Meta-analysis for model-free methods.

The intricate nature of complex genetic traits dictates that novel methodologies be developed and utilized to achieve better power, better accuracy, and more favorable balance between type I and type II errors than could be achieved by the traditional methods as they are used in mapping Mendelian traits. Meta-analysis provides one such method for synthesizing information from multiple studies. This has the advantage of being able to pool relatively weak signals from individual studies into a collectively stronger evidence of genetic effects, while at the same time providing a quantitative framework for modeling variability among studies. The traditional lod score measures significance level of a linkage effect in an individual study, and its additive property make it a natural candidate for combining results across independent studies. To incorporate the within-study variation of the linkage effect into the pooled overall measure of genetic effect, the effect sizes (such as the proportion of genes shared identical-by-descent, IBD) should be pooled directly across studies. Traditional regression models and mixed effects models can be used to estimate the overall genetic effect size and its variance, and to test heterogeneity among studies. Our simulation studies show that designing studies with moderate power and pooling their results via meta-analysis may be more cost-effective than large dedicated studies. We believe that, as a newly emerging methodology, the meta-analysis approach has the potential to become an integral part of our toolbox that will expedite the search for complex human disease genes.