Sample size requirements to detect the effect of a group of genetic variants in case-control studies

We present a simple method for determining approximate sample sizes required to detect the average joint effect of a group of genetic variants in a case-control study for multiplicative models.For a range of reasonable numbers of genetic variants, the sample size requirements for the test statistic proposed here are generally not larger than those needed for assessing marginal effects of individual variants and actually decline with increasing number of genetic variants in many situations considered in the group.When a significant effect of the group of genetic variants is detected, subsequent multiple tests could be conducted to detect which individual genetic variants and their combinations are associated with disease risk. When testing for an effect size in a group of genetic variants, one can use our global test described in this paper, because the sample size required to detect an effect size in the group is comparatively small. Our method could be viewed as a screening tool for assessing groups of genetic variants involved in pathogenesis and etiology of common complex human diseases.With the completion of the Human Genome Project and continuing advances in gene mapping and sequencing [1], there is an increasing interest in discovery and characterization of thousands of genetic variants as potential risk factors for common diseases of public health significance [2]. The search for genetic variants is currently hampered by numerous challenges, including the sheer number of genetic variants, the lack of replication of findings in many observational studies, and study design considerations (such as selection bias and confounding) [2-4]. Because the etiology of most common diseases such as cancer, heart disease and diabetes is due to complex genetic and environmental factors, a particular concern in the design of epidemiologic studies is the lack of statistical power to examine the joint effects and statistical interactions of several genetic variants, especially