Implication of next-generation sequencing on association studies

Abstract Background Next-generation sequencing technologies can effectively detect the entire spectrum of genomic variation and provide a powerful tool for systematic exploration of the universe of common, low frequency and rare variants in the entire genome. However, the current paradigm for genome-wide association studies (GWAS) is to catalogue and genotype common variants (5% Results We investigated the linkage disequilibrium (LD) pattern among common and low frequency SNPs and its implication for association studies. We found that the LD between low frequency alleles and low frequency alleles, and low frequency alleles and common alleles are much weaker than the LD between common and common alleles. We examined various tagging designs with and without statistical imputation approaches and compare their power against de novo resequencing in mapping causal variants under various disease models. We used the low coverage pilot data which contain ~14 M SNPs as a hypothetical genotype-array platform (Pilot 14 M) to interrogate its impact on the selection of tag SNPs, mapping coverage and power of association tests. We found that even after imputation we still observed 45.4% of low frequency SNPs which were untaggable and only 67.7% of the low frequency variation was covered by the Pilot 14 M array. Conclusions This suggested GWAS based on SNP arrays would be ill-suited for association studies of low frequency variation.