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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