Method for using complete and incomplete trios to identify genes related to a quantitative trait.

A number of tests for linkage and association with qualitative traits have been developed, with the most well-known being the transmission/disequilibrium test (TDT). For quantitative traits, varying extensions of the TDT have been suggested. The quantitative trait approach we propose is based on extending the log-linear model for case-parent trio data (Weinberg et al. [1998] Am. J. Hum. Genet. 62:969-978). Like the log-linear approach for qualitative traits, our proposed polytomous logistic approach for quantitative traits allows for population admixture by conditioning on parental genotypes. Compared to other methods, simulations demonstrate good power and robustness of the proposed test under various scenarios of the genotype effect, distribution of the quantitative trait, and population stratification. In addition, missing parental genotype data can be accommodated through an expectation-maximization (EM) algorithm approach. The EM approach allows recovery of most of the lost power due to incomplete trios.

Kistner EO ，Weinberg CR 《GENETIC EPIDEMIOLOGY》

A method for identifying genes related to a quantitative trait, incorporating multiple siblings and missing parents.

Kistner EO ，Weinberg CR 《GENETIC EPIDEMIOLOGY》

A method for using incomplete triads to test maternally mediated genetic effects and parent-of-origin effects in relation to a quantitative trait.

Kistner EO ，Infante-Rivard C ，Weinberg CR 《AMERICAN JOURNAL OF EPIDEMIOLOGY》

Power comparison of regression methods to test quantitative traits for association and linkage.

George et al. [1999 Am J Hum Genet 65:236-245] proposed a regression-based TDT method for quantitative traits consisting of regressing the trait on the parental transmission of a marker allele. Zhu and Elston [2000] also developed a TDT method for quantitative traits by defining a linear transformation to condition out founder information. Both methods test the null hypothesis of no linkage or association and can be applied to general pedigree structures. In this paper, we compare the power of these two methods through simulation, sampling those nuclear families with at least one heterozygous parent. Overall, we find that a variant of Zhu and Elston's method with 2 d.f. is more powerful. However, if the mode of inheritance is known, then a most powerful test with 1 d.f. can be found. All these regression TDT tests require linkage to detect association, but a test that does not require linkage will be more powerful.

Zhu X ，Elston RC 《GENETIC EPIDEMIOLOGY》

Informative-transmission disequilibrium test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring.

To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506-516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886-1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol.

Guo CY ，Lunetta KL ，DeStefano AL ，Ordovas JM ，Cupples LA ... -  《GENETIC EPIDEMIOLOGY》