Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture
Our paper on "Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture" by Greene et al. was published today in PLoS One. This paper demonstrates that replication is not everything and thus challenges the one-SNP-at-a-time analysis strategy used in genome-wide association studies (GWAS). We were specifically told by someone from the Wellcome-Trust not to publish this study because it might confuse people. I would be happy to field your questions if you find yourself confused after reading this paper.
Greene CS, Penrod NM, Williams SM, Moore JH. Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture. PLoS One 4(6), e5639 (2009). [PDF] [PubMed]
Replication has become the gold standard for assessing statistical results from genome-wide association studies. Unfortunately this replication requirement may cause real genetic effects to be missed. A real result can fail to replicate for numerous reasons including inadequate sample size or variability in phenotype definitions across independent samples. In genome-wide association studies the allele frequencies of polymorphisms may differ due to sampling error or population differences. We hypothesize that some statistically significant independent genetic effects may fail to replicate in an independent dataset when allele frequencies differ and the functional polymorphism interacts with one or more other functional polymorphisms. To test this hypothesis, we designed a simulation study in which case-control status was determined by two interacting polymorphisms with heritabilities ranging from 0.025 to 0.4 with replication sample sizes ranging from 400 to 1600 individuals. We show that the power to replicate the statistically significant independent main effect of one polymorphism can drop dramatically with a change of allele frequency of less than 0.1 at a second interacting polymorphism. We also show that differences in allele frequency can result in a reversal of allelic effects where a protective allele becomes a risk factor in replication studies. These results suggest that failure to replicate an independent genetic effect may provide important clues about the complexity of the underlying genetic architecture. We recommend that polymorphisms that fail to replicate be checked for interactions with other polymorphisms, particularly when samples are collected from groups with distinct ethnic backgrounds or different geographic regions.
Here is Figure 4 from the paper: