Even when there is only a single confirmed SNP, linkage disequilibrium (LD) with other SNPs can make it very difficult to isolate the true causal polymorphism. When a single SNP is confirmed to be associated with a phenotype and is in strong LD with several other SNPs, the genotypes at these so-called ‘LD proxies’ will be very similar. While this property is often exploited by manufacturers of commercial SNP microarrays (3) to reduce the number of SNPs required for genotyping, in this case it proves to be a serious problem because all the LD proxies show the same evidence for association and no amount of further genotyping will resolve this ambiguity. Instead, expensive and time-consuming functional experiments, possibly involving model organisms, must be conducted in an effort to identify the true causal variant.
