PT - JOURNAL ARTICLE AU - Andriy Derkach AU - Haoyu Zhang AU - Nilanjan Chatterjee TI - Simplified Power Calculations for Aggregate-level Association Tests Provide Insights to Challenges for Rare Variant Association Studies AID - 10.1101/100891 DP - 2017 Jan 01 TA - bioRxiv PG - 100891 4099 - http://biorxiv.org/content/early/2017/01/16/100891.short 4100 - http://biorxiv.org/content/early/2017/01/16/100891.full AB - Genome-wide association studies are now shifting focus from analysis of common to uncommon and rare variants with an anticipation to explain additional heritability of complex traits. As power for association testing for individual rare variants may often be low, various aggregate level association tests have been proposed to detect genetic loci that may contain clusters of susceptibility variants. Typically power calculations for such tests require specification of large number of parameters, including effect sizes and allele frequencies of individual markers, making them difficult to use in practice. In this report, we approximate power to varying degree of accuracy using a smaller number of key parameters, including the total genetic variance explained by multiple variants within a locus. We perform extensive simulation studies to assess the accuracy of the proposed approximation in realistic settings. Using the simplified power calculation methods, we then develop an analytic framework to obtain bounds on genetic architecture of an underlying trait given results from a genome-wide study and observe important implications for lack or limited number of findings in many currently reported studies. Finally, we provide insights into the required quality of annotation/functional information for identification of likely causal variants to make meaningful improvement in power of subsequent association tests. A shiny application in R implementing the methods is made publicly available.