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Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture

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  • Casey S Greene
  • Nadia M Penrod
  • Scott M Williams
  • Jason H Moore

Abstract

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.

Suggested Citation

  • Casey S Greene & Nadia M Penrod & Scott M Williams & Jason H Moore, 2009. "Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture," PLOS ONE, Public Library of Science, vol. 4(6), pages 1-7, June.
  • Handle: RePEc:plo:pone00:0005639
    DOI: 10.1371/journal.pone.0005639
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    References listed on IDEAS

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    1. Juergen Kroymann & Thomas Mitchell-Olds, 2005. "Epistasis and balanced polymorphism influencing complex trait variation," Nature, Nature, vol. 435(7038), pages 95-98, May.
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    Cited by:

    1. Tom Cattaert & Víctor Urrea & Adam C Naj & Lizzy De Lobel & Vanessa De Wit & Mao Fu & Jestinah M Mahachie John & Haiqing Shen & M Luz Calle & Marylyn D Ritchie & Todd L Edwards & Kristel Van Steen, 2010. "FAM-MDR: A Flexible Family-Based Multifactor Dimensionality Reduction Technique to Detect Epistasis Using Related Individuals," PLOS ONE, Public Library of Science, vol. 5(4), pages 1-15, April.

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