Functional single nucleotide polymorphism-based association studies

Abstract

Association studies hold great promise for the elucidation of the genetic basis of diseases. Studies based on functional single nucleotide polymorphisms (SNPs) or on linkage disequilibrium (LD) represent two main types of designs. LD-based association studies can be comprehensive for common causative variants, but they perform poorly for rare alleles. Conversely, functional SNP-based studies are efficient because they focus on the SNPs with the highest a priori chance of being associated. Our poor ability to predict the functional effect of SNPs, however, hampers attempts to make these studies comprehensive. Recent progress in comparative genomics, and evidence that functional elements tend to lie in conserved regions, promises to change the landscape, permitting functional SNP association studies to be carried out that comprehensively assess common and rare alleles. SNP genotyping technologies are already sufficient for such studies, but studies will require continued genomic sequencing of multiple species, research on the functional role of conserved sequences and additional SNP discovery and validation efforts (including targeted SNP discovery to identify the rare alleles in functional regions). With these resources, we expect that comprehensive functional SNP association studies will soon be possible.