Broadly, genetic follow-up aims to validate and refine notable SNP associations to identify underlying causal variants and map their relation to clinical phenotypes. One approach, beyond simple replication, is to investigate an implicated genomic region at higher marker density to refine the association signal (fine-mapping). For other complex diseases this approach has met with mixed results, suggesting that in many cases the impact of risk variants on common disease phenotypes is complex and not necessarily related to obvious effects on gene function, such as alteration of protein structure. This may relate to the limited coverage achieved by these studies, but it has been estimated that by direct genotyping and imputation a large percentage (>85%) of common SNP variation is already being assayed by GWAS studies although this can vary markedly by genomic region.
