Obesity Epidemiology

452 EPIDEMIOLOGIC STUDIES OF DETERMINANTS OF OBESITYto small sample size and insufficient power. Indeed, recent association studies with muchlarger sample sizes have further replicated the association. 148,149 This example illustratesthat meta-analysis can substantially improve the power of genetic analyses and help reconciledivergent findings from multiple association studies. However, meta-analysis is nota substitute for large and well-designed association studies.The frequency of the polymorphism is also an important determinant of the powerof an association study. Most studies are designed to test the hypothesis that the geneticrisk for a complex trait is due to disease predisposing alleles or haplotypes with relativelyhigh frequencies (>5%) on the basis of the common disease-common varianthypothesis. 131 A meta-analysis of 25 different reported associations has provided somesupport for this hypothesis, 131 and several recent studies 150,151 have suggested that a limitednumber of common haplotypes account for most of the variation in a candidate gene.However, there is also evidence that rare alleles or haplotypes contribute to complextraits. For example, the GRL N365S and MC4R V103I polymorphisms associated withobesity (discussed earlier) have