A Robust Test for Two‐Stage Design in Genome‐Wide Association Studies

Summary A two‐stage design is cost‐effective for genome‐wide association studies (GWAS) testing hundreds of thousands of single nucleotide polymorphisms (SNPs). In this design, each SNP is genotyped in stage 1 using a fraction of case–control samples. Top‐ranked SNPs are selected and genotyped in stage 2 using additional samples. A joint analysis, combining statistics from both stages, is applied in the second stage. Follow‐up studies can be regarded as a two‐stage design. Once some potential SNPs are identified, independent samples are further genotyped and analyzed separately or jointly with previous data to confirm the findings. When the underlying genetic model is known, an asymptotically optimal trend test (TT) can be used at each analysis. In practice, however, genetic models for SNPs with true associations are usually unknown. In this case, the existing methods for analysis of the two‐stage design and follow‐up studies are not robust across different genetic models. We propose a simple robust procedure with genetic model selection to the two‐stage GWAS. Our results show that, if the optimal TT has about 80% power when the genetic model is known, then the existing methods for analysis of the two‐stage design have minimum powers about 20% across the four common genetic models (when the true model is unknown), while our robust procedure has minimum powers about 70% across the same genetic models. The results can be also applied to follow‐up and replication studies with a joint analysis.