The Application of Pooled DNA Sequencing in Disease Association Study

Abstract

Hundreds of common genetic variants related to the risk of human disease, such as diabetes, hypertension, bipolar, and Crohn’s disease, have been successfully discovered by Genomewide Association Studies (GWAS) (Barret et al., 2008; Hindorff, 2009; Thomas et al., 1991; WTCCC, 2007). Current GWAS are based on the strategy of linkage disequilibrium (LD) mapping, in which a sufficient number of single nucleotide polymorphism (SNP) markers are selectively genotyped to capture the genetic variation of the whole genome. However, there are two major issues related to the results of GWAS. First, the results only explain a small fraction of the heritability of complex diseases. One of the reasons may be that many functional variants, in particular rare variants, which are not directly genotyped in GWAS, have a weak LD with SNP markers, and hence are missed by GWAS (Iyengar et al., 2004; Manolio et al., 2009). Second, the identified associations in GWAS are often inconsistent between different populations. The reason for this may be the varied LD structures between markers and underlying causal variants among populations, resulting in associations can only be observed in specific populations.