Genome wide association studies are reliant on linkage disequilibrium for the initial identification of signals since it is unlikely that the causal variant (or variants) at any locus will actually be represented on any given genotyping array. However, once a signal has been found and shown, by replication, to be genuine, linkage disequilibrium becomes an obstacle, frustrating efforts to home in on the causal variant at the locus. For example, at the FTO locus, attempts at further refinement of the association signal (through resequencing, dense genotyping or imputation from HapMap or 1,000 Genomes reference panels) have been unsuccessful: as far as we can tell, from studies of European samples at least, the causal allele could be any one of dozens of highly-correlated alleles carried on a 50 kb haplotype.
However, since local patterns of linkage disequilibrium often differ between major population groups [22
], one would hope that fine-mapping studies conducted at the transethnic level might enable some refinement of location, and in some circumstances, provide strong statistical evidence in favour of a single causal variant. Naturally there are some assumptions behind such analyses, the first being that the same single causal variant is shared between the populations concerned. The overlap in common variant signals reported above is clearly reassuring in this respect as it suggests that allelic heterogeneity is limited, at least amongst non-African populations.
The major limitation of this approach is likely to be the fact that patterns of linkage disequilibrium and haplotype structure are quite similar between non-African populations [22
], and this has fostered growing interest in the interrogation of samples of recent African origin (for example African Americans) [26
]. The high genetic diversity of African populations, and the long period of divergence, means that the linkage disequilibrium patterns in African populations are often markedly different to those seen in Europeans and Asians. This has the potential therefore to offer considerable benefits in terms of fine-mapping, but only provided locus and allelic heterogeneity are not extreme. Put simply, there is a danger that at some loci, there will be no susceptibility alleles segregating in accessible African populations, meaning that there is "nothing to fine-map." The limited data for type 2 diabetes susceptibility in African Americans is reassuring in this respect [16
], and it will be interesting to see the results of the genome wide association studies that are currently being completed using samples from this population.
In the meantime, it seems sensible to pursue a broad strategy that attempts fine mapping in both non-African and African populations. Interestingly, several of the strongest diabetes susceptibility signals (TCF7L2
, and KCNQ1
) do demonstrate rather unusually divergent haplotype structures between major ethnic groups [5
], providing some encouragement that, as the data sets available become larger, effective fine-mapping will be possible. Fortunately such studies can be based around existing genome wide association data (complemented with imputation from ethnically-diverse reference panels, such as those forthcoming from the 1,000 Genomes Project [27
]), so the costs are largely those of analysis.