996, American journal of human genetics.

[9]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[10]  F. Clerget-Darpoux,et al.  Statistical properties of the allelic and genotypic transmission/disequilibrium test for multiallelic markers , 1995, Genetic epidemiology.

[11]  B S Weir,et al.  A comparative study of sibship tests of linkage and/or association. , 1998, American journal of human genetics.

[12]  B S Weir,et al.  Tests for linkage and association in nuclear families. , 1997, American journal of human genetics.

[13]  D J Schaid,et al.  Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and disease. , 1998, American journal of human genetics.

[14]  D. Allison,et al.  Transmission-disequilibrium tests for quantitative traits. , 1997, American journal of human genetics.

[15]  M. Boehnke,et al.  Genetic association mapping based on discordant sib pairs: the discordant-alleles test. , 1998, American journal of human genetics.

[16]  E. Martin,et al.  Sibling-based tests of linkage and association for quantitative traits. , 1999, American journal of human genetics.

[17]  D. Curtis,et al.  Use of siblings as controls in case‐control association studies , 1997, Annals of human genetics.

[18]  K. Lange,et al.  A Conditional Inference Framework for Extending the Transmission/Disequilibrium Test , 1998, Human Heredity.

[19]  L M McIntyre,et al.  Circumventing multiple testing: A multilocus Monte Carlo approach to testing for association , 2000, Genetic epidemiology.

[20]  D. Curtis,et al.  An extended transmission/disequilibrium test (TDT) for multi‐allele marker loci , 1995, Annals of human genetics.

[21]  D J Schaid,et al.  Quantitative trait transmission disequilibrium test: Allowance for missing parents , 1999, Genetic epidemiology.