On the Replication of Genetic Associations: Timing Can Be Everything!

Am J Hum Genet. 2008 Apr;82(4):849-58. doi: 10.1016/j.ajhg.2008.01.018.

Abstract

The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Body Mass Index*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Cross-Sectional Studies
  • Female
  • Gene Frequency
  • Genetic Linkage*
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide*
  • Receptors, Immunologic / genetics*

Substances

  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • roundabout protein