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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.

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The aim of this work was to explore the associations between family factors, including divorce, and children's overweight as well as eating and physical activity patterns in a population-based sample of healthy school-aged children. In this cross-sectional study, 1,138 children (53% girls; age: 11.2 ± 0.7 years) from elementary schools in the Attica region participated. Their parents provided sociodemographic information, including their marital status. Overweight status classification was based on weight and height measurements and BMI evaluation. Children completed a physical activity checklist and a questionnaire on meal patterns and eating behaviors. The Eating Style score was calculated: the higher the score, the more frequent a child was engaged in less-structured feeding practices promoting food intake for reasons other than hunger. Analysis revealed significant association between family divorce and children's overweight: compared with children of married parents, those of divorced had significantly higher BMI levels (20.0 ± 3.6 kg/m 2 vs. 21.3 ± 3.4 kg/m 2 , respectively, P = 0.007). Controlling for socioeconomic and physical activity factors, divorce remains a significant predictor of a higher BMI, along with older age, higher father's and mother's BMI, less children in the family, and more minutes of daily screen time. Children who had experienced a divorce in their family also reported higher Eating Style score, even after adjusting for potential confounders. In conclusion, in this sample of fifth and sixth graders, unfavorable family circumstances have been associated with children's overweight, as well as with aspects of their eating behavior, namely eating style in relation to conditions around food consumption and hunger, independent of other socioeconomic factors.