Sample reproducibility of genetic association using different multimarker TDTs in genome-wide association studies: characterization and a new approach

Abstract

Multimarker Transmission/Disequilibrium Tests (TDTs) are very robust association tests to population admixture and structure which may be used to identify susceptibility loci in genome-wide association studies. Multimarker TDTs using several markers may increase power by capturing high-degree associations. However, there is also a risk of spurious associations and power reduction due to the increase in degrees of freedom. In this study we show that associations found by tests built on simple null hypotheses are highly reproducible in a second independent data set regardless the number of markers. As a test exhibiting this feature to its maximum, we introduce the multimarker 2-Groups TDT (mTDT(2G)), a test which under the hypothesis of no linkage, asymptotically follows a χ2 distribution with 1 degree of freedom regardless the number of markers. The statistic requires the division of parental haplotypes into two groups: disease susceptibility and disease protective haplotype groups. We assessed the test behavior by performing an extensive simulation study as well as a real-data study using several data sets of two complex diseases. We show that mTDT(2G) test is highly efficient and it achieves the highest power among all the tests used, even when the null hypothesis is tested in a second independent data set. Therefore, mTDT(2G) turns out to be a very promising multimarker TDT to perform genome-wide searches for disease susceptibility loci that may be used as a preprocessing step in the construction of more accurate genetic models to predict individual susceptibility to complex diseases.

Figure 1. Association rates of and using a second data set to test reproducibility.

Results for 100 simulations of 250 family trios as a function of the recombination rate using the dominant and one-locus genetic model and haplotypes of lengths (left plot), (plot in the middle) and (right plot). A nominal level of and a relative risk of were used for all plots. Results for and are plotted in purple circles and blue triangles respectively. Dashed lines show results for the data subset (125 trios randomly chosen) used to build the model while solid lines show results for a second data subset (the remaining 125 trios) used to test reproducibility.

Figure 2. Association rates under the holdout approach using a second data set to test reproducibility.

Results for 100 simulations of family trios as a function of the recombination rate using the recessive and one-locus genetic model and haplotypes of lengths (left plot), (plot in the middle) and (right plot). A nominal level of and a relative risk of were used for all plots. Results for and i.e. all tests were applied under the holdout approach, are plotted in purple circles, blue triangles, green squares and red diamonds respectively. Dashed lines show results for a data subset of trios randomly chosen while solid lines show results for a second data subset of trios used to test reproducibility of the holdout approach.

Figure 3. Association rates for different proportions of missing haplotypes.

Results for 100 simulations of family trios as a function of the proportion of missing haplotypes using the additive and one-locus genetic model and haplotypes of lengths (left plot), (plot in the middle) and (right plot). A nominal level of and a relative risk of were used for all plots. Results for and i.e. all tests were applied under the holdout approach, are plotted in purple circles, blue triangles, green squares and red diamonds respectively.

Figure 4. Sliding window maps for the -affected data set.

Window size is TDTs used were (red diamonds), (green squares), (purple circles) and (blue triangles).

Figure 5. Sliding window maps for the -affected data set.

Window size is TDTs used were (red diamonds), (green squares), (purple circles) and (blue triangles).

Figure 6. Sliding window maps for the -affected data set.

Window size is TDTs used were (red diamonds), (green squares), (purple circles) and (blue triangles).