Linkage Disequilibrium-Based Quality Control for Large-Scale Genetic Studies

Quality control (QC) is a critical step in large-scale studies of genetic variation. While, on average, high-throughput single nucleotide polymorphism (SNP) genotyping assays are now very accurate, the errors that remain tend to cluster into a small percentage of “problem” SNPs, which exhibit unusually high error rates. Because most large-scale studies of genetic variation are searching for phenomena that are rare (e.g., SNPs associated with a phenotype), even this small percentage of problem SNPs can cause important practical problems. Here we describe and illustrate how patterns of linkage disequilibrium (LD) can be used to improve QC in large-scale, population-based studies. This approach has the advantage over existing filters (e.g., HWE or call rate) that it can actually reduce genotyping error rates by automatically correcting some genotyping errors. Applying this LD-based QC procedure to data from The International HapMap Project, we identify over 1,500 SNPs that likely have high error rates in the CHB and JPT samples and estimate corrected genotypes. Our method is implemented in the software package fastPHASE, available from the Stephens Lab website (http://stephenslab.uchicago.edu/software.html).