No gene is an island: the flip-flop phenomenon

Am J Hum Genet. 2007 Mar;80(3):531-8. doi: 10.1086/512133. Epub 2007 Jan 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Computer Simulation
  • Gene Frequency
  • Genes / physiology*
  • Genetic Linkage
  • Genetic Markers*
  • Genetic Predisposition to Disease*
  • Humans
  • Linkage Disequilibrium*
  • Models, Genetic*
  • Penetrance
  • Polymorphism, Genetic*
  • Probability


  • Genetic Markers