Response to Zaykin and Shibata.

Opposite directions of association of the same allele with disease in different populations (i.e., the flip-flop phenomenon) complicate the interpretation of association findings. We recently reported that variation in linkage disequilibrium (LD) or interlocus correlation in the context of multilocus effects may lead to flip-flop associations.1xNo gene is an island: The flip-flop phenomenon. Lin, P.I., Vance, J.M., Pericak-Vance, M.A., and Martin, E.R. Am. J. Hum. Genet. 2007; 80: 531–538Abstract | Full Text | Full Text PDF | PubMed | Scopus (317)See all References1 In the current issue of the Journal Zaykin and Shibata report that the flip-flop phenomenon may also be observed when there is constant LD, even without interactive multilocus effects, or when there is no LD for certain interactive disease models.Zaykin and Shibata show how a flip-flop can occur in the case of constant LD with an example in which the frequencies of two haplotypes (i.e., A1B2 and A2B1) are switched in two populations, resulting in the same level of LD, but a reversal of the effect of allele A1 in the two populations. This occurs because the effect of A1 is a weighted sum of the haplotype effects over alleles at the B locus. The weights change in the two populations with different haplotype-frequency configurations. This example represents a special case in which haplotype frequencies differ significantly but LD remains the same. This may be the exception rather than the rule when haplotype frequencies diverge. Nevertheless, this example correctly demonstrates that it is differences in haplotype-frequency configuration, not necessarily LD itself, that give conditions in which a flip of allelic effects can occur. It is important, even if estimates of LD measures are the same, to examine the distribution of haplotype frequencies in different samples with apparent flip-flop effects.As a second case, Zaykin and Shibata consider loci in linkage equilibrium. They show how certain configurations of haplotypes penetrances can give rise to a flip-flop when there is an unobserved variant whose allele frequency varies in different populations. This results when the effects at the observed locus (A) and unobserved locus (B) interact such that the effect of A1 may be revessed depending on whether it is on the B1 or B2 background. This example highlights our point that failure to account for other interacting variants can produce ambiguous association results at the observed locus under question,1xNo gene is an island: The flip-flop phenomenon. Lin, P.I., Vance, J.M., Pericak-Vance, M.A., and Martin, E.R. Am. J. Hum. Genet. 2007; 80: 531–538Abstract | Full Text | Full Text PDF | PubMed | Scopus (317)See all References1 and it shows that this can happen even without LD.Zaykin and Shibata's study and our study have given evidence-based explanations for the controversial phenomenon of flip-flop associations. They demonstrate that failure to account for multilocus differences in samples can lead to legitimate flip-flops in a variety of scenarios. However, neither of these two studies has attempted to provide a definitive explanation for the flip-flops because such a phenomenon can stem from various reasons, ranging from genotyping errors to genomic complexity. Still, the lesson is consistent: Genomic context is important. We need to interpret associations in the context of differences in haplotype structure that occur in different populations or as a result of sample heterogeneity. Furthermore, the effect of one locus on disease risk may be inconsistent or missed completely if we fail to examine it jointly in the context of other known disease variants. These examples help to emphasize the key point that “no gene is an island.”