Article

No Gene Is an Island: The Flip-Flop Phenomenon

Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 04/2007; 80(3):531-8. DOI: 10.1086/512133
Source: PubMed

ABSTRACT An increasing number of publications are replicating a previously reported disease-marker association but with the risk allele reversed from the previous report. Do such "flip-flop" associations confirm or refute the previous association findings? We hypothesized that these associations may indeed be confirmations but that multilocus effects and variation in interlocus correlations contribute to this flip-flop phenomenon. We used theoretical modeling to demonstrate that flip-flop associations can occur when the investigated variant is correlated, through interactive effects or linkage disequilibrium, with a causal variant at another locus, and we show how these findings could explain previous reports of flip-flop associations.

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    • "However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, but it only attained borderline statistical significance in females. It is possible that this result could be explained by the presence of a flip-flop mutation [31] or allelic heterogeneity [8]. The rs915942 polymorphism (and others in LD) was found to be associated with asymptomatic malaria in Dogon females. "
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    • "This finding, already described in the literature as “flip-flop phenomenon” where significant associations for the same disease occur at opposite alleles of the same polymorphism, has been observed quite frequently [23]. Some authors hypothesized that this phenomenon can occur due to variation in linkage disequilibrium architecture [23], which is also present within the same ethnic origin [24]; while others explain it through differences in haplotypic frequencies [25]. Whatever the case, it has been proven that the probability of randomly observing a significant allele flip in samples ascertained similarly from a common population is negligible [26]. "
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