No gene is an island: the flip-flop phenomenon.
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.
Lin
Ping-I
PI
Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.
Vance
Jeffery M
JM
Pericak-Vance
Margaret A
MA
Martin
Eden R
ER
D000483:Alleles; D003198:Computer Simulation; D005787:Gene Frequency; D005796:Genes / Q000502:physiology*; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D019683:Penetrance; D011110:Polymorphism, Genetic; D011336:Probability
D005819:Genetic Markers